Peptide inhibitors of the interleukin-23 receptor and their use for treating inflammatory diseases - Patents.com

Abstract

The present invention provides novel peptide inhibitors of the interleukin-23 receptor, as well as related compositions and methods of using these peptide inhibitors to treat or prevent various diseases and disorders, including inflammatory bowel disease. [Selection diagram] None

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 697,218, filed July 12, 2018, and U.S. Provisional Patent Application No. 62 / 872,477, filed July 10, 2019, each of which is incorporated by reference in its entirety.

[0002] Sequence Listing This application has been filed electronically via EFS-Web and includes an electronically submitted sequence listing in .txt format. The .txt file contains a sequence listing entitled "PRTH_036_01WO_ST25.txt" having a size of approximately 172 kilobytes, created on July 10, 2019. The sequence listing contained in this .txt file is part of the present specification and is incorporated herein by reference in its entirety.

[0003] The present invention relates to novel peptide inhibitors of the interleukin-23 receptor (IL-23R) and their use to treat or prevent a variety of diseases and disorders, including inflammatory bowel disease, Crohn's disease and psoriasis. [Background technology]

[0004] Interleukin-23 (IL-23) cytokine has been implicated as playing a crucial role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease. Studies in acute and chronic mouse models of IBD have revealed a key role for IL-23R and downstream effector cytokines in disease pathogenesis. IL-23R is expressed on a variety of adaptive and innate immune cells, including Th17 cells, γδ T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphocytes, which are abundantly found in the intestine. At the intestinal mucosal surface, gene expression and protein levels of IL-23R have been found elevated in IBD patients. IL-23 is involved in the regulation of pathogenic CD4 T cells that produce IL-6, IL-17, and tumor necrosis factor (TNF). + It is believed to mediate this effect by promoting the development of T cell populations.

[0005] IL-23 production is enriched in the intestine, where it is believed to play a key role in constraining regulatory T cell responses in the intestine in favor of inflammation, as well as regulating the balance between tolerance and immunity through T cell-dependent and T cell-independent pathways of intestinal inflammation through its effects on T-helper 1 (Th1) and Th17-associated cytokines. Additionally, polymorphisms in the IL-23 receptor (IL-23R) have been associated with susceptibility to inflammatory bowel disease (IBD), further establishing the essential role of the IL-23 pathway in intestinal homeostasis.

[0006] Psoriasis, a chronic skin disease that affects approximately 2%-3% of the general population, has been shown to be mediated by the body's T cell inflammatory response mechanisms. IL-23 is one of several interleukins implicated as a key player in the pathogenesis of psoriasis, purportedly by maintaining chronic autoimmune inflammation through induction of interleukin-17, regulation of T memory cells, and activation of macrophages. Expression of IL-23 and IL-23R has been shown to be increased in tissues of patients with psoriasis, and antibodies neutralizing IL-23 have shown IL-23-dependent inhibition of psoriasis development in animal models of psoriasis.

[0007] IL-23 inhibits interferon-γ (IFN-γ)-producing T helper 1 (T H 1) It is a heterodimer composed of the unique p19 and p40 subunits of IL-12, a cytokine involved in the development of IL-12 cells. Although both IL-23 and IL-12 contain the p40 subunit, they have different phenotypic properties. For example, animals deficient in IL-12 are susceptible to inflammatory autoimmune diseases, whereas IL-23-deficient animals show a reduced expression of CD4 T cells, which presumably produces IL-6, IL-17, and TNF in the CNS of IL-23-deficient animals. + Due to the reduction in the number of T cells, they are resistant. IL-23 binds to IL-23R, a heterodimeric receptor composed of IL-12Rβ1 and IL-23R subunits. IL-23 binding to IL-23R activates Jak-stat signaling molecules, Jak2, Tyk2, and Stat1, Stat 3, Stat 4, and Stat 5, but Stat4 is activated substantially less and forms a different DNA-binding Stat complex in response to IL-23 compared to IL-12. IL-23R associates with Jak2 constitutively and with Stat3 in a ligand-dependent manner. In contrast to IL-12, which acts primarily on naive CD4(+) T cells, IL-23 acts preferentially on memory CD4(+) T cells.

[0008] Efforts have been made to identify therapeutic moieties that inhibit the IL-23 pathway for use in the treatment of IL-23-related diseases and disorders. Numerous antibodies that bind to IL-23 or IL-23R have been identified, including ustekinumab, a humanized antibody that binds to IL-23 that has been approved for the treatment of psoriasis. More recently, polypeptide inhibitors that bind to IL-23R and inhibit the binding of IL-23 to IL-23R have been identified (see, for example, US Patent Application Publication No. US2013 / 0029907). Clinical trials in Crohn's disease or psoriasis with ustekinumab and briakinumab (targeting the common p40 subunit) and tildrakizumab, guselkumab, MEDI2070, and BI-655066 (targeting the unique p19 subunit of IL-23) highlight the potential of blocking IL-23 signaling in the treatment of human inflammatory diseases. Although these findings are promising, challenges remain with regard to identifying stable and selective agents that preferentially target the IL-23 pathway in the intestine that can be used for the treatment of intestinal inflammation, such as intestinal diseases, including Crohn's disease, ulcerative colitis and related disorders. Clearly, there remains a need in the art for new therapeutics targeting the IL-23 pathway that can be used to treat and prevent IL-23-associated diseases, including those associated with autoimmune inflammation in the intestinal tract. Additionally, compounds and methods for specific targeting of IL-23R from the luminal side of the intestine may provide therapeutic benefit to IBD patients who suffer from localized inflammation of the intestinal tissue. The present invention addresses these needs by providing novel peptide inhibitors that bind to IL-23R and inhibit IL-23 binding and signaling, and are suitable for oral administration. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] US Patent Application Publication No. 2013 / 0029907 Summary of the Invention [Means for solving the problem]

[0010] The present invention provides, inter alia, novel peptide inhibitors of IL-23R and related methods of use.

[0011] In a first aspect, the present invention provides a compound of formula (I): X7-X8-X9-X10-X11(I) or a pharma- ceutically acceptable salt or solvate thereof, comprising the amino acid sequence of formula (I): X7 is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp; X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen; X10 is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and X11 is 2-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal; however, i) at least one of X7 and X11 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; ii) if X7 is a 5-F substituted Trp, then X11 is other than 2-Nal; and iii) when X7 is a 5-OH or 6-Cl substituted Trp, then X9 is other than Cys; and Peptide inhibitors block the binding of interleukin-23 (IL-23) to the IL-23 receptor. A peptide inhibitor, or a pharma- ceutically acceptable salt or solvate thereof, is provided.

[0012] In a second aspect, the present invention provides a compound of formula (II): X4-X5-X6-X7-X8-X9-X10-X11(II) or a pharma- ceutically acceptable salt or solvate thereof, comprising the amino acid sequence of formula (II): X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X5 is Cit, Glu, Gly, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, Asp, or Cys; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp; X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); when X4 is Abu, X9 is Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); and when X9 is Abu, X4 is Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X10 is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and X11 is 2-Nal, unsubstituted Trp, or Trp substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal; The peptide inhibitor is cyclized via the bond between X4 and X9, provided that i) at least one of X7 and X11 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; ii) if X7 is a 5-F substituted Trp, then X11 is other than 2-Nal; and iii) when X7 is a 5-OH or 6-Cl substituted Trp, then X9 is other than Cys; and Peptide inhibitors block the binding of interleukin-23 (IL-23) to the IL-23 receptor. A peptide inhibitor, or a pharma- ceutically acceptable salt or solvate thereof, is provided.

[0013] In one embodiment, X7 is other than 5-F substituted Trp. In another embodiment, when X7 is unsubstituted Trp, or Trp substituted with 1-Me, ​​5-OH or 6-Cl, X9 is other than Cys.

[0014] In another aspect, the present invention provides a compound of formula (I): X7-X8-X9-X10-X11(I) or a pharma- ceutically acceptable salt or solvate thereof, comprising the amino acid sequence of formula (I): X7 is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp; X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen; X10 is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and X11 is 2-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal; however, i) at least one of X7 and X11 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; ii) X7 is other than a 5-F substituted Trp, and iii) when X7 is unsubstituted Trp, or Trp substituted with 1-Me, ​​5-OH or 6-Cl, then X9 is other than Cys; and Peptide inhibitors block the binding of interleukin-23 (IL-23) to the IL-23 receptor. A peptide inhibitor, or a pharma- ceutically acceptable salt or solvate thereof, is provided.

[0015] In another aspect, the present invention provides a compound of formula (II): X4-X5-X6-X7-X8-X9-X10-X11(II) or a pharma- ceutically acceptable salt or solvate thereof, comprising the amino acid sequence of formula (II): X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X5 is Cit, Glu, Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, Asp, or Cys; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp; X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); when X4 is Abu, X9 is Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); and when X9 is Abu, X4 is Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X10 is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and X11 is 2-Nal, unsubstituted Trp, or Trp substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal; The peptide inhibitor is cyclized via the bond between X4 and X9, provided that i) at least one of X7 and X11 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; ii) X7 is other than a 5-F substituted Trp, and iii) when X7 is unsubstituted Trp, or Trp substituted with 1-Me, ​​5-OH or 6-Cl, then X9 is other than Cys; and Peptide inhibitors block the binding of interleukin-23 (IL-23) to the IL-23 receptor. A peptide inhibitor, or a pharma- ceutically acceptable salt or solvate thereof, is provided.

[0016] In certain embodiments, X5 is Cit, Glu, Gly, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, Asp, or Cys. In certain embodiments, X5 is Cit, Glu, Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, Asp, or Cys.

[0017] In certain embodiments, X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp. In certain embodiments, X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp.

[0018] In certain embodiments, X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, Trp, or Lys(R'), and R' is Aib, bAla, IVA, Ala, cyclohexanoic acid, octanoic acid, -C(O)CH2Ph(-C(O)benzyl), trifluorpropionic acid, Gly, acetyl, valeric acid, or trifluoroacetyl. In certain embodiments, X8 is Asn, alpha-Me-Lys, alpha-MeLeu, Aib, Cit, or Lys(R'). In certain embodiments, X8 is Lys(R'). In one embodiment, R' is acetyl. In another embodiment, R' is Gly, Aib, Ala, or bAla. In another embodiment, R' is Gly, or Aib.

[0019] In one embodiment, X4 is Abu and X9 is Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen. In another embodiment, X4 is Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen, and X9 is Abu. In another embodiment, each of X4 and X9 is independently Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen. In another embodiment, each of X4 and X9 is Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen.

[0020] In a specific embodiment, the present invention provides a compound of formula (XIa) or (XIb): Pen-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-[2-Nal]-aMeLeu-K(Ac)-Asn-Asn(XIa) (SEQ ID NO: 100) or Pen-Asn-Thr-W-Gln-Pen-[F(4-2ae)]-W'-aMeLeu-K(Ac)-Asn-Asn(XIb) (SEQ ID NO: 101) or a pharma- ceutically acceptable salt or solvate thereof, wherein the peptide inhibitor of the interleukin-23 receptor comprises or consists of an amino acid sequence of W' is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; A peptide inhibitor, or a pharma- ceutically acceptable salt or solvate thereof, is provided.

[0021] In another specific embodiment, the present invention relates to a compound of formula (XIc) or (XId): Abu-Asn-Thr-W'-Gln-Cys-[F(4-2ae)]-[2-Nal]-aMeLeu-K(Ac)-Asn-Asn(XIc) (SEQ ID NO: 102), or Abu-Asn-Thr-W-Gln-Cys-[F(4-2ae)]-W'-aMeLeu-K(Ac)-Asn-Asn(XId) (SEQ ID NO: 103) or a pharma- ceutically acceptable salt or solvate thereof, wherein the peptide inhibitor of the interleukin-23 receptor comprises or consists of an amino acid sequence of W' is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, and the peptide inhibitor is cyclized via an Abu-Cys thioether bond; A peptide inhibitor, or a pharma- ceutically acceptable salt or solvate thereof, is provided.

[0022] In another specific embodiment, the present invention relates to a compound of formula (XIe) or (XIf): Abu-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-[2-Nal]-aMeLeu-K(Ac)-Asn-Asn(XIe) (SEQ ID NO: 104), or Abu-Asn-Thr-W-Gln-Pen-[F(4-2ae)]-W'-aMeLeu-K(Ac)-Asn-Asn(XIf) (SEQ ID NO: 105) or a pharma- ceutically acceptable salt or solvate thereof, wherein the peptide inhibitor of the interleukin-23 receptor comprises or consists of an amino acid sequence of W' is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, and the peptide inhibitor is cyclized via an Abu-Pen thioether bond; A peptide inhibitor, or a pharma- ceutically acceptable salt or solvate thereof, is provided.

[0023] In another specific embodiment, the present invention provides a compound of formula (Z): R 1 -XR 2 (Z) or a pharma- ceutically acceptable salt or solvate thereof, wherein: (Z) is a peptide inhibitor of the interleukin-23 receptor, the peptide inhibitor comprising or consisting of an amino acid sequence of R 1 is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 alkanoyl, including PEGylated versions of any of the above alone or as a spacer, X is an amino acid sequence of Formula (I), Formula (II)-(XIf), or an amino acid sequence shown in Table E1, Table E2, or Table E3, and R 2 is OH or NH2, A peptide inhibitor, or a pharma- ceutically acceptable salt or solvate thereof, is provided.

[0024] In specific embodiments of any peptide inhibitor disclosed herein, including peptide inhibitors comprising an amino acid sequence of Formula (II)-(XIf), X4 is Pen and X9 is Pen, and the bond is a disulfide bond.

[0025] In specific embodiments, any of the peptide inhibitors described herein comprises one or more half-life extending moieties and / or one or more linker moieties conjugated to the peptide inhibitor. In specific embodiments, the half-life extending moieties are conjugated to the peptide inhibitor via one or more linker moieties.

[0026] In certain embodiments, any peptide inhibitor described herein further comprises a conjugated chemical substituent. In specific embodiments, the conjugated chemical substituent is a lipophilic substituent or polymer moiety, such as Ac, Palm, gamaGlu-Palm, isoGlu-Palm, PEG2-Ac, PEG4-isoGlu-Palm, (PEG)5-Palm, succinic acid, glutaric acid, pyroglutaric acid, benzoic acid, IVA, octanoic acid, 1,4 diaminobutane, isobutyl, Alexa488, Alexa647, or biotin. In certain embodiments, the conjugated chemical substituent is polyethylene glycol having a molecular weight of 400 Da to 40,000 Da. In a specific embodiment, the peptide is conjugated at X8. In another specific embodiment, the peptide is conjugated at X9. In a more specific embodiment, the peptide is conjugated at X10.

[0027] In a related aspect, the invention includes peptide dimeric inhibitors of the interleukin-23 receptor, comprising two peptide monomer subunits connected via one or more linker moieties, each peptide monomer subunit comprising a sequence of formula (I), formula (II)-(XIf), or any other sequence or structure described herein. In certain embodiments, one or both peptide monomer subunits are cyclized via an intramolecular bond between X4 and X9. In certain embodiments, one or both intramolecular bonds are disulfide bonds or thioether bonds. In certain embodiments, the linker is any of those shown in Table 2 or described herein. In certain embodiments, the linker moiety is a diethylene glycol linker, an iminodiacetic acid (IDA) linker, a β-Ala-iminodiacetic acid (β-Ala-IDA) linker, or a PEG linker. In specific embodiments, the N-terminus of each peptide monomer subunit is connected by a linker moiety. In specific embodiments, the C-terminus of each peptide monomer subunit is connected by a linker moiety, hi certain embodiments, the linker connects an internal amino acid residue of at least one peptide monomer subunit to the N-terminus, C-terminus, or internal amino acid residue of another peptide monomer subunit.

[0028] In a further related aspect, the invention includes a polynucleotide comprising a sequence encoding a peptide inhibitor of the invention or one or both peptide monomer subunits of a peptide dimeric inhibitor of the invention. The invention also includes a vector comprising said polynucleotide.

[0029] In another aspect, the present invention includes a pharmaceutical composition comprising a peptide inhibitor or peptide dimer inhibitor of the present invention and a pharma- ceutically acceptable carrier, excipient, or diluent. In a specific embodiment, the pharmaceutical composition comprises an enteric coating. In certain embodiments, the enteric coating protects and releases the pharmaceutical composition in the lower gastrointestinal system of a subject.

[0030] In another aspect, the invention provides a method for treating inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation or chemotherapy, colitis associated with impaired innate immunity such as in leukocyte adhesion deficiency type 1, chronic granulomatous disease, glycosuria, inflammatory bowel disease, ... The present invention includes a method for treating or preventing diseases associated with IL-23 signaling, including, but not limited to, Gent's storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich syndrome, pouchitis resulting from proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, or graft-versus-host disease. In certain embodiments, the inflammatory bowel disease is ulcerative colitis or Crohn's disease. In specific embodiments, the peptide inhibitor or peptide dimer inhibitor inhibits the binding of interleukin-23 (IL-23) to the interleukin-23 receptor (IL-23R). In certain embodiments, the pharmaceutical composition is provided to the subject by oral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization, sublingual, buccal, parenteral, rectal, ocular, inhalation, vaginal, or external administration.In a specific embodiment, the pharmaceutical composition is provided orally to treat inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease.In certain embodiments, the pharmaceutical composition is provided to the subject externally, parenterally, intravenously, subcutaneously, peritoneally, or intravenously to treat psoriasis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] Unless otherwise defined herein, scientific and technical terms used in this application have the meanings commonly understood by those skilled in the art. In general, the nomenclature used in the context of chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry described herein, and the techniques thereof, are well known and commonly used in the art.

[0032] As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0033] Throughout this specification, the word "comprise" or variations thereof such as "comprises" or "comprising" are understood to imply the inclusion of a stated integer (or component) or group of integers (or components) but not the exclusion of any other integer (or component) or group of integers (or components).

[0034] The singular forms "a," "an," and "the" include plurals unless the context clearly dictates otherwise.

[0035] The term "including" is used to mean "including but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0036] The terms "patient," "subject," and "individual" are used interchangeably and can refer to either human or non-human animals. These terms include mammals, such as humans, primates, livestock animals (e.g., cows, pigs), companion animals (e.g., dogs, cats), and rodents (e.g., mice and rats).

[0037] The term "peptide" as used herein broadly refers to a sequence of two or more amino acids joined together by peptide bonds. It should be understood that the term does not imply a specific length of a polymer of amino acids, nor is it intended to imply or distinguish whether the polypeptide is produced using recombinant technology, chemical or enzymatic synthesis, or is naturally occurring.

[0038] The description "sequence identity", "percentage of identity", "percentage of homology", or including, for example, "50% identical sequence to" as used herein, refers to the extent to which sequences are identical on a nucleotide-by-nucleotide or amino acid-by-amino acid basis over a window of comparison.Therefore, "percentage of sequence identity" can be calculated by comparing two optimally aligned sequences over a window of comparison, determining the number of positions where identical nucleobases (e.g., A, T, C, G, I) or identical amino acid residues (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys and Met) are present in both sequences to obtain the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., window size), and multiplying the result by 100 to obtain the percentage of sequence identity.

[0039] Calculation of sequence similarity or sequence identity (these terms are used interchangeably herein) between sequences can be performed as follows. To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences can be aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of the first and second amino acid or nucleic acid sequences for optimal alignment, and non-homologous sequences can be ignored for comparison purposes). In certain embodiments, the length of the reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at the corresponding amino acid positions or nucleotide positions are then compared. If a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecules are identical at that position.

[0040] The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps that need to be introduced for optimal alignment of the two sequences, and the length of each gap.

[0041] The comparison of sequences and the determination of percent identity between two sequences can be achieved using mathematical algorithms.In some embodiments, the percent identity between two amino acid sequences is determined using the algorithm of Needleman and Wunsch (1970, J. Mol. Biol. 48: 444-453) incorporated in the GAP program in the GCG software package, using either Blossum 62 matrix or PAM250 matrix, and gap weighting of 16, 14, 12, 10, 8, 6, or 4, and length weighting of 1, 2, 3, 4, 5, or 6.In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package, using NWSgapdna.CMP matrix, and gap weighting of 40, 50, 60, 70, or 80, and length weighting of 1, 2, 3, 4, 5, or 6. Another exemplary set of parameters includes a Blossum 62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5. Percent identity between two amino acid or nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller (1989, Cabios, 4:11-17) incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.

[0042] The peptide sequences described herein can be used as "query sequences" to perform searches against public databases, for example to identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al., (1990, J. Mol. Biol, 215:403-10). BLAST nucleotide searches can be performed using the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to the nucleic acid molecules of the present invention. BLAST protein searches can be performed using the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the protein molecules of the present invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al. (Nucleic Acids Res. 25:3389-3402, 1997). When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (eg, XBLAST and NBLAST) can be used.

[0043] The term "conservative substitution" as used herein refers to the replacement of one or more amino acids with another biologically similar residue. Examples include substitution with amino acid residues with similar characteristics, such as small amino acids, acidic amino acids, polar amino acids, basic amino acids, hydrophobic amino acids and aromatic amino acids. For example, see the table below. In some embodiments of the invention, one or more Met residues are replaced with norleucine (Nle), which is a biological equivalent of Met but is not easily oxidized in contrast to Met. Another example of a conservative substitution with a residue not normally found in endogenous mammalian peptides and proteins is, for example, the conservative substitution of Arg or Lys with ornithine, canavanine, aminoethylcysteine ​​or another basic amino acid. In some embodiments, one or more cysteines of the peptide analogs of the invention may be replaced with another residue, such as serine. For more information on phenotypically silent substitutions in peptides and proteins, see, for example, Bowie et.al. Science 247,1306-1310,1990. In the following scheme, conservative substitutions of amino acids are classified by physicochemical properties: I: neutral, hydrophilic, II: acids and amides, III: basic, IV: hydrophobic, V: aromatic, bulky amino acids. [Table 3]

[0044] In the following scheme, conservative substitutions of amino acids are classified by physicochemical properties: VI: neutral or hydrophobic, VII: acidic, VIII: basic, IX: polar, X: aromatic. [Table 9]

[0045] The term "amino acid" or "any amino acid" as used herein refers to any and all amino acids, including naturally occurring amino acids (e.g., a-amino acids), unnatural amino acids, modified amino acids, and non-natural amino acids. It includes both D-amino acids and L-amino acids. Natural amino acids include those found in nature, such as the 23 amino acids that combine into peptide chains to form the building blocks of a large array of proteins. These are primarily L stereoisomers, although a small number of D-amino acids are present in bacterial envelopes and some antibiotics. The 20 "standard" natural amino acids are listed in the table above. The "non-standard" natural amino acids are pyrrolidine (found in methanogens and other eukaryotes), selenocysteine ​​(present in most eukaryotes, as well as many non-eukaryotes), and N-formylmethionine (encoded by the start codon AUG in bacteria, mitochondria, and chloroplasts). "Unnatural" or "non-natural" amino acids are non-proteinogenic amino acids (i.e., not naturally encoded and not found in the genetic code) that are either naturally occurring or chemically synthesized. Over 140 non-natural amino acids are known, with thousands of possible combinations. Examples of "non-natural" amino acids include the β-amino acids (β 3 and β 2), homo-amino acids, proline and pyruvate derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linear core amino acids, diamino acids, D-amino acids, alpha-methyl amino acids and N-methyl amino acids. Unnatural or non-natural amino acids also include modified amino acids. "Modified" amino acids include amino acids (e.g., natural amino acids) that have been chemically modified to include a group, groups, or chemical moiety that does not naturally occur on the amino acid. According to certain embodiments, the peptide inhibitor comprises an intramolecular bond between two amino acid residues present in the peptide inhibitor. It is understood that the amino acid residues that form the bond are somewhat altered when bound to each other compared to when not bound to each other. Reference to a specific amino acid is meant to encompass that amino acid in both its unbound and bound states. For example, the amino acid residue homoserine (hSer) or homoserine (Cl) in its unbound form may take the form of 2-aminobutyric acid (Abu) when participating in an intramolecular bond according to the present invention. The present invention inclues both peptide inhibitors that contain a bridge between X4 and X9, as well as peptide inhibitors that do not contain a bridge between X4 and X9, e.g., prior to bridge formation. Thus, the names hSer and Abu are intended to refer to the same amino acid and are used interchangeably.

[0046] For the most part, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions suggested by the IUPAC Commission on the Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature as set forth in "Nomenclature of α-Amino Acids (Recommendations, 1974)" Biochemistry, 14(2), (1975). Where the names and abbreviations of amino acids and aminoacyl residues used in this specification and the appended claims differ from those suggestions, they will be made clear to the reader. Some abbreviations useful in describing the present invention are defined below in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0047] Throughout this specification, naturally occurring amino acids are designated by their conventional three-letter or one-letter abbreviations (e.g., Ala or A for alanine, Arg or R for arginine, etc.) unless otherwise indicated. The three-letter and one-letter abbreviations of amino acids refer to the L-isomer form of the amino acid in question. The term "L-amino acid" as used herein refers to the "L" isomeric form of a peptide, whereas the term "D-amino acid" refers to the "D" isomeric form of a peptide (e.g., Dasp, (D)Asp or D-Asp; Dphe, (D)Phe or D-Phe). The D-isomer form of an amino acid residue can be substituted for any L-amino acid residue, so long as the desired function is retained by the peptide. When D-amino acids are referred to using one-letter abbreviations, they may be conventionally referred to in lower case.

[0048] For less common or non-naturally occurring amino acids, if they are not referred to by their full name (e.g., sarcosine, ornithine, etc.), frequently used three or four letter codes are used for those residues, including Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutyric acid), Dapa (2,3-diaminopropanoic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutanoic acid), β-Pro (pyrrolidine-3-carboxylic acid), and 8Ado (8-amino-3,6-dioxaoctanoic acid), Abu (2-aminobutyric acid), βhPro (β-homoproline), βhPhe (β-homophenylalanine) and Bip (β,β diphenylalanine), and Ida (iminodiacetic acid).

[0049] As will be appreciated by those skilled in the art, peptide sequences disclosed herein are presented from left to right, with the left end of the sequence being the N-terminus of the peptide and the right end of the sequence being the C-terminus of the peptide. Some sequences disclosed herein incorporate a "Hy-" moiety at the amino terminus (N-terminus) of the sequence and either a "-OH" or "-NH2" moiety at the carboxy terminus (C-terminus) of the sequence. In such cases, unless otherwise indicated, the "Hy-" moiety at the N-terminus of the sequence in question refers to a hydrogen atom, corresponding to the presence of a free primary or secondary amino group at the N-terminus, and the "-OH" or "-NH2" moiety at the C-terminus of the sequence refers to a hydroxyl or amino group, respectively, corresponding to the presence of an amide (CONH2) group at the C-terminus. In each of the sequences of the present invention, the "-OH" moiety at the C-terminus may be substituted for the "-NH2" moiety at the C-terminus, and vice versa.

[0050] Those skilled in the art understand that certain amino acids and other chemical moieties are modified when they are bonded to another molecule. For example, an amino acid side chain may be modified when it forms an intramolecular bridge with another amino acid side chain, for example, one or more hydrogens may be removed or replaced by a bond. Thus, as used herein, a reference to an amino acid or modified amino acid present in a peptide dimer of the present invention (e.g., at position X4 or position X9) is meant to include the form of such amino acid or modified amino acid present in the peptide both before and after forming an intramolecular bond.

[0051] The term "dimer" as used herein broadly refers to a peptide that comprises two or more monomeric subunits. Certain dimers comprise two monomeric subunits that comprise the sequence of formula (I) or described herein. Dimers of the present invention include homodimers and heterodimers. The monomeric subunits of a dimer may be linked at their C- or N-terminus, or may be linked via internal amino acid residues. Each monomeric subunit of a dimer may be linked through the same site, or each may be linked through a different site (e.g., C-terminus, N-terminus, or internal site).

[0052] The term "NH2" as used herein can refer to the free amino group present at the amino terminus of a polypeptide. The term "OH" as used herein can refer to the free carboxy group present at the carboxy terminus of a peptide. Additionally, the term "Ac" as used herein refers to acetyl protection through acylation of the C- or N-terminus of a polypeptide. In certain peptides shown herein, NH2 located at the C-terminus of the peptide refers to an amino group.

[0053] The term "carboxy" as used herein refers to -CO2H.

[0054] The term "isosteric substitution," as used herein, refers to any amino acid or other analog moiety that has similar chemical and / or structural properties to a specified amino acid. In certain embodiments, an isosteric substitution is a conservative substitution or analog of a specified amino acid.

[0055] The term "cyclized," as used herein, refers to one portion of a polypeptide molecule being linked to another portion of the polypeptide molecule to form a closed ring, such as by formation of a disulfide bridge or a thioether bond.

[0056] The term "subunit," as used herein, refers to one of a pair of polypeptide monomers that are joined to form a dimeric peptide composition.

[0057] The term "linker moiety," as used herein, refers broadly to a chemical structure capable of linking or joining two peptide monomer subunits together to form a dimer.

[0058] The term "pharmaceutically acceptable salts" as used herein refers to water- or oil-soluble or dispersible salts or zwitterionic forms of the peptides or compounds of the invention that are suitable for the treatment of disease without undue toxicity, irritation, and allergic responses, are commensurate with a reasonable benefit / risk ratio, and are effective for the intended use. The salts can be prepared during the final isolation and purification of the compound or separately by reacting an amino group with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, and the like. The salts of the amino groups in the compounds of the present invention include phosphate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. The amino groups in the compounds of the present invention can also be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. The pharma- ceutically acceptable salt may suitably be, for example, a salt selected from among acid addition salts and base salts.Examples of acid addition salts include chlorides, citrates and acetates. Examples of basic salts include salts in which the cation is selected from among alkali metal cations, such as sodium or potassium ions, alkaline earth metal cations, such as calcium or magnesium ions, as well as substituted ammonium ions, such as ions of the type N(R1)(R2)(R3)(R4)+, where R1, R2, R3 and R4 independently typically represent hydrogen, optionally substituted C1-6 alkyl or optionally substituted C2-6 alkenyl. Examples of relevant C1-6 alkyl groups include methyl, ethyl, 1-propyl and 2-propyl groups. Examples of potentially relevant C2-6 alkenyl groups include ethenyl, 1-propenyl and 2-propenyl. Other examples of pharma- ceutically acceptable salts are described in "Remington's Pharmaceutical Sciences", 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions thereof), and J.Pharm.Sci.66:2 (1977), in "Encyclopaedia of Pharmaceutical Technology", 3rd edition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, 2007. Also see Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl and Wermuth (Wiley-VCH, 2002) for a review of suitable salts. Other suitable base salts are formed from bases which form non-toxic salts. Representative examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts. Hemisalts of acids and bases can also be formed, such as hemisulfate and hemicalcium salts.

[0059] The term "N (alpha) methylation," as used herein, describes the methylation of the alpha amine of an amino acid, also commonly referred to as N-methylation.

[0060] The term "sym methylation" or "Arg-Me-sym" as used herein describes the symmetric methylation of the two nitrogens of the guanidine group of arginine. Additionally, the term "asym methylation" or "Arg-Me-asym" describes the methylation of a single nitrogen of the guanidine group of arginine.

[0061] The term "acylating organic compound" as used herein refers to various compounds having a carboxylic acid functionality that are used to acylate the N-terminus of an amino acid or monomer or dimer, e.g., a monomeric subunit prior to the formation of a C-terminal dimer. Non-limiting examples of acylating organic compounds include cyclopropylacetic acid, 4-fluorobenzoic acid, 4-fluorophenylacetic acid, 3-phenylpropionic acid, succinic acid, glutaric acid, cyclopentanecarboxylic acid, 3,3,3-trifluoropropionic acid, 3-fluoromethylbutyric acid, and tetrahydro-2H-pyran-4-carboxylic acid.

[0062] The term "alkyl" includes straight or branched, acyclic or cyclic, saturated aliphatic hydrocarbons containing 1 to 24 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl, and saturated branched chain alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, and isopentyl. Representative saturated cyclic alkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and unsaturated cyclic alkyls include, but are not limited to, cyclopentenyl, and cyclohexenyl.

[0063] "Halo" or "halogen" refers to a bromo (Br), chloro (Cl), fluoro (F) or iodo (I) substituent.

[0064] The term "haloalkyl" includes alkyl structures in which at least one hydrogen has been replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms have been replaced with halogen atoms, the halogen atoms are all the same as each other. In other embodiments in which two or more hydrogen atoms have been replaced with halogen atoms, the halogen atoms are not all the same as each other.

[0065] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0066] An "aryloxy" group refers to an (aryl)O- group, where aryl is as defined herein.

[0067] "Carboxy" means the radical --C(O)OH.

[0068] "Aminocarbonyl" or "carboxamide" refers to the -CONH2 radical.

[0069] “2-aminoethoxy” refers to the —OCH2CH2—NH2 radical.

[0070] “2-Acetylaminoethoxy” refers to the —OCH2CH2—N(H)C(O)Me radical.

[0071] The term "mammal" refers to any mammalian species, such as, for example, humans, mice, rats, dogs, cats, hamsters, guinea pigs, rabbits, and farm animals.

[0072] As used herein, a "therapeutically effective amount" of a peptide inhibitor of the invention is meant to describe a sufficient amount of the peptide inhibitor to treat an IL-23 / IL-23R-associated disease, including but not limited to any disease and disorder described herein (e.g., to reduce inflammation associated with IBD). In specific embodiments, a therapeutically effective amount achieves a desired benefit / risk ratio applicable to any medical treatment.

[0073] An "analog" of an amino acid, e.g., a "Phe analog" or a "Tyr analog", refers to an analog of the referenced amino acid. A variety of amino acid analogs are known and available in the art, including Phe and Tyr analogs. In certain embodiments, an amino acid analog, e.g., a Phe analog or a Tyr analog, contains 1, 2, 3, 4, or 5 substitutions compared to Phe or Tyr, respectively. In certain embodiments, the substitutions are in the side chain of the amino acid. In certain embodiments, a Phe analog has the structure Phe(R 2 )(wherein, R 2 is Hy, OH, CH, COH, CONH, CONHOCHCHNH, t-Bu, OCHCHNH, phenoxy, OCH, Oallyl, Br, Cl, F, NH, N, or guanadino. 2is CONH2OCH2CH2NH2, OCH3, CONH2, OCH3 or CO2H. Examples of Phe analogs include hPhe, Phe(4-OMe), α-Me-Phe, hPhe(3,4-dimethoxy), Phe(4-CONH2), Phe(4-phenoxy), Phe(4-guanidino), Phe(4-tBu), Phe(4-CN), Phe(4-Br), Phe(4-OBzl), Phe(4-NH2), BhPhe(4-F), Phe(4-F), Phe(3,5 Examples of Tyr analogs include, but are not limited to, hTyr, N-Me-Tyr, Tyr(3-tBu), Tyr(4-N3), and βhTyr.

[0074] Peptide inhibitors of IL-23R Genome-wide association studies (GWAS) have demonstrated a significant association of the IL-23 receptor (IL-23R) gene with inflammatory bowel disease (IBD), suggesting that disruption of IL-23 signaling may be associated with the pathogenesis of this disease as well as other inflammatory diseases and disorders. The present invention provides compositions and methods for modulating the IL-23 pathway through antagonism of IL-23R.

[0075] The present invention generally relates to peptides with IL-23R antagonist activity, including both peptide monomers and peptide dimers.In certain embodiments, the present invention demonstrates a new paradigm for the treatment of IBD and other diseases and disorders by oral delivery of IL-23 antagonists.IBD represents local inflammation of intestinal tissue, and therefore, advantageous therapeutic agents act from the luminal side of the intestine, resulting in high drug concentration in diseased tissue, minimizing systemic availability, and resulting in improved efficacy and safety when compared with systemic approaches.It is expected that oral administration of the compounds of the present invention maximizes drug levels in diseased intestinal tissue while limiting drug concentration in circulation, thereby providing effective, safe, and durable delivery for the lifelong treatment of IBD and other diseases and disorders.

[0076] In certain embodiments, the present invention relates to peptide dimers that include various peptides or hetero- or homo-monomeric subunits that form a cyclized structure through disulfide or other bonds. In certain embodiments, the disulfide or other bonds are intramolecular bonds. The cyclized structure of the monomeric subunits of peptide monomeric inhibitors and peptide dimeric inhibitors has been shown to increase the potency and selectivity of peptide inhibitors. In certain embodiments, peptide dimeric inhibitors may include one or more intermolecular bonds that connect two monomeric peptide subunits in the peptide dimeric inhibitor, such as an intermolecular bridge between two Pen residues, one in each peptide monomeric subunit.

[0077] The present invention provides peptide inhibitors that bind to IL-23R, which may be monomeric or dimeric. In a specific embodiment, the peptide inhibitors inhibit the binding of IL-23 to IL-23R. In certain embodiments, the IL-23R is human IL-23R and the IL-23 is human IL-23. In certain embodiments, the peptide inhibitors of the present invention reduce the binding of IL-23 to IL-23R by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% when compared to a negative control peptide. Methods for determining binding are known in the art and include ELISA assays such as those described in the accompanying examples.

[0078] In certain embodiments, peptide inhibitors of the invention have an IC of >1 mM, <1 mM, 500 nM-1000 nM, <500 nM, <250 nM, <100 nM, <50 nM, <25 nM, <10 nM, <5 nM, <2 nM, <1 nM, or <5 mM, for example, inhibition of binding of IL-23 to IL-23R (e.g., human IL-23 and human IL-23R). 50 Methods for determining activity are known in the art and include any of those described in the accompanying examples.

[0079] In certain embodiments, the peptide inhibitors of the present invention have increased stability, increased gastrointestinal stability, or increased stability in stimulated intestinal fluid (SIF) or simulated gastric fluid (SGF) and / or under redox conditions (e.g., DTT) when compared to a control peptide. In certain embodiments, the control peptide is an unrelated peptide of the same or similar length. In a specific embodiment, the control peptide is a peptide that has the same or highly related amino acid sequence (e.g., >90% sequence identity) as the peptide inhibitor. In a specific embodiment, the control peptide is a peptide that has the same or highly related amino acid sequence (e.g., >90% sequence identity) as the peptide inhibitor, but does not have a cyclized structure, or does not dimerize, or does not contain a conjugate for stabilization, for example, through an intramolecular bond between two amino acid residues in the control peptide. In a specific embodiment, the only difference between the peptide inhibitor and the control peptide is that the peptide inhibitor contains one or more amino acid substitutions that introduce one or more amino acid residues into the peptide inhibitor, and the introduced amino acid residue forms an intrasulfide disulfide or thioether bond with another amino acid residue in the peptide inhibitor. One example of a control for a peptide dimeric inhibitor is a monomer that has the same sequence as one of the monomeric subunits present in the peptide dimeric inhibitor. One example of a control for a peptide inhibitor that includes a conjugate is a peptide that has the same sequence but does not contain a conjugated portion. In certain embodiments, the control peptide is a peptide (e.g., a naturally occurring peptide) that corresponds to the region of IL-23 that binds to IL-23R.

[0080] Methods for determining peptide stability are known in the art. In certain embodiments, the stability of peptide inhibitors is determined using SIF assay, for example, as described in Example 3. In certain embodiments, the stability of peptide inhibitors is determined using SGF assay, for example, as described in Example 3. In specific embodiments, peptide inhibitors have a half-life (e.g., in SIF or SGF or DTT) of more than 1 minute, more than 10 minutes, more than 20 minutes, more than 30 minutes, more than 60 minutes, more than 90 minutes, more than 120 minutes, more than 3 hours, or more than 4 hours under a given set of conditions (e.g., temperature) when exposed to SIF or SGF or DTT. In certain embodiments, the temperature is about 25°C, about 4°C, or about 37°C, and the pH is physiological pH, or about pH 7.4.

[0081] In some embodiments, half-life is measured in vitro using any suitable method known in the art, for example, in some embodiments, the stability of the peptides of the invention is determined by incubating the peptide with human serum (Sigma) pre-warmed to 37° C. Samples are typically taken at various time points up to 24 hours, and the stability of the samples is analyzed by separating the peptide or peptide dimer from serum proteins and then analyzing for the presence of the peptide or peptide dimer of interest using LC-MS.

[0082] In some embodiments, the peptide inhibitors of the invention exhibit characteristics of improved solubility or improved aggregation when compared to a control peptide. Solubility may be determined via any suitable method known in the art. In some embodiments, suitable methods known in the art for determining solubility include incubating the peptide in various buffers (Acetate pH 4.0, Acetate pH 5.0, Phos / Citrate pH 5.0, Phos Citrate pH 6.0, Phos pH 6.0, Phos pH 7.0, Phos pH 7.5, Strong PBS pH 7.5, Tris pH 7.5, Tris pH 8.0, Glycine pH 9.0, Water, Acetic acid (pH 5.0 and others known in the art) and testing for aggregation or solubility using standard techniques. These include, but are not limited to, for example, visual precipitation, dynamic light scattering, circular dichroism and fluorescent dyes to measure surface hydrophobicity and to detect aggregation or fibrillation. In some embodiments, improved solubility means that the peptide is more soluble in a given liquid than a control peptide. In some embodiments, improved aggregation means that the peptide has less aggregation in a given liquid under a given set of conditions than a control peptide.

[0083] In certain embodiments, which are advantageous for achieving high compound concentrations in intestinal tissues when delivered orally, the peptide inhibitors of the present invention are stable in the gastrointestinal (GI) environment. Proteolytic metabolism in the GI tract is driven by enzymes secreted into the lumen from the pancreas or produced as brush border enzymes, including pepsin, trypsin, chymotrypsin, elastase, aminopeptidase, and carboxypeptidase A / B. Proteases typically cleave peptides and proteins in extended conformations. In the reducing environment of intestinal fluids, disulfide bonds can be broken, resulting in linear peptides and rapid protein hydrolysis. The redox environment of the lumen is largely determined by the Cys / CySS redox cycle. In enterocytes, relevant activities include numerous digestive enzymes, such as CYP450 and UDP-glucuronsyl-transferase. Finally, 10 10 ~10 12 Bacteria present in the large intestine at concentrations in the range of CFU / ml constitute another metabolic barrier. In certain embodiments, peptide inhibitors are stable to a range of pHs, ranging from strongly acidic in the stomach (pH 1.5-1.9), tending towards basic in the small intestine (pH 6-7.5), and then weakly acidic in the colon (pH 5-7). Such peptide inhibitors are stable during transit through the various GI compartments, a process estimated to take 3-4 h in the intestine and 6-48 h in the colon.

[0084] In some embodiments, the peptide inhibitors of the present invention have lower degradation (i.e., higher degradation stability) than the control peptide, for example, over a period of time, for example, more than or about 10% lower, more than or about 20% lower, more than or about 30% lower, more than or about 40% lower, or more than or about 50% lower. In some embodiments, the degradation stability is determined via any suitable method known in the art. In some embodiments, the degradation is enzymatic degradation. For example, in certain embodiments, the peptide inhibitor has reduced susceptibility to degradation by trypsin, chymotrypsin, or elastase. In some embodiments, suitable methods known in the art for determining degradation stability include the methods described in Hawe et al., J Pharm Sci, VOL.101, No.3,2012, p 895-913 (incorporated herein in its entirety). Such methods are used in some embodiments to select potent peptide sequences with enhanced shelf life. In specific embodiments, peptide stability is determined using a SIF assay or an SGF assay, for example, as described in PCT International Publication No. WO2016 / 011208.

[0085] In certain embodiments, the peptide inhibitors of the present invention inhibit or reduce IL-23-mediated inflammation. In related embodiments, the peptide inhibitors of the present invention inhibit or reduce IL-23-mediated secretion of one or more cytokines, for example, by binding to IL-23R on the cell surface, thereby inhibiting the binding of IL-23 to the cell. In specific embodiments, the peptide inhibitors of the present invention inhibit or reduce IL-23-mediated activation of Jak2, Tyk2, Stat1, Stat3, Stat4, or Stat5. Methods for determining inhibition of cytokine secretion and inhibition of signaling molecules are known in the art. For example, inhibition of IL-23 / IL-23R signaling may be determined by measuring inhibition of phospho-Stat3 levels in cell lysates, for example, as described in PCT International Publication No. WO2016 / 011208.

[0086] In certain embodiments, the peptide inhibitor has increased redox stability when compared to a control peptide.Various assays that can be used to determine redox stability are known and available in the art.Any of these can be used to determine the redox stability of the peptide inhibitor of the present invention.

[0087] In certain embodiments, the present invention provides various peptide inhibitors that bind or associate with IL-23R in vitro or in vivo and interfere with or block the binding between IL-23 and IL-23R. In certain embodiments, the peptide inhibitors bind and / or inhibit human IL-23R. In certain embodiments, the peptide inhibitors bind and / or inhibit both human and rodent IL-23R. In certain embodiments, the peptide inhibitors bind and / or inhibit both human and rat IL-23R. In specific embodiments, the peptide inhibitors inhibit rat IL-23R at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the binding or inhibition of human IL-23R, e.g., as determined by the assays described herein. In certain embodiments, the peptide inhibitors preferentially bind and / or inhibit human and / or rat IL-23R when compared to mouse IL-23R. In a specific embodiment, the peptide inhibitor preferentially binds to rat IL-23R as compared to mouse IL-23R. In a specific embodiment, the peptide inhibitor preferentially binds to human IL-23R as compared to mouse IL-23R. In certain embodiments, the binding of the peptide inhibitor to mouse IL-23R is less than 75%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the binding of the same peptide inhibitor to human IL-23R and / or rat IL-23R. In certain embodiments of peptide inhibitors that preferentially bind to and / or inhibit human IL-23R and / or rat IL-23R as compared to mouse IL-23R, the peptide inhibitor binds to a region of IL-23R that is disrupted by the presence of additional amino acids that are present in mouse IL-23R but not present in human IL-23R or rat IL-23. In one embodiment, the additional amino acids present in mouse IL-23R are in a region corresponding to about amino acid residue 315 to about amino acid residue 340 of the mouse IL23R protein, e.g., the amino acid region NWQPWSSPFVHQTSQETGKR (SEQ ID NO: 106).In a specific embodiment, the peptide inhibitor binds to a region of human IL-23R from about amino acid 230 to about amino acid residue 370.

[0088] In certain embodiments, the peptide inhibitor shows GI-restricted localization after oral administration.In specific embodiments, more than 50%, more than 60%, more than 70%, more than 80%, or more than 90% of the orally administered peptide inhibitor is localized in gastrointestinal organs and tissues.In specific embodiments, the plasma level of the orally administered peptide inhibitor is less than 20%, less than 10%, less than 5%, less than 2%, less than 1%, or less than 0.5% of the level of the peptide inhibitor found in small intestinal mucosa, colonic mucosa, or proximal colon.

[0089] The various peptide inhibitors of the present invention may be constructed only from natural amino acids. Alternatively, the peptide inhibitors may include unnatural amino acids, including but not limited to modified amino acids. In certain embodiments, modified amino acids include natural amino acids that are chemically modified to include a non-natural group, groups, or chemical moieties on the amino acid. The peptide inhibitors of the present invention may additionally include one or more D-amino acids. Furthermore, the peptide inhibitors of the present invention may include amino acid analogs.

[0090] In certain embodiments, the peptide inhibitors of the present invention comprise one or more modified or unnatural amino acids. In some embodiments of the present invention, the peptide inhibitors comprise one or more unnatural amino acids as shown in Table 1A. In certain embodiments, the peptide inhibitors of the present invention include any of those described herein, including but not limited to any that comprise an amino acid sequence or peptide inhibitor structure as shown in any one of the tables herein.

[0091] The present invention also includes any of the peptide inhibitors described herein, either in free form or in salt form, and thus embodiments of any of the peptide inhibitors described herein (and related methods of use thereof) include pharma- ceutically acceptable salts of the peptide inhibitors.

[0092] The present invention also includes variants of any of the peptide inhibitors described herein, including but not limited to any that contain a sequence shown in any one of the tables herein, in which one or more L-amino acid residues are replaced with the D-isomer form of the amino acid residue, e.g., L-Ala is replaced with D-Ala.

[0093] The peptide inhibitors described herein include isotopically labeled peptide inhibitors.In a specific embodiment, the present disclosure provides peptide inhibitors that have the various formulas and structures presented herein or are identical to any of those described herein, except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those usually found in nature.Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, respectively. 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Certain isotopically labeled compounds described herein, such as 3 H and 14 Incorporating a radioactive isotope such as C is useful in drug and / or substrate tissue distribution assays. Additionally, deuterium, i.e., 2 Substitution with isotopes such as H can afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0094] The present invention also includes any peptide monomer inhibitor described herein linked to a linker moiety, including any specific linker moiety described herein. In specific embodiments, the linker is attached to the N-terminal or C-terminal amino acid, and in other embodiments, the linker is attached to an internal amino acid. In specific embodiments, the linker is attached to two internal amino acids, for example, to the internal amino acids in each of the two monomer subunits that form a dimer. In some embodiments of the present invention, the peptide inhibitor is attached to one or more linker moieties as shown.

[0095] The present invention also includes peptides and peptide dimers comprising peptides having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the peptide sequences of the peptide inhibitors described herein.In a specific embodiment, the peptide inhibitors of the present invention comprise a core peptide sequence and one or more N-terminal and / or C-terminal modifications (e.g., Ac and NH2) and / or one or more conjugated linker moieties and / or half-life extension moieties.As used herein, a core peptide sequence is the amino acid sequence of a peptide without such modifications and conjugates.

[0096] In certain embodiments, a peptide inhibitor or monomeric subunit of a peptide inhibitor of the invention consists essentially of, or consists of, between 7 and 35 amino acid residues, between 8 and 35 amino acid residues, between 9 and 35 amino acid residues, between 10 and 35 amino acid residues, between 7 and 25 amino acid residues, between 8 and 25 amino acid residues, between 9 and 25 amino acid residues, between 10 and 25 amino acid residues, between 7 and 20 amino acid residues, between 8 and 20 amino acid residues, between 9 and 20 amino acid residues, between 10 and 20 amino acid residues, between 7 and 18 amino acid residues, between 8 and 18 amino acid residues, between 9 and 18 amino acid residues, or between 10 and 18 amino acid residues, and optionally one or more additional non-amino acid moieties, e.g., including a conjugated chemical moiety, e.g., a PEG or a linker moiety. In specific embodiments, the peptide inhibitors of the invention (or monomeric subunits thereof), including but not limited to any of the embodiments of Formula I, are more than 10, more than 12, more than 15, more than 20, more than 25, more than 30, or more than 35 amino acids, e.g., 35-50 amino acids. In certain embodiments, the peptide inhibitors (or monomeric subunits thereof) are less than 50, less than 35, less than 30, less than 25, less than 20, less than 15, less than 12, or less than 10 amino acids. In specific embodiments, a monomeric subunit of a peptide inhibitor (or peptide monomeric inhibitor) comprises or consists of 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 amino acid residues. In specific embodiments, a monomeric subunit of a peptide inhibitor of the invention comprises or consists of 10-23 amino acid residues, and, optionally, one or more additional non-amino acid moieties, such as conjugated chemical moieties, such as PEG or linker moieties.In various embodiments, the monomeric subunit comprises or consists of 7-35 amino acid residues, 7-20 amino acid residues, 8-20 amino acid residues, 9-20 amino acid residues, 10-20 amino acid residues, 8-18 amino acid residues, 8-19 amino acid residues, 8-18 amino acid residues, 9-18 amino acid residues, or 10-18 amino acid residues. In specific embodiments of any of the various formulas described herein, X comprises or consists of 7-35 amino acid residues, 8-35 amino acid residues, 9-35 amino acid residues, 10-35 amino acid residues, 7-25 amino acid residues, 8-25 amino acid residues, 9-25 amino acid residues, 10-25 amino acid residues, 7-18 amino acid residues, 8-18 amino acid residues, 9-18 amino acid residues, or 10-18 amino acid residues.

[0097] Certain illustrative peptide inhibitors described herein contain 12 or more amino acid residues. However, the invention also includes peptide inhibitors comprising fragments of any of the peptide sequences described herein, including peptide inhibitors having 7, 8, 9, 10, or 11 amino acid residues. For example, peptide inhibitors of the invention include peptides comprising or consisting of X4-X9, X4-X10, X4-X11, X4-X12, X4-X13, X4-X14, or X4-X15.

[0098] In a specific embodiment of the invention, the amino acid sequence of the peptide inhibitor is not present in an antibody or is not present in the V H or V L Not present in the region.

[0099] Peptide inhibitors The peptide inhibitors of the present invention include peptides that comprise or consist of any amino acid sequence described herein, compounds that have any structure described herein, including compounds that comprise any peptide sequence described herein, and dimers of any of such peptides and compounds.The peptide inhibitors of the present invention include both peptides that do not have a bond between X4 and X9 and peptides that do have a bond between X4 and X9, for example, before and after a bridge is introduced between X4 and X9.The illustrative peptides of the present invention include any of the amino acid sequences or structures described in the accompanying table.

[0100] In certain embodiments, the present invention provides a method for the preparation of a compound of formula (I): X7-X8-X9-X10-X11(I) or a pharma- ceutically acceptable salt or solvate thereof, wherein the peptide inhibitor of the interleukin-23 receptor comprises an amino acid sequence of X7 is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp; X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen; X10 is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and X11 is 2-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal; however, i) at least one of X7 and X11 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; ii) if X7 is a 5-F substituted Trp, then X11 is other than 2-Nal; and iii) if X7 is a 5-OH or 6-Cl substituted Trp, then X9 is other than Cys; and Peptide inhibitors block the binding of interleukin-23 (IL-23) to the IL-23 receptor. In a related embodiment, the present invention provides a peptide inhibitor having formula (II): X4-X5-X6-X7-X8-X9-X10-X11(II) or a pharma- ceutically acceptable salt or solvate thereof, wherein the peptide inhibitor of the interleukin-23 receptor comprises an amino acid sequence of X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X5 is Cit, Glu, Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, Asp, or Cys; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp; X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); when X4 is Abu, X9 is Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); and when X9 is Abu, X4 is Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X10 is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and X11 is 2-Nal, unsubstituted Trp, or Trp substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal; The peptide inhibitor is cyclized via the bond between X4 and X9, provided that i) at least one of X7 and X11 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; ii) if X7 is a 5-F substituted Trp, then X11 is other than 2-Nal; and iii) when X7 is a 5-OH or 6-Cl substituted Trp, then X9 is other than Cys; and Peptide inhibitors block the binding of interleukin-23 (IL-23) to the IL-23 receptor. The present invention includes a peptide inhibitor, or a pharma- ceutically acceptable salt or solvate thereof.

[0101] In one embodiment, when X7 is a 5-F substituted Trp, X11 is not 2-Nal.

[0102] In one embodiment, when X7 is 5-F substituted Trp, X11 is unsubstituted Trp or Trp substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal.

[0103] In certain embodiments, X4 or X9 is Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen, and the bond between X4 and X9 is a disulfide bond.

[0104] In certain embodiments, X4 is Cys, (D)Cys, or alpha-MeCys.

[0105] In certain embodiments, X4 is (D)Pen, or Pen, or X4 is Pen(sulfoxide).

[0106] In certain embodiments, X4 is Pen.

[0107] In certain embodiments, X9 is Cys, (D)Cys, or alpha-MeCys.

[0108] In certain embodiments, X9 is Pen or (D)Pen.

[0109] In certain embodiments, X9 is Pen.

[0110] In certain embodiments, X4 is Pen and X9 is Pen, and the bond is a disulfide bond.

[0111] In certain embodiments, X4 is Pen and X9 is Cys, and the bond is a disulfide bond.

[0112] In certain embodiments, X4 or X9 is Abu, and the bond between X4 and X9 is a thioether bond.

[0113] In certain embodiments, X4 is Abu and X9 is Cys, (D)Cys, or alpha-MeCys. In certain embodiments, X9 is Pen or (D)Pen. In specific embodiments, X9 is Pen. In more specific embodiments, X9 is Cys. In the most specific embodiments, X4 is Abu and X9 is Cys.

[0114] In certain embodiments, X4 is Abu and X9 is Cys or Pen, and the bond is a thioether bond.

[0115] In certain embodiments, X4 is Abu, X9 is Cys, and the bond is a thioether bond.

[0116] In certain embodiments, the peptide inhibitor is according to formula (IIa), (IIb), or (IIc) or comprises a sequence of formula (IIa), (IIb), or (IIc): Pen-X5-X6-X7-X8-Pen-X10-X11(IIa) Abu-X5-X6-X7-X8-Cys-X10-X11(IIb), or Abu-X5-X6-X7-X8-Pen-X10-X11(IIc) In formulas (IIa), (IIb), and (IIc), X5 to X8 and X10 to X11 are as described for formula (II), and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or the peptide inhibitor is cyclized via an Abu-Cys or Abu-Pen thioether bond.

[0117] In certain embodiments, X5 is Asn, Gln, or Glu.

[0118] In certain embodiments, X5 is Asn, or Gln.

[0119] In certain embodiments, X5 is Asn.

[0120] In certain embodiments, the peptide inhibitor is according to formula (IIIa), (IIIb), (IIIc), or (IIId) or comprises the sequence of formula (IIIa), (IIIb), (IIIc), or (IIId): Pen-Asn-X6-X7-X8-Pen-X10-X11(IIIa), Pen-Gln-X6-X7-X8-Pen-X10-X11(IIIb), Abu-Asn-X6-X7-X8-Cys-X10-X11(IIIc), or Abu-Gln-X6-X7-X8-Pen-X10-X11(IIId) In formulas (IIIa), (IIIb), (IIIc), and (IIId), X6-X8 and X10-X11 are as described for formula (II), and the peptide inhibitors are cyclized via a Pen-Pen disulfide bond, or the peptide inhibitors are cyclized via an Abu-Cys or Abu-Pen thioether bond.

[0121] In certain embodiments, X6 is Thr.

[0122] In certain embodiments, the peptide inhibitor is according to formula (IVa), (IVb), (IVc), or (IVd), or comprises the sequence of formula (IVa), (IVb), (IVc), or (IVd): Pen-Asn-Thr-X7-X8-Pen-X10-X11(IVa), Pen-Gln-Thr-X7-X8-Pen-X10-X11(IVb), Abu-Asn-Thr-X7-X8-Cys-X10-X11(IVc), or Abu-Gln-Thr-X7-X8-Pen-X10-X11(IVd) In formulas (IVa), (IVb), (IVc), and (IVd), X7-X8 and X10-X11 are as described for formula (II), and the peptide inhibitors are cyclized via a Pen-Pen disulfide bond, or the peptide inhibitors are cyclized via an Abu-Cys or Abu-Pen thioether bond.

[0123] In certain embodiments, X8 is Gln, alpha-Me-Lys, alpha-MeLys(Ac), or Glu.

[0124] In certain embodiments, X8 is Gln. In certain embodiments, X8 is Cit.

[0125] In certain embodiments, the peptide inhibitor is according to formula (Va), (Vb), (Vc), or (Vd) or comprises a sequence of formula (Va), (Vb), (Vc), or (Vd): Pen-Asn-Thr-X7-Gln-Pen-X10-X11(Va), Pen-Gln-Thr-X7-Gln-Pen-X10-X11(Vb), Abu-Asn-Thr-X7-Gln-Cys-X10-X11(Vc), or Abu-Gln-Thr-X7-Gln-Pen-X10-X11(Vd) In formulas (Va), (Vb), (Vc), and (Vd), X7-X8 and X10-X11 are as described for formula (II), and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or the peptide inhibitor is cyclized via an Abu-Cys or Abu-Pen thioether bond.

[0126] In certain embodiments, X10 is Phe, Phe[4-(2-aminoethoxy)][F(4-2ae)], Phe[4-(2-acetylaminoethoxy)], or Phe(4-CONH2).

[0127] In certain embodiments, X10 is Phe[4-(2-aminoethoxy)], or Phe[4-(2-acetylaminoethoxy)].

[0128] In certain embodiments, the peptide inhibitor is according to formula (VIa), (VIb), (VIc), or (VId) or comprises the sequence of formula (VIa), (VIb), (VIc), or (VId): Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11(VIa), Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11(VIb), Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11(VIc), or Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11(VId) In formulas (VIa), (VIb), (VIc), and (VId), X7 and X11 are as described for formula (II), [F(4-2ae)] is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or the peptide inhibitor is cyclized via an Abu-Cys or Abu-Pen thioether bond.

[0129] In certain embodiments, the peptide inhibitor has formula (II'): X7-X8-X9-X10-X11-X12-X13-X14-X15(II') wherein the amino acid sequence is X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, or cyclohexyl Ala, Lys, or Aib; X13 is Aib, Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys, or X13 is Lys, pegylated Lys, b-homoGlu, or Lys(Y2-Ac), where Y2 is an amino acid; X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Ala, (D)Ala, beta-Ala, His, Thr, n-Leu, Gln, Ser, (D)Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Leu, Aib, (D)Leu, beta-Ala, Cit, Gln, Asp, alpha-MeGln, alpha-MeAsn, Lys(Ac), (D)Lys, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), or homo-Lys(Ac), or absent.

[0130] In certain embodiments, the peptide inhibitor is according to formula (VIIa), (VIIb), or (VIIc) or comprises the sequence of formula (VIIa), (VIIb), or (VIIc): Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15(VIIa), Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-X12-X13-X14-X15(VIIb), or Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15(VIIc) In formulae (VIIa), (VIIb), and (VIIc), X7 and X11 are as described for formula (II), and X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, or cyclohexyl Ala, Lys, or Aib; X13 is Aib, Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys, or X13 is Lys, pegylated Lys, b-homoGlu, or Lys(Y2-Ac), where Y2 is an amino acid; X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Ala, (D)Ala, beta-Ala, His, Thr, n-Leu, Gln, Ser, (D)Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Leu, Aib, (D)Leu, beta-Ala, Cit, Gln, Asp, alpha-MeGln, alpha-MeAsn, Lys(Ac), (D)Lys, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), or homo-Lys(Ac), or is absent, and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or the peptide inhibitor is cyclized via an Abu-Cys or Abu-Pen thioether bond.

[0131] In certain embodiments, each of X12, X13, X14, or X15 is independently any amino acid. In one embodiment, the amino acid is a natural amino acid. In another embodiment, the amino acid is a non-natural amino acid.

[0132] In certain embodiments, X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Asn, n-Leu, Gln, Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac). In certain embodiments, X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Ala, (D)Ala, beta-Ala, His, Thr, n-Leu, Gln, Ser, (D)Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac).

[0133] In certain embodiments, X15 is Asn, Aib, beta-Ala, Cit, Gln, Asp, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), or homo-Lys(Ac), or absent. In certain embodiments, X15 is Asn, Leu, Aib, (D)Leu, beta-Ala, Cit, Gln, Asp, alpha-MeGln, alpha-MeAsn, Lys(Ac), (D)Lys, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), or homo-Lys(Ac), or absent.

[0134] In certain embodiments, X13 is Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys, or X13 is Lys, pegylated Lys, b-homoGlu, or Lys(Y2-Ac), where Y2 is an amino acid. In certain embodiments, X13 is Aib, Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys, or X13 is Lys, pegylated Lys, b-homoGlu, or Lys(Y2-Ac), where Y2 is an amino acid.

[0135] In certain embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, Ala, cyclohexyl Ala, Lys, or Aib.

[0136] In certain embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, or alpha-MeLeu.

[0137] In certain embodiments, X12 is alpha-MeLeu. In certain embodiments, X12 is alpha-MeLys. In certain embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran (THP).

[0138] In certain embodiments, X13 is Glu, Gln, Lys(Ac), or Lys.

[0139] In certain embodiments, X13 is Gln, Lys(Ac), or Lys.

[0140] In certain embodiments, X13 is Lys(Ac), or Lys.

[0141] In certain embodiments, X13 is Lys(Ac).

[0142] In certain embodiments, the peptide inhibitor is according to formula (VIIIa), (VIIIb) or (VIIIc) or comprises a sequence of formula (VIIIa), (VIIIb) or (VIIIc): Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-aMeLeu-K(Ac)-X14-X15(VIIIa), Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-aMeLeu-K(Ac)-X14-X15(VIIIb), or Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-aMeLeu-K(Ac)-X14-X15(VIIIc) In formulae (VIIIa), (VIIIb) and (VIIIc), X7 and X11 are as described for formula (II), X14, and X15 are as described for formulae (VIIa-c), and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or an Abu-Cys or Abu-Pen thioether bond.

[0143] In certain embodiments, X14 is Asn.

[0144] In certain embodiments, X15 is Asn.

[0145] In certain embodiments, the peptide inhibitor is according to formula (IXa), (IXb), or (IXc) or comprises a sequence of formula (IXa), (IXb), or (IXc): Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-K(Ac)-Asn-Asn(IXa), Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-K(Ac)-Asn-Asn(IXb), or Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-K(Ac)-Asn-Asn(IXc) In formulae IXa), (IXb), and (IXc), X7 and X11 are as described for formula (II), and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or an Abu-Cys or Abu-Pen thioether bond.

[0146] In certain embodiments, X7 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, and X11 is as described herein.

[0147] In certain embodiments, X11 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, and X7 is as described herein.

[0148] In certain embodiments, the peptide inhibitor is according to formula (Xa), (Xb), (Xc), (Xd), (Xe), or (Xf), or comprises the sequence of formula (Xa), (Xb), (Xc), (Xd), (Xe), or (Xf): Pen-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-K(Ac)-Asn-Asn(Xa), Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-W'-[α-MeLeu]-K(Ac)-Asn-Asn(Xb), Abu-Asn-Thr-W'-Gln-Cys-[F(4-2ae)]-X11-[α-MeLeu]-K(Ac)-Asn-Asn(Xc), Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-W'-[α-MeLeu]-K(Ac)-Asn-Asn(Xd), Abu-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-K(Ac)-Asn-Asn(Xe), or Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-W'-[α-MeLeu]-K(Ac)-Asn-Asn(Xf) In formulas (Xa), (Xb), (Xc), (Xd), (Xe), and (Xf), X7 and X11 are as described for formula (II), W' is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or an Abu-Cys or Abu-Pen thioether bond.

[0149] In certain embodiments, X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal.

[0150] In certain embodiments, X11 is 2-Nal, or 1-Nal.

[0151] In certain embodiments, X11 is 2-Nal.

[0152] In certain embodiments, X7 is unsubstituted Trp.

[0153] In certain embodiments, the peptide inhibitor is according to formula (XIa), (XIb), (XIc), (XId), (XIe), or (XIf) or comprises the sequence of formula (XIa), (XIb), (XIc), (XId), (XIe), or (XIf): Pen-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-[2-Nal]-[α-MeLeu]-K(Ac)-Asn-Asn(XIa) (SEQ ID NO: 100), Pen-Asn-Thr-W-Gln-Pen-[F(4-2ae)]-W'-[α-MeLeu]-K(Ac)-Asn-Asn(XIb) (SEQ ID NO: 101), Abu-Asn-Thr-W'-Gln-Cys-[F(4-2ae)]-[2-Nal]-[α-MeLeu]-K(Ac)-Asn-Asn(XIc) (SEQ ID NO: 102), Abu-Asn-Thr-W-Gln-Cys-[F(4-2ae)]-W'-[α-MeLeu]-K(Ac)-Asn-Asn(XId) (SEQ ID NO: 103), Abu-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-[2-Nal]-[α-MeLeu]-K(Ac)-Asn-Asn(XIe) (SEQ ID NO: 104), or Abu-Asn-Thr-W-Gln-Pen-[F(4-2ae)]-W'-[α-MeLeu]-K(Ac)-Asn-Asn(XIf) (SEQ ID NO: 105) In formulas (XIa), (XIb), (XIc), (XId), (XIe), and (XIf), W' is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond.

[0154] In certain embodiments, W' is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy. In one embodiment, W' is Trp substituted with alkyl. In certain embodiments, W' is Trp substituted with Me, Et, n-Pr, or i-Pr.

[0155] In certain embodiments, the peptide inhibitor has the formula (Z): R 1 -XR 2 (Z) or a pharma- ceutically acceptable salt or solvate thereof, wherein: R 1is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl-C1-C6 alkyl, C1-C20 alkanoyl, including PEGylated versions of any of the above alone or as a spacer, X is an amino acid sequence of Formula (I), Formula (II)-(XIf), or an amino acid sequence shown in any of Tables E1, E2 or E3, and R 2 is OH or NH2.

[0156] In certain embodiments, R 1 is H or C1~C 20 is an alkanoyl group.

[0157] In certain embodiments, R 1 is H or Ac.

[0158] In certain embodiments, R 1 is Ac.

[0159] In certain embodiments, W' is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, and the substitution is at the 4, 5, 6, or 7 position.

[0160] In certain embodiments, W' is Trp substituted with cyano, F, Cl, Br, I, Me, Et, i-Pr, n-Pr, n-Bu, t-Bu, CF3, hydroxy, OMe, or OEt, and the substitution is at position 4, 5, 6, or 7. In specific embodiments, the substitution is at position 7.

[0161] In certain embodiments, W' is Trp substituted with 5-F, 6-F, 7-F, 5-Cl, 6-Cl, 7-Cl, 5-Me, 6-Me, 7-Me, 7-n-Pr, 7-i-Pr, 5-OH, 6-OH, 7-OH, 5-OMe, 6-OMe, or 7-OMe.

[0162] In specific embodiments, W' is Trp substituted with 7-Me, 5-F, 7-F, 6-Cl, 6-Me, 4-OMe, 5-OMe, or 5-Br. In more specific embodiments, W' is Trp substituted with 7-Me, 6-Me, 4-OMe, or 6-Cl. In the most specific embodiments, W' is Trp substituted with 7-Me.

[0163] In one embodiment, the peptide inhibitor consists of about 25 or fewer than 25 amino acids. In another embodiment, the peptide inhibitor consists of about 20 or fewer than 20 amino acids. In another embodiment, the peptide inhibitor consists of about 18 or fewer than 18 amino acids. In another embodiment, the peptide inhibitor consists of about 15 or fewer than 15 amino acids. In another embodiment, the peptide inhibitor consists of about 12 or fewer than 12 amino acids. In another embodiment, the peptide inhibitor consists of about 10 or fewer than 10 amino acids.

[0164] In certain embodiments, the peptide is [Table 10] or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via a Pen-Pen disulfide bond.

[0165] In certain embodiments, the peptide is [Table 11] or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via a Pen-Pen disulfide bond.

[0166] In certain embodiments, the peptide is -[(D)Arg]-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-(SEQ ID NO: 27), -[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-(SEQ ID NO: 28), -[(D)Arg]-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NN-(SEQ ID NO: 29), or -[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NN-(SEQ ID NO: 30) or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via an Abu-C thioether bond.

[0167] In certain embodiments, the peptide is [Table 12] or a pharma- ceutically acceptable salt or solvate thereof; The peptide inhibitors are cyclized via an Abu-Cys thioether bond.

[0168] In certain embodiments, the peptide is [Table 13] or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via an Abu-Cys thioether bond.

[0169] In certain embodiments, the peptide is [Table 14] or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via an Abu-Pen thioether bond.

[0170] In certain embodiments, the peptide is [Table 15] or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via an Abu-Pen thioether bond.

[0171] In certain embodiments, the peptide is [Table 16] or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via a Pen-Pen disulfide bond.

[0172] In certain embodiments, the peptide is [Table 17] or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via a Pen-Pen disulfide bond.

[0173] In certain embodiments, the peptide is Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-NH2 (SEQ ID NO: 27), Ac-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-NH2 (SEQ ID NO: 28), Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 29), or Ac-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 30) or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via an Abu-C thioether bond. do.

[0174] In certain embodiments, the peptide is [Table 18] or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via an Abu-Cys thioether bond.

[0175] In certain embodiments, the peptide is [Table 19] or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via an Abu-Cys thioether bond.

[0176] In certain embodiments, the peptide is [Table 20] or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via an Abu-Pen thioether bond.

[0177] In certain embodiments, the peptide is [Table 21] or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via an Abu-Pen thioether bond.

[0178] In certain embodiments, the peptide is Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Arg]-NH2 (SEQ ID NO: 256), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Phe]-NH2 (SEQ ID NO: 257), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Phe]-NH2 (SEQ ID NO: 258), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Tyr]-NH2 (SEQ ID NO: 259), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NS-NH2 (SEQ ID NO: 260), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Ser]-NH2 (SEQ ID NO: 261), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Thr]-NH2 (SEQ ID NO: 263), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Aib]-NH2 (SEQ ID NO: 264), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-[N-MeAla]-NH2 (SEQ ID NO: 265), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 267); Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[diethylGly]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 276); Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acbc]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 277), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeOrn]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 278), or Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[Quin]-[a-MeLys]-[Lys(Ac)]-N-dL-NH2 (SEQ ID NO: 141) or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via a Pen-Pen disulfide bond.

[0179] In certain embodiments, the peptide is Ac-[Pen]-NT-[W(7-Me)]-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 6) or a pharma- ceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond.

[0180] In certain embodiments, the peptide is Ac-[Pen]-NT-[W(4-OMe)]-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 4), Ac-[Pen]-NT-[W(6-Me)]-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 5), Ac-[Pen]-NTW-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-W(6-Cl)-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 13), Ac-[Pen]-NTW-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-W(6-Me)-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 16), or Ac-[Pen]-NTW-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-W(5-Br)-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 22) or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via a Pen-Pen disulfide bond.

[0181] In certain embodiments, the peptide is Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-NH2 (SEQ ID NO: 27), Ac-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-NH2 (SEQ ID NO: 28), Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 29), or Ac-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 30) or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via an Abu-Cys thioether bond.

[0182] In certain embodiments, the peptide is Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 201); Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 227), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 242), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 245), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-H-NH2 (SEQ ID NO: 248), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Cit]-NH2 (SEQ ID NO: 249), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Val]-NH2 (SEQ ID NO: 251), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-NH2 (SEQ ID NO: 252), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Arg]-NH2 (SEQ ID NO: 256), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Phe]-NH2 (SEQ ID NO: 258), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Tyr]-NH2 (SEQ ID NO: 259), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-S-NH2 (SEQ ID NO: 260), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Ser]-NH2 (SEQ ID NO: 261), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Thr]-NH2 (SEQ ID NO: 263), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Aib]-NH2 (SEQ ID NO: 264), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-[N-MeAla]-NH2 (SEQ ID NO: 265), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 267); Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Achc]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 274), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[diethylGly]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 276); Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acbc]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 277), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeOrn]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 278); Ac-[Pen]-NT-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 284), Ac-[Pen]-NT-[W(7-n-Pr)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 285), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2; (SEQ ID NO: 320), or Ac-[Pen]-NT-[W(7-Me)]-[Lys(Aib)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2; (SEQ ID NO: 322) or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via a Pen-Pen disulfide bond.

[0183] In certain embodiments, the peptide is Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 202); Ac-[(D)Arg]-Abu-QT-[W(7-Me)]-QC-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[bA]-NH2 (SEQ ID NO: 203), Ac-Abu-QT-[W(7-Me)]-QC-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[bA]-NH2 (SEQ ID NO: 204), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-G-[bA]-NH2 (SEQ ID NO: 205); Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-A-[bA]-NH2 (SEQ ID NO: 207), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-L-[bA]-NH2 (SEQ ID NO: 208); Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-[(D)Ala]-[bA]-NH2 (SEQ ID NO: 209), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-H-[bA]-NH2 (SEQ ID NO: 214), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-[(D)His]-[bA]-NH2 (SEQ ID NO: 215), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-T-[bA]-NH2 (SEQ ID NO: 217); Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-S-[bA]-NH2 (SEQ ID NO: 221); Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-[(D)Ser]-[bA]-NH2 (SEQ ID NO: 222); Ac-[Pen]-NT-[W(4-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 231); Ac-[Pen]-NT-[W(1-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 232); Ac-[Pen]-NT-[W(7-Me)]-[a-MeLys]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 234); Ac-[Pen]-NT-[W(7-Me)]-[a-MeLeu]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 235); Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Aib]-N-[bA]-NH2 (SEQ ID NO: 236), Ac-[Pen]-QT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 237); Ac-[Pen]-[Cit]-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 238); Ac-[Pen]-[Lys(Ac)]-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 239), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-R-NH2 (SEQ ID NO: 243), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-L-NH2 (SEQ ID NO: 244), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[NMeArg]-NH2 (SEQ ID NO: 246), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bhPhe]-NH2 (SEQ ID NO: 247), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-V-NH2 (SEQ ID NO: 250), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-P-NH2 (SEQ ID NO: 253), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Pro]-NH2 (SEQ ID NO: 254), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NI-NH2 (SEQ ID NO: 255), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Phe]-NH2 (SEQ ID NO: 257), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-[bA]-[bA]-NH2 (SEQ ID NO: 268), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-L-[bA]-NH2 (SEQ ID NO: 269); Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-[bA]-[bA]-NH2 (SEQ ID NO: 270), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-S-[bA]-NH2 (SEQ ID NO: 271), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-H-[bA]-NH2 (SEQ ID NO: 272), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-E-[bA]-[bA]-NH2 (SEQ ID NO: 273), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Spiral_Pip]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 275), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Cit]-[bA]-[bA]-NH2 (SEQ ID NO: 279), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-EN-[bA]-NH2 (SEQ ID NO: 282), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[W(1-Me)]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 283); Ac-[Pen]-NT-[W(7-i-Pr)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 286), Ac-[Pen]-NT-[W(7-OMe)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 288), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[2-Nal]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 289), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-H-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 290), Ac-[Pen]-N-T-[W(7-OMe)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-NH2 (SEQ ID NO: 297), Ac-[Pen]-N-T-[W(7-OMe)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-NH2 (SEQ ID NO: 299), Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ala)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2; (SEQ ID NO: 314), Ac-[Pen]-N-T-[W(7-Me)]-[Lys(IVA)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2; (SEQ ID NO: 315), Ac-[Pen]-N-T-[W(7-Me)]-[Lys(cyclohexanoic acid)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2; (SEQ ID NO: 316), Ac-[Pen]-N-T-[W(7-Me)]-[Lys(bAla)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2; (SEQ ID NO: 321), Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2; (SEQ ID NO: 323), or Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2; (SEQ ID NO: 325) or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via a Pen-Pen disulfide bond.

[0184] In certain embodiments, the peptide is Ac-[Pen]-NT-[W(7-Me)]-[Lys(trifluoropropionic acid)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 319); Ac-[Pen]-NT-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 320), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Aib)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 322), Ac-[Pen]-[Lys(Ac)]-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 330), Ac-[Pen]-[Dab(Ac)]-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 335), Ac-[Pen]-[(D)Asn]-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 338), Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Sarc]-NH2 (SEQ ID NO: 339), Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Aib]-[bA]-NH2 (SEQ ID NO: 340), Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Aib]-G-NH2 (SEQ ID NO: 341), Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Aib]-A-NH2 (SEQ ID NO: 342), Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Aib]-[(D)Lys]-NH2 (SEQ ID NO: 344), Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Aib]-[(D)Phe]-NH2 (SEQ ID NO: 346), or Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Aib]-[(D)Tyr]-NH2 (SEQ ID NO: 347) or a pharma- ceutically acceptable salt or solvate thereof, The peptide inhibitors are cyclized via a Pen-Pen disulfide bond.

[0185] In certain embodiments, the peptide comprises or is Ac-[Pen]-NT-[W(5-F)]-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 7).

[0186] In certain embodiments, the peptide comprises or is Ac-[Pen]-NTW-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-W(5-OH)-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 21).

[0187] In certain embodiments, any Phe[4-(2-aminoethoxy)] residue present in the peptide inhibitors described herein may be replaced with Phe[4-(2-acetylaminoethoxy)].

[0188] In additional embodiments, the invention includes peptide inhibitors comprising peptides comprising variants of Formula (I)-(XIf), or any of the sequences set forth in Table E1, Table E2, or Table E3, comprising an isostere substitution of one or more amino acid residues at X4 through X15. In specific embodiments, the isostere substitution is a conservative amino acid substitution, and in certain embodiments, the isostere substitution is a substitution with an amino acid analog.

[0189] In additional embodiments, the invention includes peptide inhibitors comprising peptides comprising variants of Formula (I)-(XIf), or any of the sequences shown in Tables E1, E2, or E3, which comprise different amino acid residues (or chemical entities) at one or both of amino acid residues X4 and X9, but where the amino acid residues at X4 and X9 can be linked to each other, for example, to form an intramolecular bond within the peptide or a triazole ring. In specific embodiments, the bond is a disulfide bond, a thioether bond, a lactam bond, a triazole ring, a selenoether bond, a diselenide bond, or an olefin bond.

[0190] In a specific embodiment, the peptide inhibitor is Ac-[Pen]-NT-[W(6-Cl)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 228) Contains or consists of.

[0191] In a specific embodiment, the peptide inhibitor is Ac-[Pen]-NT-[W(1-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 232) Contains or consists of.

[0192] In a specific embodiment, the peptide inhibitor is

[0193] Ac-[Pen]-[Cit]-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 238) Contains or consists of.

[0194] In a specific embodiment, the peptide inhibitor is Ac-[Pen]-[Lys(Ac)]-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 239) Contains or consists of.

[0195] Representative disulfide and thioether bonds In one embodiment, the Cys and Cys disulfide bonds are as shown below: [ka]

[0196] In one embodiment, the Pen and Pen disulfide bonds are as shown below: [ka]

[0197] In one embodiment, the Abu and Cys thioether bonds are as shown below: [ka]

[0198] In a specific embodiment, the peptide inhibitor is Ac-[Pen]-[Cit]-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 238) [ka] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH2 (SEQ ID NO: 242) [ka] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 245)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

[0199] Additional Features of Peptide Inhibitors Any peptide inhibitor of the invention may be further defined, for example as described below. Each of the further defining features described herein may be applied to any peptide inhibitor in which the amino acid specified at a particular position permits the presence of that further defining feature. In specific embodiments, these features may be present in any peptide of formula (I)-(XIf).

[0200] In various embodiments, R 1 R is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, or C1-C20 alkanoyl, including PEGylated versions of any of the above alone or as a spacer, e.g., acetyl. 1 It is understood that R may be present in place of or in addition to the typical amine group located at the amino terminus of a peptide. 1 It is further understood that R may be absent. In certain embodiments, the peptide inhibitor comprises an N-terminus selected from hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, or C1-C20 alkanoyl (including PEGylated versions of any of the above alone or as a spacer), e.g., acetyl. In specific embodiments of any of the peptide inhibitors described herein, R 1 Or the N-terminal moiety is hydrogen. In certain embodiments, R 1 is a bond, e.g., a covalent bond.

[0201] In certain embodiments of any peptide inhibitor having any of the various formulas described herein, R 1 Or the N-terminal moiety is selected from methyl, acetyl, formyl, benzoyl, trifluoroacetyl, isovaleryl, isobutyryl, octanyl, and conjugated amides of lauric acid, hexadecanoic acid, and γ-Glu-hexadecanoic acid. 1 Or the N-terminal portion is pGlu. 1 is hydrogen. In specific embodiments, R 1 is acetyl, whereby the peptide inhibitor is acylated at its N-terminus, e.g., to cap or protect the N-terminal amino acid residue, e.g., the N-terminal Pen residue.

[0202] In certain embodiments of any of the peptide inhibitors described herein, R 1 Or the N-terminal moiety is an acid. In certain embodiments, R 1 or the N-terminal moiety is an acid selected from acetic acid, formic acid, benzoic acid, trifluoroacetic acid, isovaleric acid, isobutyric acid, octanoic acid, lauric acid, hexadecanoic acid, 4-biphenylacetic acid, 4-fluorophenylacetic acid, gallic acid, pyroglutamic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, 4-methylbicyclo(2.2.2)-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, alkylsulfonic acids, and arylsulfonic acids.

[0203] In specific embodiments, R 1 Or the N-terminal moiety is an alkylsulfonic acid selected from methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, and 2-hydroxyethanesulfonic acid.

[0204] In specific embodiments, R 1 Or the N-terminal moiety is an arylsulfonic acid selected from benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, and camphorsulfonic acid.

[0205] Peptide dimers In certain embodiments, the present invention includes dimers of the monomeric peptide inhibitors described herein, including dimers of any of the monomeric peptide inhibitors described herein or in the accompanying tables. These dimers fall within the general term "peptide inhibitor" as used herein. Illustrative dimers of the present invention are also shown in the accompanying tables, which indicate the dimerized monomeric subunits in brackets, followed by a linker. Unless otherwise indicated, the subunits are linked via their C-terminus. The term "dimer," as in peptide dimer, refers to a compound in which two peptide monomeric subunits are linked. The peptide dimeric inhibitors of the present invention may include two identical monomeric subunits, resulting in a homodimer, or two non-identical monomeric subunits, resulting in a heterodimer. A cysteine ​​dimer includes two peptide monomeric subunits linked through a disulfide bond between a cysteine ​​residue in one monomeric subunit and a cysteine ​​residue in the other monomeric subunit.

[0206] In some embodiments, the peptide inhibitor of the present invention can be active in dimeric conformation, specifically when free cysteine ​​residues are present in peptide.In certain embodiments, this occurs either as a synthesized dimer, or specifically when free cysteine ​​monomer peptides are present and dimerize under oxidizing conditions.In some embodiments, the dimer is a homodimer.In other embodiments, the dimer is a heterodimer.

[0207] In certain embodiments, the monomer subunits of the present invention may be dimerized by a suitable linking moiety, such as a disulfide bridge between two cysteine ​​residues, one in each peptide monomer subunit, or another suitable linker moiety, including but not limited to those defined herein.Some of the monomer subunits are shown with C- and N-termini, both of which contain free amines.Therefore, to produce peptide dimeric inhibitors, the monomer subunits may be modified to eliminate either the C- or N-terminal free amine, thereby allowing dimerization at the remaining free amine. Further, in some cases, one or more of the monomer subunits are acylated with an acylating organic compound selected from the group consisting of trifluoropentyl, acetyl, octenyl, butyl, pentyl, hexyl, palmityl, trifluoromethylbutyric acid, cyclopentane carboxylic acid, cyclopropyl acetic acid, 4-fluorobenzoic acid, 4-fluorophenyl acetic acid, 3-phenylpropionic acid, tetrahydro-2H-pyran-4 carboxylic acid, succinic acid, and glutaric acid. In some cases, the monomer subunits include both free carboxy and free amino termini, allowing the user to selectively modify the subunits to achieve dimerization at the desired termini. Those skilled in the art will therefore appreciate that the monomer subunits of the present invention may be selectively modified to achieve a single specific amine for the desired dimerization.

[0208] It is further understood that the C-terminal residue of the monomer subunit disclosed herein is optionally an amide.Furthermore, it is understood that in certain embodiments, dimerization at the C-terminus is promoted by using a suitable amino acid with a side chain having an amine functionality, as is generally understood in the art.With respect to the N-terminal residue, it is generally understood that dimerization can be achieved through the free amine of the terminal residue, or by using a suitable amino acid side chain with a free amine, as is generally understood in the art.

[0209] The linker moiety connecting the monomeric subunits may comprise any structure, length, and / or size compatible with the teachings herein. In at least one embodiment, the linker moiety is selected from the non-limiting group consisting of cysteine, lysine, DIG, PEG4, PEG4-biotin, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, ADA, Boc-IDA, glutaric acid, isophthalic acid, 1,3-phenylene diacetic acid, 1,4-phenylene diacetic acid, 1,2-phenylene diacetic acid, triazine, Boc-triazine, IDA-biotin, PEG4-biotin, AADA, suitable aliphatic groups, aromatic groups, heterocyclic aromatic groups, and polyethylene glycol-based linkers having a molecular weight of about 400 Da to about 40,000 Da. In certain embodiments, PEG2 is HO2CCH2CH2OCH2CH2OCH2CH2CO2H. Non-limiting examples of suitable linker moieties are provided in Table 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0210] In some embodiments, the peptide dimer inhibitor is dimerized through a linker moiety. In some embodiments, the peptide dimer inhibitor is dimerized through an intermolecular disulfide bond formed between two cysteine ​​residues, one in each monomer subunit. In some embodiments, the peptide dimer inhibitor is dimerized through both a linker moiety and an intermolecular disulfide bond formed between two cysteine ​​residues. In some embodiments, the intramolecular bond is thioether, lactam, triazole, selenoether, diselenide or olefin instead of disulfide bond.

[0211] Those skilled in the art will understand that the linker (e.g., C- and N-terminal linkers) moieties disclosed herein are non-limiting examples of suitable linkers, and the present invention may include any suitable linker moiety. Thus, some embodiments of the present invention include homo- or heterodimeric peptide inhibitors comprising two monomeric subunits selected from peptides comprising or consisting of sequences shown in any table herein or presented in any table herein, wherein the C- or N-terminus (or internal amino acid residue) of each monomeric subunit is linked by any suitable linker moiety to provide a dimeric peptide inhibitor having IL-23R inhibitory activity. In certain embodiments, the linker is attached to the N- or C-terminus of one monomeric subunit and to an internal amino acid residue of the other monomeric subunit that constitutes the dimer. In certain embodiments, the linker is attached to an internal amino acid residue of one monomeric subunit and to an internal amino acid residue of the other monomeric subunit that constitutes the dimer. In further embodiments, the linker is attached to the N- or C-terminus of both subunits.

[0212] In specific embodiments, one or both of the monomeric subunits comprises any one of Formulas (I)-(XIf), or any peptide sequence or structure shown in Table E1, Table E2, or Table E3, or described herein.

[0213] In certain embodiments, the peptide dimer inhibitor has formula XII: (R 1 -XR 2 )2-L(XII)

[0214] or a pharma- ceutically acceptable salt or solvate thereof,

[0215] In formula XII, each R 1 is independently absent, a bond (e.g., a covalent bond), or R1 is selected from hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 alkanoyl (including PEGylated versions of any of the above alone or as a spacer);

[0216] Each R 2 is independently absent, a bond (e.g., a covalent bond), or selected from OH or NH2, L is a linker moiety, and each X is an independently selected peptide monomer subunit comprising a sequence of formula (I)-(XIf) as described herein. In certain embodiments, one or both peptide monomer subunits of the peptide dimeric inhibitor are cyclized, for example, via an intramolecular bond between X4 and X9. In certain embodiments, one or both peptide monomer subunits are linear or non-cyclized.

[0217] In specific embodiments, each R 1are independently a bond (e.g., a covalent bond) or selected from hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 alkanoyl (including PEGylated versions of any of the above alone or as a spacer). In specific embodiments, the N-terminus of each subunit comprises a moiety selected from hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 alkanoyl (including PEGylated versions of any of the above alone or as a spacer).

[0218] In certain embodiments of any peptide inhibitor having any of the various formulas described herein, each R 1 (or the N-terminal moiety) is selected from methyl, acetyl, formyl, benzoyl, trifluoroacetyl, isovaleryl, isobutyryl, octanyl, and conjugated amides of lauric acid, hexadecanoic acid, and γ-Glu-hexadecanoic acid.

[0219] In specific embodiments, each R 2 (or the C-terminal portion) is independently a bond (eg, a covalent bond), or selected from OH or NH2.

[0220] In specific embodiments of any of the peptide dimeric inhibitors described herein, either or both R 1 is hydrogen.

[0221] In specific embodiments of the peptide dimeric inhibitors of the invention, the linker moiety (L) is any linker described herein or shown in Table 1 or Table 7. In certain embodiments, L is a lysine linker, a diethylene glycol linker, an iminodiacetic acid (IDA) linker, a β-Ala-iminodiacetic acid (β-Ala-IDA) linker, or a PEG linker.

[0222] In various embodiments of any peptide dimeric inhibitor, each of the peptide monomer subunits is attached to a linker moiety via its N-terminus, C-terminus, or internal amino acid residue. In certain embodiments of any peptide dimeric inhibitor, the N-terminus of each peptide monomer subunit is connected by a linker moiety. In certain embodiments of any peptide dimeric inhibitor, the C-terminus of each peptide monomer subunit is connected by a linker moiety. In certain embodiments of any peptide dimeric inhibitor, each peptide monomer subunit is connected by a linker moiety attached to an internal amino acid.

[0223] Peptide Inhibitor Conjugates and Biopolymers In certain embodiments, the peptide inhibitor of the present invention, including both monomers and dimers, comprises one or more conjugated chemical substituents, such as lipophilic substituents and polymer moieties, which may be referred to herein as half-life extending moieties.Without wishing to be bound by any specific theory, it is believed that lipophilic substituents bind to albumin in bloodstream, thereby protecting peptide inhibitors from enzymatic degradation, and thus enhancing their half-life.In addition, it is believed that polymer moieties enhance half-life and reduce clearance in bloodstream.

[0224] In additional embodiments, any of the peptide inhibitors, e.g., the peptides of Formulae (I)-(XIf), further comprise a linker moiety attached to an amino acid residue present in the inhibitor, e.g., the linker moiety may be attached to the side chain of any amino acid of the peptide inhibitor, to the N-terminal amino acid of the peptide inhibitor, or to the C-terminal amino acid of the peptide inhibitor.

[0225] In additional embodiments, any of the peptide inhibitors, e.g., the peptides of Formulae (I)-(XIf), further comprise a half-life extending moiety attached to an amino acid residue present in the inhibitor, e.g., the half-life extending moiety may be attached to the side chain of any amino acid of the peptide inhibitor, to the N-terminal amino acid of the peptide inhibitor, or to the C-terminal amino acid of the peptide inhibitor.

[0226] In additional embodiments, any of the peptide inhibitors, e.g., peptides of Formula (I)-(XIf), further comprise a half-life extending moiety attached to a linker moiety attached to an amino acid residue present in the inhibitor, e.g., the half-life extending moiety may be attached to the side chain of any amino acid of the peptide inhibitor, to the N-terminal amino acid of the peptide inhibitor, or to a linker moiety attached to the C-terminal amino acid of the peptide inhibitor.

[0227] In specific embodiments, the peptide inhibitor comprises a half-life extending moiety having the structure shown below, where n=0-24 or n=14-24: [ka]

[0228] In certain embodiments, the peptide inhibitors of the invention comprise a half-life extending moiety as shown in Table 8. [Table 8-1] [Table 8-2]

[0229] In certain embodiments, the half-life extending moiety is directly attached to the peptide inhibitor, while in other embodiments, the half-life extending moiety is attached to the peptide inhibitor via a linker moiety, e.g., any of those depicted in Tables 1, 2, or 4. [Table 4-1] [Table 4-2] [Table 4-3]

[0230] In specific embodiments, the peptide inhibitors of the invention comprise any linker moiety shown in Table 2 or Table 4 and any half-life extending moiety shown in Table 3, including any of the following combinations shown in Table 5: [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0231] In some embodiments, there may be multiple linkers between the peptide and the conjugated moiety, e.g., half-life extending moiety, as depicted in Table 6. [Table 6]

[0232] In certain embodiments, the half-life of the peptide inhibitors of the invention comprising a conjugated chemical substituent, i.e., a half-life extending moiety, is at least 100%, at least 120%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400%, or at least 500% of the half-life of the same peptide inhibitor without the conjugated chemical substituent. In certain embodiments, the lipophilic substituent and / or the polypermic moieties enhance the permeability of the peptide inhibitor through the epithelium and / or its retention in the lamina propria. In certain embodiments, the permeability of the peptide inhibitors of the invention comprising a conjugated chemical substituent through the epithelium and / or its retention in the lamina propria is 100%, at least 120%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400%, or at least 500% of the half-life of the same peptide inhibitor without the conjugated chemical substituent.

[0233] In one embodiment, the side chain of one or more amino acid residues (e.g., Lys residues) in the peptide inhibitors of the invention is conjugated (e.g., covalently attached) to a lipophilic substituent. The lipophilic substituent may be covalently attached to an atom in the amino acid side chain or, alternatively, may be conjugated to the amino acid side chain via one or more spacers. If a spacer is present, it may provide spacing between the peptide analog and the lipophilic substituent. In a specific embodiment, the peptide inhibitor comprises any of the conjugated moieties shown in the peptides disclosed in Tables 2-6.

[0234] In certain embodiments, the lipophilic substituent may comprise a hydrocarbon chain having 4 to 30 C atoms, for example at least 8 or 12 C atoms, preferably 24 or fewer C atoms, or 20 or fewer C atoms. The hydrocarbon chain may be linear or branched, saturated or unsaturated. In certain embodiments, the hydrocarbon chain is substituted with a moiety that forms part of the attachment to the amino acid side chain or spacer, for example an acyl group, a sulfonyl group, an N atom, an O atom or an S atom. In some embodiments, the hydrocarbon chain is substituted with an acyl group, so that the hydrocarbon chain may form part of an alkanoyl group, for example palmitoyl, caproyl, lauroyl, myristoyl or stearoyl.

[0235] Lipophilic substituents may be conjugated to any amino acid side chain in the peptide inhibitors of the present invention. In certain embodiments, the amino acid side chain comprises a carboxy, hydroxyl, thiol, amide or amine group to form an ester, sulfonyl ester, thioester, amide or sulfonamide with a spacer or lipophilic substituent. For example, lipophilic substituents may be conjugated to Asn, Asp, Glu, Gln, His, Lys, Arg, Ser, Thr, Tyr, Trp, Cys or Dbu, Dpr or Orn. ​​In certain embodiments, lipophilic substituents are conjugated to Lys. The amino acid shown as Lys in any formula provided herein may be replaced by, for example, Dbu, Dpr or Orn to which lipophilic substituents are added.

[0236] In certain embodiments, the peptide inhibitors of the present invention may be modified through the conjugation of chemical moieties to one or more amino acid side chains in the peptide, for example, to enhance stability, increase permeability, or enhance drug-like characteristics. For example, the N(epsilon) of lysine N(epsilon), the β-carboxyl of aspartic acid, or the γ-carboxyl of glutamic acid may be appropriately functionalized. Thus, to produce modified peptides, amino acids in the peptide may be appropriately modified. Furthermore, in some cases, the side chains are acylated with an acylating organic compound selected from the group consisting of trifluoropentyl, acetyl, octenyl, butyl, pentyl, hexyl, palmityl, trifluoromethylbutyric acid, cyclopentane carboxylic acid, cyclopropyl acetic acid, 4-fluorobenzoic acid, 4-fluorophenyl acetic acid, 3-phenylpropionic acid, tetrahydro-2H-pyran-4 carboxylic acid, succinic acid, glutaric acid, or bile acid. Those skilled in the art will appreciate that a range of conjugates can be linked, such as, for example, PEG4, isoglu and combinations thereof. Those skilled in the art will appreciate that amino acids can be isosterically replaced with peptides, for example, Lys can be replaced with Dap, Dab, α-MeLys or Orn. ​​Examples of modified residues in peptides are shown in Table 7. [Table 7-1] [Table 7-2]

[0237] In further embodiments of the invention, alternatively or additionally, the side chains of one or more amino acid residues in the peptide inhibitors of the invention are conjugated to a polymer moiety, for example to increase solubility and / or half-life in vivo (e.g., in plasma) and / or bioavailability. Such modifications are also known to reduce the clearance (e.g., renal clearance) of therapeutic proteins and peptides.

[0238] As used herein, "polyethylene glycol" or "PEG" is a polyether compound of the general formula H-(O-CH2-CH2)n-OH. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), and depending on the molecular weight, PEO, PEE, or POG, as used herein, refer to oligomers or polymers of ethylene oxide. Although the three names are chemically synonymous, PEG tends to refer to oligomers and polymers with molecular weights below 20,000 Da, PEO to polymers with molecular weights above 20,000 Da, and POE to polymers of any molecular weight. PEG and PEO are liquids or low melting solids, depending on the molecular weight. Throughout this disclosure, the three names are used interchangeably. PEG is prepared by polymerization of ethylene oxide and is commercially available over a wide range of molecular weights, from 300 Da to 10,000,000 Da. PEG and PEO with different molecular weights have uses in different applications and have different physical properties (e.g., viscosity) due to chain length effects, but their chemical properties are nearly identical. The polymer moiety is preferably water-soluble (amphiphilic or hydrophilic), non-toxic, and pharma- ceutical inert. Suitable polymer moieties include polyethylene glycol (PEG), homo- or copolymers of PEG, monomethyl-substituted polymers of PEG (mPEG), or polyoxyethylene glycerol (POG). See, for example, Int. J. Hematology 68:1 (1998); Bioconjugate Chem. 6:150 (1995); and Crit. Rev. Therap. Drug Carrier Sys. 9:249 (1992). Also included are PEGs prepared for the purpose of half-life extension, e.g., monoactivated alkoxy-terminated polyalkylene oxides (POA's), e.g., monomethoxy-terminated polyethyelene glycols (mPEG's), bis-activated polyethylene oxides (glycols) or other PEG derivatives are also contemplated. Suitable polymers vary substantially in weight within the range of about 200 Da to about 40,000 Da, with about 200 Da to about 60,000 Da typically being selected for purposes of the present invention.Certain embodiments use PEG with molecular weights of 200 to 2,000 or 200 to 500. Different forms of PEG may be used depending on the initiator used for the polymerization process, with a common generic initiator being monofunctional methyl ether PEG, or methoxypoly(ethylene glycol), abbreviated as mPEG.

[0239] Lower molecular weight PEG is also available as pure oligomers, termed monodisperse, uniform, or discrete, and these find use in certain embodiments of the invention.

[0240] PEGs with different geometries are also available, with branched PEGs having 3-10 PEG chains emanating from a central core group, star PEGs having 10-100 PEG chains emanating from a central core group, and comb PEGs having multiple PEG chains usually grafted to the polymer backbone. PEGs can also be linear. The number often included in the name of the PEG indicates the average molecular weight, such as a PEG with n=9, which has an average molecular weight of about 400 daltons and is labeled PEG400.

[0241] As used herein, "PEGylation" refers to the act of covalently coupling a PEG structure to a peptide inhibitor of the invention, which is then referred to as a "PEGylated peptide inhibitor." In certain embodiments, the PEG of the PEGylated side chain is a PEG having a molecular weight of about 200 to about 40,000. In some embodiments, the spacer of the peptide of Formula I, Formula I', or Formula I'' is PEGylated. In certain embodiments, the PEG of the PEGylated spacer is PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, or PEG11. In certain embodiments, the PEG of the PEGylated spacer is PEG3 or PEG8.

[0242] Other suitable polymer moieties include polyamino acids, such as polylysine, polyaspartic acid, and polyglutamic acid (see, e.g., Gombotz, et al. (1995), Bioconjugate Chem., vol. 6:332-351; Hudecz, et al. (1992), Bioconjugate Chem., vol. 3, 49-57, and Tsukada, et al. (1984), J. Natl. Cancer Inst., vol. 73,:721-729. The polymer moiety may be linear or branched. In some embodiments, it has a molecular weight of 500 to 40,000 Da, e.g., 500 to 10,000 Da, 1000 to 5000 Da, 10,000 to 20,000 Da, or 20,000 to 40,000 Da.

[0243] In some embodiments, the peptide inhibitors of the invention may include two or more such polymer moieties, in which case the total molecular weight of all such moieties will generally fall within the ranges provided above.

[0244] In some embodiments, the polymer moiety is coupled (by a covalent linkage) to the amino, carboxyl or thiol group of an amino acid side chain. Certain examples are the thiol group of Cys residues and the epsilon amino group of Lys residues, although the carboxyl groups of Asp and Glu residues may also be involved.

[0245] Those skilled in the art are well aware of suitable techniques that can be used to carry out coupling reactions.For example, PEG moieties bearing methoxy groups can be coupled to Cys thiol groups via maleimide linkages using commercially available reagents from Nektar Therapeutics AL.For details of suitable chemistries, see also WO2008 / 101017 and the references cited above.Maleimide-functionalized PEG can also be conjugated to the side chain sulfhydryl groups of Cys residues.

[0246] As used herein, oxidation of disulfide bonds can occur in a single step or is a two-step process. As used herein, for a single oxidation step, a trityl protecting group is often used during assembly to allow deprotection during cleavage, followed by solution oxidation. If a second disulfide bond is required, there are options for natural or selective oxidation. For selective oxidation, which requires orthogonal protecting groups, Acm and trityl are used as protecting groups for cysteines. Cleavage results in the removal of one protecting pair of cysteines to allow oxidation of this pair. A second oxidative deprotection step of the cysteine-protecting Acm group is then performed. For natural oxidation, a trityl protecting group is used for all cysteines to allow native folding of the peptide. Those skilled in the art are well aware of suitable techniques that can be used to perform the oxidation step.

[0247] Several chemical moieties, including poly(ethylene) glycol, react with functional groups present in the 20 naturally occurring amino acids, such as the epsilon amino group in lysine amino acid residues, cysteine ​​amino acid residues, or thiols present in other nucleophilic amino acid side chains. When multiple naturally occurring amino acids react in a peptide inhibitor, these non-specific chemical reactions result in a final peptide inhibitor that contains many isomers of the peptide conjugated to one or more poly(ethylene) glycol chains at different positions within the peptide inhibitor.

[0248] One advantage of certain embodiments of the present invention includes the ability to add one or more chemical moieties (e.g., PEG) by incorporating one or more unnatural amino acids with unique functional groups that react with activated PEG through chemistry that is unreactive with naturally occurring amino acids present in the peptide inhibitor. For example, azide and alkyne groups are unreactive with all naturally occurring functional groups in proteins. Thus, unnatural amino acids may be incorporated at one or more specific sites in the peptide inhibitor where PEG or another modification is desired without undesired non-specific reactions. In certain embodiments, the specific chemistry involved in the reaction results in a stable covalent linkage between the PEG chain and the peptide inhibitor. Additionally, such reactions may be performed in mild aqueous conditions that are not damaging to most peptides. In certain embodiments, the unnatural amino acid residue is AHA.

[0249] Chemical moieties attached to natural amino acids are limited in number and scope. In contrast, chemical moieties attached to unnatural amino acids can utilize a significantly wider range of useful chemistries for attaching chemical moieties to target molecules. Essentially any target molecule can serve as a substrate for attaching chemical moieties, including any protein (or part thereof) that contains unnatural amino acids, e.g., unnatural amino acids that contain reactive sites or side chains to which chemical moieties can be attached, e.g., aldehyde or keto derivatized amino acids.

[0250] Numerous chemical moieties can be conjugated or linked to specific molecules through various methods known in the art. Various such methods are described in U.S. Pat. No. 8,568,706. By way of illustration, azide moieties can be useful in conjugating chemical moieties such as PEG or others described herein. Azide moieties act as reactive functional groups and are absent in most naturally occurring compounds (and therefore are non-reactive with the natural amino acids of naturally occurring compounds). Azides also undergo selective ligation with a limited number of reaction partners, and azides are small and can be introduced into biological samples without significantly changing the molecular size. One reaction that allows the incorporation or introduction of azides into molecules is the copper-mediated Huisgen [3+2] cycloaddition of azides. This reaction can be used for selective PEG of peptide inhibitors. (Tornoe et al., J.Org.Chem.67:3057,2002; Rostovtsev et al.,Angew.Chem.,Int.Ed.41:596,2002; and Wang et al.,J.Am.Chem.Soc.125:3192,2003,Speers et al. al., J. Am. Chem. Soc., 2003, 125, 4686).

[0251] Synthesis of peptide inhibitors The peptide inhibitors of the present invention can be synthesized by a number of techniques known to those of skill in the art. In certain embodiments, the monomeric subunits are synthesized, purified, and dimerized using the techniques described in the accompanying examples. In certain embodiments, the present invention provides a method of producing the peptide inhibitors of the present invention (or monomeric subunits thereof) comprising chemically synthesizing a peptide comprising, consisting of, or consisting essentially of a peptide having an amino acid sequence as described herein, including but not limited to any amino acid sequence shown in Formula I, II, or any of the tables herein. In other embodiments, the peptide is recombinantly synthesized instead of being chemically synthesized. In certain embodiments, the peptide inhibitor is a dimer, and the method comprises synthesizing both monomeric subunits of the peptide dimeric inhibitor and then dimerizing the two monomeric subunits to produce the peptide dimeric inhibitor. In various embodiments, the dimerization is achieved via any of the various methods described herein. In specific embodiments, the method of producing the peptide inhibitor (or monomeric subunits thereof) further comprises cyclizing the peptide inhibitor (or monomeric subunits thereof) after its synthesis. In specific embodiments, cyclization is accomplished via any of the various methods described herein. In certain embodiments, the present invention provides methods of making a peptide inhibitor of the present invention (or a monomeric subunit thereof) comprising introducing an intramolecular bond, e.g., a disulfide, amide, or thioether bond, between two amino acid residues in a peptide comprising, consisting of, or consisting essentially of a peptide having an amino acid sequence described herein, including but not limited to any of the amino acid sequences shown in any of the formulas (I)-(IX) or the accompanying Examples or Tables.

[0252] In related embodiments, the invention includes a polynucleotide encoding a polypeptide having a sequence as shown in any one of Formulas (I)-(IX), or the accompanying Examples or Tables.

[0253] Additionally, the present invention includes vectors, eg, expression vectors, comprising the polynucleotides of the present invention.

[0254] Treatment method In certain embodiments, the present invention includes a method for inhibiting the binding of IL-23 to IL-23R on a cell, comprising contacting IL-23 with a peptide inhibitor of the present invention. In certain embodiments, the cell is a mammalian cell. In specific embodiments, the method is performed in vitro or in vivo. Inhibition of binding may be determined by a variety of routine experimental methods and assays known in the art.

[0255] In certain embodiments, the present invention includes a method for inhibiting IL-23 signaling by a cell, comprising contacting IL-23 with a peptide inhibitor of the present invention. In certain embodiments, the cell is a mammalian cell. In specific embodiments, the method is performed in vitro or in vivo. In specific embodiments, inhibition of IL-23 signaling may be determined by measuring changes in phospho-STAT3 levels in the cell.

[0256] In some embodiments, the invention provides a method of treating a subject suffering from a condition or indication associated with IL-21 or IL-23R (e.g., activation of the IL-23 / IL-23R signaling pathway), comprising administering to the subject a peptide inhibitor of the invention. In one embodiment, a method of treating a subject suffering from a condition or indication characterized by inappropriate, dysregulated, or increased IL-23 or IL-23R activity or signaling is provided, comprising administering to the individual a peptide inhibitor of the invention in an amount sufficient to inhibit (partially or completely) binding of IL-23 to IL-23R in the subject. In a specific embodiment, inhibition of IL-23 binding to IL-23R occurs in a specific organ or tissue of the subject, e.g., stomach, small intestine, large intestine / colon, intestinal mucosa, lamina propria, Peyer's patches, mesenteric lymph nodes, or lymphatic vessels.

[0257] In some embodiments, the methods of the invention comprise providing a peptide inhibitor of the invention to a subject in need thereof. In a specific embodiment, the subject in need thereof is one who has been diagnosed with, or determined to be at risk for developing, a disease or disorder associated with IL-23 / IL-23R. In a specific embodiment, the subject is a mammal.

[0258] In certain embodiments, the disease or disorder is autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease (IBD), juvenile IBD, adolescent IBD, Crohn's disease, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, or psoriasis. In specific embodiments, the disease or disorder is psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, plaque psoriasis, or erythrodermic psoriasis), atopic dermatitis, ectopic acne (acne ectopica), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radiation or chemotherapy, colitis associated with impaired innate immunity as in leukocyte adhesion deficiency type 1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, pouchitis, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cholangitis, viral-associated enteropathy, pericholeductitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease.

[0259] In certain related embodiments, the present invention provides a method of selectively inhibiting IL-23 or IL-23R signaling (or binding of IL-23 to IL-23R) in a subject in need thereof, comprising providing a peptide inhibitor of the present invention to the subject. In a specific embodiment, the present invention includes a method of selectively inhibiting IL-23 or IL-23R signaling (or binding of IL-23 to IL-23R) in the GI tract of a subject in need thereof, comprising providing a peptide inhibitor of the present invention to the subject by oral administration. In a specific embodiment, the exposure of the administered peptide inhibitor in the GI tissue (e.g., small intestine or colon) is at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold higher than the exposure in the blood. In a specific embodiment, the present invention includes a method of selectively inhibiting IL23 or IL23R signaling (or binding of IL23 to IL23R) in the GI tract of a subject in need thereof, comprising providing a peptide inhibitor to the subject, wherein the peptide inhibitor does not block the interaction of IL-6 with IL-6R and does not antagonize the IL-12 signaling pathway. In further related embodiments, the invention includes a method of inhibiting GI inflammation and / or neutrophil infiltration into the GI, comprising providing a peptide inhibitor of the invention to a subject in need thereof. In some embodiments, the method of the invention includes providing a peptide inhibitor of the invention (i.e., a first therapeutic agent) in combination with a second therapeutic agent to a subject in need thereof. In certain embodiments, the second therapeutic agent is provided to the subject before and / or simultaneously and / or after the peptide inhibitor is administered to the subject. In a specific embodiment, the second therapeutic agent is an anti-inflammatory agent. In certain embodiments, the second therapeutic agent is a nonsteroidal anti-inflammatory drug, a steroid, or an immunomodulatory agent. In another embodiment, the method includes administering a third therapeutic agent to the subject. In certain embodiments, the second therapeutic agent is an antibody that binds to IL-23 or IL-23R.

[0260] In a specific embodiment, the peptide inhibitor or pharmaceutical composition comprising the peptide inhibitor is suspended in a sustained release matrix. A sustained release matrix, as used herein, is a matrix made of a material, usually a polymer, that can be degraded by enzyme or acid-base hydrolysis or by dissolution. When inserted into the body, the matrix is ​​acted upon by enzymes and body fluids. The sustained release matrix is ​​preferably selected from biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolides (polymers of glycolic acid), polylactide co-glycolides (copolymers of lactic acid and glycolic acid), polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinylpropylene, polyvinylpyrrolidone and silicone. One embodiment of a biodegradable matrix is ​​a matrix of either polylactide, polyglycolide, or polylactide-co-glycolide (a copolymer of lactic acid and glycolic acid).

[0261] In certain embodiments, the present invention includes pharmaceutical compositions comprising one or more peptide inhibitors of the present invention and a pharma- ceutically acceptable carrier, diluent or excipient. A pharma- ceutically acceptable carrier, diluent or excipient refers to any type of non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid. Prevention of microbial action can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, and phenol sorbic acid. It may also be desirable to include isotonic agents, such as sugars and sodium chloride.

[0262] In certain embodiments, the composition is administered orally, parenterally, intravesically, intravaginally, intraperitoneally, rectally, topically (by powder, ointment, drops, suppository, or transdermal patch), by inhalation (e.g., intranasal spray), ocularly (e.g., intraocularly) or bucally. The term "parenteral" as used herein refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal, and intraarticular injection and infusion. Thus, in certain embodiments, the composition is formulated for delivery by any of these administration routes.

[0263] In certain embodiments, pharmaceutical compositions for parenteral injection include pharma- ceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders, for reconstitution immediately before use into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, and polyethylene glycol, etc.), carboxymethylcellulose and suitable mixtures thereof, β-cyclodextrin, vegetable oils (e.g., olive oil), and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. The compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prolonged absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0264] Injectable depot forms include those made by forming microencapsule matrices of peptide inhibitors in one or more biodegradable polymers, such as polylactide-polyglycolide, poly(orthoesters), poly(anhydrides), and (poly)glycols, such as PEG.Depending on the ratio of peptide to polymer and the nature of the specific polymer used, the release rate of peptide inhibitors can be controlled.Depot injectable formulations are also prepared by encapsulating peptide inhibitors in liposomes or microemulsions that are compatible with body tissues.

[0265] The injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water, or other sterile injectable medium immediately before use.

[0266] External administration includes administration to the skin or mucous membranes, including the lungs and the eye surface. Compositions for external pulmonary administration, including those for inhalation and intranasal use, may involve solutions and suspensions in aqueous and non-aqueous formulations, and may be prepared as dry powders, which may be pressurized or non-pressurized. In non-pressurized powder compositions, the active ingredient may be in finely divided form, or may be used in admixture with a pharma- ceutically acceptable inert carrier of larger size, including particles with a diameter of up to 100 micrometers. Suitable inert carriers include sugars such as lactose.

[0267] Alternatively, the composition may be pressurized and contain compressed gas, such as nitrogen or liquefied gaseous propellant. The liquefied propellant medium, and indeed the entire composition, may be such that the active ingredient does not dissolve therein to any substantial extent. The pressurized composition may also contain a surfactant, such as a liquid or solid non-ionic surfactant, or a solid anionic surfactant. It is preferred to use a solid anionic surfactant in the form of a sodium salt.

[0268] Another form of external administration is to the eye.The peptide inhibitor of the present invention may be delivered in a pharmaceutically acceptable ophthalmic vehicle so that the peptide inhibitor maintains contact with the ocular surface for a sufficient period of time to allow the peptide inhibitor to penetrate the cornea and internal regions of the eye, such as the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris / ciliary body, lens, choroid / retina and sclera.The pharmaceutically acceptable ophthalmic vehicle may be, for example, an ointment, vegetable oil or an encapsulating material.Alternatively, the peptide inhibitor of the present invention may be directly injected into the vitreous body and aqueous humor.

[0269] Compositions for rectal or vaginal administration include suppositories, which may be prepared by mixing the peptide inhibitors of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax that is solid at room temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity to release the active compound.

[0270] The peptide inhibitors of the present invention may also be administered in liposomes or other lipid-based carriers. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolayer or multilayer hydrated crystals dispersed in aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid that can form liposomes can be used. The composition of the present invention in liposomal form can contain stabilizers, preservatives, excipients, and the like, in addition to the peptide inhibitors of the present invention. In certain embodiments, the lipid comprises phospholipids, which include phosphatidylcholine (lecithin) and serine, both natural and synthetic. Methods for forming liposomes are known in the art.

[0271] Pharmaceutical compositions used in the present invention suitable for parenteral administration may comprise sterile aqueous solutions and / or suspensions of the peptide inhibitos, generally made isotonic with the blood of the recipient using sodium chloride, glycerin, glucose, mannitol, sorbitol, and the like.

[0272] In some aspects, the present invention provides pharmaceutical compositions for oral delivery.The compositions and peptide inhibitors of the present invention can be prepared for oral administration according to any method, technique, and / or delivery vehicle described herein.Furthermore, those skilled in the art understand that the peptide inhibitors of the present invention can be modified or incorporated into systems or delivery vehicles that are not disclosed herein but are well known in the art and are suitable for use in oral delivery of peptides.

[0273] In certain embodiments, formulations for oral administration may contain adjuvants to artificially increase the permeability of the intestinal wall (e.g., resorcinol and / or non-ionic surfactants, such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether), and / or enzyme inhibitors to inhibit enzymatic degradation (e.g., pancreatic trypsin inhibitor, diisopropyl fluorophosphate (DFF) or trasylol). In certain embodiments, the peptide inhibitors in solid dosage forms for oral administration may be mixed with at least one additive, such as sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers, or glycerides. These dosage forms may also contain other types of additives, such as inert diluents, lubricants, e.g., magnesium stearate, parabens, preservatives, e.g., sorbic acid, ascorbic acid, alpha-tocopherol, antioxidants, e.g., cysteine, disintegrants, binders, thickening agents, buffers, pH adjusting agents, sweetening agents, flavoring agents, or perfuming agents.

[0274] In a specific embodiment, the oral dosage form or unit dose suitable for use with the peptide inhibitor of the present invention may include other non-reusable materials that can be considered as either ingredients or packaging, in addition to the mixture of the peptide inhibitor and non-drug ingredients or excipients. The oral composition may include at least one of liquid, solid, and semi-solid dosage forms. In some embodiments, an oral dosage form is provided that includes an effective amount of the peptide inhibitor, the oral dosage form including at least one of pills, tablets, capsules, gels, pastes, beverages, syrups, ointments, and suppositories. In some cases, an oral dosage form is provided that is designed and configured to achieve delayed release of the peptide inhibitor in the small intestine and / or colon of a subject.

[0275] In one embodiment, oral pharmaceutical compositions comprising the peptide inhibitors of the present invention comprise an enteric coating designed to delay the release of the peptide inhibitor in the small intestine. At least some embodiments provide pharmaceutical compositions comprising the peptide inhibitors of the present invention and a protease inhibitor, such as aprotinin, in a delayed release pharmaceutical formulation. In some cases, pharmaceutical compositions of the present invention comprise an enteric coat that is soluble in gastric juice at a pH of about 5.0 or higher. In at least one embodiment, pharmaceutical compositions are provided that comprise an enteric coating that comprises a polymer with a dissociable carboxy group, such as a derivative of cellulose, including hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate and cellulose acetate trimellitate and similar derivatives of cellulose, as well as other carbohydrate polymers.

[0276] In one embodiment, a pharmaceutical composition is provided that includes the peptide inhibitor of the present invention in an enteric coating, the enteric coating being designed to protect and release the pharmaceutical composition in a controlled manner in the lower gastrointestinal system of a subject, and to avoid systemic side effects.In addition to enteric coating, the peptide inhibitor of the present invention may be encapsulated, coated, engaged or otherwise associated with any compatible oral drug delivery system or component.For example, in some embodiments, the peptide inhibitor of the present invention is provided in a lipid carrier system, including at least one of polymer hydrogels, nanoparticles, microspheres, micelles, and other lipid systems.

[0277] To overcome peptide degradation in the small intestine, some embodiments of the present invention include hydrogel polymer carrier systems in which the peptide inhibitors of the present invention are contained, whereby the hydrogel polymer protects the peptide inhibitors from proteolytic hydrolysis in the small intestine and / or colon. The peptide inhibitors of the present invention may further be formulated for compatible use with carrier systems designed to increase dissolution kinetics and enhance intestinal absorption of the peptides. These methods include the use of liposomes, micelles and nanoparticles to increase GI tract penetration of peptides.

[0278] Various bioresponsive systems can also be combined with one or more of the peptide inhibitors of the present invention to provide a pharmaceutical agent for oral delivery. In some embodiments, the peptide inhibitors of the present invention are used in combination with bioresponsive systems, such as hydrogels and mucoadhesive polymers with hydrogen-bonding groups (e.g., PEG, poly(methacrylic) acid [PMAA], cellulose, Eudragit®, chitosan, and alginate) to provide a therapeutic agent for oral administration. Other embodiments include methods of optimizing or prolonging drug residence time of the peptide inhibitors disclosed herein, where the surface of the peptide inhibitor surface is modified to include mucoadhesive properties through hydrogen bonds, mucin-linked polymers, or / and hydrophobic interactions. These modified peptide molecules can demonstrate increased drug residence time in a subject, according to a desired feature of the present invention. Furthermore, targeted mucoadhesive systems can specifically bind to receptors on the enterocyte and M-cell surfaces, thereby further increasing the uptake of particles containing the peptide inhibitor.

[0279] Other embodiments include methods for oral delivery of the peptide inhibitors of the present invention, in which the peptide inhibitors are provided to a subject in combination with a permeation enhancer that promotes transport of the peptide across the intestinal mucosa by increasing paracellular or transcellular permeation. Various permeation enhancers and methods for oral delivery of therapeutic agents are described in Brayden, DJ, Mrsny, RJ, 2011. Oral peptide delivery: prioritizing the leading technologies. Ther. Delivery 2(12), 1567-1573.

[0280] In certain embodiments, the pharmaceutical compositions and formulations of the present invention comprise the peptide inhibitors of the present invention and one or more permeation enhancers. Examples of absorption enhancers can include, for example, bile salts, fatty acids, surfactants (anionic, cationic, and nonionic) chelators, Zonular OT, esters, cyclodextrins, dextran sulfate, azones, crown ethers, EDTA, sucrose esters, and phosphatidyl choline. Although absorption enhancers are typically not carriers themselves, they are also widely associated with other carriers to improve oral bioavailability by transporting peptides and proteins across the intestinal mucosa. Such substances can be added to the formulation as excipients or incorporated to form nonspecific interactions with the intended peptide inhibitors.

[0281] Dietary ingredients and / or other naturally occurring substances that have been affirmed as enhancing tight junction permeation and as Generally Recognized As Safe (GRAS) include, for example, acylglycerides, acylcarnitines, bile salts, and medium-chain fatty acids. Sodium salts of medium-chain fatty acids (MCFAS) have also been suggested to be permeation enhancers. The most extensively studied MCFAS is sodium caprate, a salt of capric acid, which constitutes 2-3% of the fatty acids in the milk fat fraction. To date, sodium caprate has been used primarily as an excipient in suppository formulations (Doktacillin™) to improve rectal ampicillin absorption. The permeation properties of another dietary MCFAS, sodium caprylate (8 carbons), have been shown in vitro to be lower when compared to sodium caprate. Sodium caprylate and peptide drugs were formulated in oil in admixture with other excipients to produce an oil suspension (OS) that enhances permeability (Tuvia, S. et al., Pharmaceutical Research, Vol. 31, No. 8, pp. 2010-2021 (2014)).

[0282] For example, in one embodiment, a permeation enhancer is combined with a peptide inhibitor, the permeation enhancer comprising at least one of a medium chain fatty acid, a long chain fatty acid, a bile salt, an amphiphilic surfactant, and a chelating agent. In certain embodiments, the medium chain fatty acid salt enhances absorption by increasing the paracellular permeability of the intestinal epithelium. In one embodiment, a permeation enhancer comprising sodium N-[hydroxybenzoyl)amino]caprylate is used to form a weak non-covalent association with the peptide inhibitor of the present invention, which favors membrane transport and further dissociation upon reaching the blood circulation. In another embodiment, the peptide inhibitor of the present invention is conjugated to an oligoarginine, which increases the cellular permeation of the peptide into various cell types. Furthermore, in at least one embodiment, a non-covalent bond is provided between the peptide inhibitor of the present invention and a permeation enhancer selected from the group consisting of cyclodextrins (CDs) and dendrimers, which reduces peptide aggregation and increases the stability and solubility of the peptide inhibitor molecule.

[0283] In certain embodiments, the pharmaceutical composition or formulation comprises a peptide inhibitor of the present invention and a transient permeability enhancer (TPE). The permeability enhancer and TPE may be used to increase the oral bioavailability or peptide inhibitor. One example of a TPE that can be used is an oil suspension formulation that disperses a powder containing sodium caprylate and a therapeutic agent (Tuvia, S. et al., Pharmaceutical Research, Vol. 31, No. 8, pp. 2010-2021 (2014)).

[0284] In certain embodiments, pharmaceutical compositions and formulations may include a peptide inhibitor of the invention and one or more absorption enhancers, enzyme inhibitors, or mucoso adhesive polymers.

[0285] In a specific embodiment, the peptide inhibitors of the present invention are formulated in a formulation vehicle such as an emulsion, liposome, microsphere, or nanoparticle.

[0286] Other embodiments of the invention provide methods of treating a subject with peptide inhibitors of the invention having increased half-life. In one aspect, the invention provides peptide inhibitors having a half-life of at least several hours to a day in vitro or in vivo (e.g., when administered to a human subject) sufficient for daily (qd) or twice daily (bid) administration of a therapeutically effective amount. In another embodiment, the peptide inhibitor has a half-life of 3 days or longer sufficient for weekly (qw) administration of a therapeutically effective amount. Furthermore, in another embodiment, the peptide inhibitor has a half-life of 8 days or longer sufficient for biweekly (biw) or monthly administration of a therapeutically effective amount. In another embodiment, the peptide inhibitor is derivatized or modified to have a longer half-life when compared to a non-derivatized or non-modified peptide inhibitor. In another embodiment, the peptide inhibitor contains one or more chemical modifications to increase serum half-life.

[0287] When used in at least one of the treatments or delivery systems described herein, the peptide inhibitors of the present invention may be used in pure form or, if such form exists, in the form of a pharma- ceutically acceptable salt.

[0288] The total daily dosage of the peptide inhibitors and compositions of the present invention can be determined by the attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject depends on various factors, including a) the disorder being treated and the severity of the disorder, b) the activity of the specific compound used, c) the specific composition used, the age, weight, general health, sex and diet of the patient, d) the time of administration, the route of administration and the rate of excretion of the specific peptide inhibitor used, e) the duration of treatment, f) the drug used in combination with or simultaneously with the specific peptide inhibitor used, and similar factors well known in the medical field.

[0289] In particular embodiments, the total daily dose of the peptide inhibitors of the invention administered to a human or other mammalian host in single or divided doses may be, for example, in amounts of 0.0001-300 mg / kg body weight per day or 1-300 mg / kg body weight per day.

[0290] Non-invasive detection of intestinal inflammation The peptide inhibitors of the present invention may be used as part of a non-invasive diagnostic procedure to detect, evaluate and diagnose intestinal inflammation by microPET imaging, where the peptide inhibitor is labeled with a chelating group or detectable label. In one embodiment, the peptide inhibitor is conjugated with a bifunctional chelator. In another embodiment, the peptide inhibitor is radioactively labeled. The labeled peptide inhibitor is then administered orally or intrarectally to the subject. In one embodiment, the labeled peptide inhibitor is included in drinking water. After ingestion of the peptide inhibitor, microPET imaging may be used to visualize inflammation through the intestine and digestive track of the subject. EXAMPLES

[0291] Synthesis of substituted tryptophans Synthesis of 7-methyltryptophan 7-Methyltryptophan was purchased from a commercial source. Additionally, the compound can be synthesized according to one of the methods described below.

[0292] Synthesis of 7-ethyltryptophan 7-Ethyltryptophan was synthesized according to the method depicted in Scheme 1. [ka]

[0293] Synthesis of 7-ispropyl tryptophan 7-Isopropyltryptophan was synthesized according to the method depicted in Scheme 2. [ka]

[0294] Procedure for 7-isopropyl compounds: Suzuki Coupling: To a sealed solution of (S)-methyl 3-(7-bromo-1H-indol-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (5.0 g, 12.6 mmol) in n-propanol was added potassium isoprenyltrifluoroborate (2.2 g, 15.1 mmol) and purged with nitrogen. Triethylamine (3.5 mL, 25.5 mmol) was added to the above mixture, followed by catalyst [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexed with dichloromethane (0.72 g, 0.88 mmol), purged with nitrogen for 10 min, and heated to 100° C. overnight. The solution was concentrated to give a residue, which was dissolved in ethyl acetate (150 mL) and washed with water and brine. The organic layer was concentrated and the crude product was purified by flash column (3.2 g, 71%) to give a thick foamy solid.

[0295] Transfer hydrogenation: To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(7-(prop-1-en-2-yl)-1H-indol-3-yl)propanoate (3.1 g, 8.6 mmol) in ethanol (40 mL) was added 10% Pd / C (100 mg, 50% wet catalyst), followed by ammonium formate (1.6 g, 25.3 mmol) and the resulting mixture was heated to 65-70 °C for 2 h. The reaction mixture was concentrated, water was added to the residue and extracted into ethyl acetate (2 x 100 mL). The organic layer was washed with water and brine and concentrated. The product obtained (3.1 g, quantitative) was used as is for the next reaction.

[0296] Hydrolysis: To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(7-isopropyl-1H-indol-3-yl)propanoate (3.6 g, 10.0 mmol) in THF / MeOH / water (4:1:1) was added lithium hydroxide (1.26 g, 30.0 mmol) and the solution was stirred overnight. The solution was concentrated to remove the solvent, diluted with water, and acidified with 10% aqueous citric acid. The aqueous layer containing the product was extracted with ethyl acetate (2×100 mL). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to give the desired product (2.8 g, 94%) as a thick oil. The crude product was used in the next step without further purification.

[0297] Boc deprotection: To a cold solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(7-isopropyl-1H-indol-3-yl)propanoic acid (2.8 g, 8.0 mmol) in dichloromethane (12 mL) was added trifluoroacetic acid (6 mL) and the solution was stirred for 5 h at room temperature. The solution was evaporated to dryness, redissolved in dichloromethane (10 mL), treated with HCl / ether, and concentrated. The crude hydrochloride was suspended in MTBE (25 mL), stirred for 30 min, and filtered to give S)-2-amino-3-(7-isopropyl-1H-indol-3-yl)propanoic acid hydrochloride (1.3 g, 68%) as an off-white solid (hygroscopic).

[0298] Fmoc protection: To a solution of (S)-2-amino-3-(7-isopropyl-1H-indol-3-yl)propanoic acid hydrochloride (1.3 g, 4.6 mmol) in THF / water (33 mL:10 mL) was added sodium bicarbonate (1.55 g, 18.4 mmol) followed by N-(9-fluorenylmethoxycarbonyloxy)succinimide (1.55 g, 4.6 mmol) in small portions. The resulting mixture was stirred overnight and concentrated to remove THF. The residue was diluted with water, acidified with 2N HCl, and extracted with ethyl acetate (2×75 mL). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to give the product as a foamy low-melting solid (1.85 g, 86%).

[0299] Synthesis of additional 7-substituted tryptophans Additional 7-substituted tryptophans have been or can be synthesized according to the method depicted in Scheme 3. [ka]

[0300] Example 1 Synthesis of peptide monomers The peptide monomers of the invention were synthesized using Merrifield solid phase synthesis technology on a Protein Technology Symphony multiple channel synthesizer. Peptides were assembled using HBTU (O-Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate), diisopropylethylamine (DIEA) coupling conditions. For coupling of some amino acids, PyAOP (7-Azabenzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate) and DIEA conditions were used. Rink Amide MBHA resin (100-200 mesh, 0.57 mmol / g) was used for peptides with C-terminal amides, and Wang resin preloaded with N-α-Fmoc protected amino acids was used for peptides with C-terminal acids. Coupling reagents (premixed HBTU and DIEA) were prepared at a concentration of 100 mmol. Similarly, amino acid solutions were prepared at a concentration of 100 mmol. Peptide inhibitors of the present invention were identified based on medicinal chemistry optimization and / or phage display and screened to identify those with superior binding and / or inhibitory properties.

[0301] set The peptides were assembled using the standard Symphony protocol. The peptide sequence was assembled as follows: the resin in each reaction vial (250 mg, 0.14 mmol) was washed twice with 4 ml of DMF, followed by treatment with 2.5 ml of 20% 4-methylpiperidine (Fmoc deprotection) for 10 min. The resin was then filtered, washed twice with DMF (4 ml), and re-treated with N-methyl piperifine for another 30 min. The resin was washed again three times with DMF (4 ml), followed by addition of 2.5 ml of amino acid and 2.5 ml of HBTU-DIEA mixture. After 45 min of frequent agitation, the resin was filtered and washed three times with DMF (4 ml each). For a typical peptide of the invention, a double coupling was performed. After completion of the coupling reaction, the resin was washed three times with DMF (4 ml each) before proceeding to the coupling of the next amino acid.

[0302] Ring-closing metathesis to form olefins The resin (100 μmol) was washed with 2 ml of DCM (3×1 min), then 2 ml of DCE (3×1 min), before being treated with 2 ml of a 6 mM solution of Grubbs' first generation catalyst (4.94 mg ml-1; 20 mol% with respect to resin substitution) in DCE. The solution was refluxed overnight (12 h) under nitrogen and then drained. The resin was washed three times with DMF (4 ml each), DCM (4 ml), then dried and cleavaed.

[0303] Disconnect After completion of peptide assembly, the peptide was cleaved from the resin by treatment with a cleavage reagent such as reagent K (82.5% trifluoroacetic acid, 5% water, 5% thioanisole, 5% phenol, 2.5% 1,2-ethanedithiol), which was able to successfully cleave all remaining side chain protecting groups as well as the peptide from the resin.

[0304] The cleaved peptide was precipitated in cold diethyl ether and subsequently washed twice with ethyl ether. The filtrate was poured off, a second aliquot of cold ether was added, and the procedure was repeated. The crude peptide was dissolved in a solution of acetonitrile:water (7:3 with 1% TFA) and filtered. The quality of the linear peptide was then verified using electrospray ionization mass spectrometry (ESI-MS) (Micromass / Waters ZQ) before purification.

[0305] Oxidation-mediated disulfide bond formation Peptides containing a free thiol (e.g., diPen) were assembled on Rink Amide-MBHA resin following the general Fmoc-SPPS procedure. The peptide was cleaved from the resin by treatment with the cleavage reagent (90% trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5% tri-isopropylsilane). The cleaved peptide was precipitated in cold diethyl ether, followed by two washes with ethyl ether. The filtrate was poured off, a second aliquot of cold ether was added, and the procedure was repeated. The crude peptide was dissolved in a solution of acetonitrile:water (7:3 with 1% TFA) and filtered to obtain the crude peptide of the desired unoxidized peptide.

[0306] Crude cleaved peptides with X4 and X9 either Cys, Pen, hCys, (D)Pen, (D)Cys or (D)hCys were dissolved in 20 ml water:acetonitrile. Saturated iodine in acetic acid was then added dropwise with stirring until the yellow color persisted. The solution was stirred for 15 minutes and the reaction was monitored using analytical HPLC and LCMS. When the reaction was complete, solid ascorbic acid was added until the solution was clear. The solvent mixture was then purified by first diluting with water and then loading onto a reverse phase HPLC system (Luna C18 support, 10u, 100A, mobile phase A: water containing 0.1% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA, gradient starting at 5% B and changing to 50% B over 60 minutes at a flow rate of 15 ml / min). Fractions containing pure product were then freeze-dried on a lyophilizer.

[0307] Thioether bond formation Peptides containing free thiols (e.g., Cys) and hSer(OTBDMS) were assembled on Rink Amide-MBHA resin following the general Fmoc-SPPS procedure. Chlorination was carried out by treating the resin with PPh3 (10 equiv.) and Cl3CCN (10 equiv.) in DCM for 2 h. The peptide was cleaved from the resin by treatment with the cleavage reagent 90% trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5% tri-isopropylsilane). The cleaved peptide was precipitated in cold diethyl ether, followed by two washes with ethyl ether. The filtrate was poured off, a second aliquot of cold ether was added, and the procedure was repeated. The crude peptide was dissolved in a solution of acetonitrile:water (7:3 with 1% TFA) and filtered to obtain the desired uncyclized crude peptide.

[0308] Crude peptides bearing free thiols (e.g., Cys, Pen, hCys, (D)Pen, (D)Cys or (D)hCys and alkyl halide (hSer(Cl)) at either X4 and X9 or X9 and X4 positions were dissolved in 0.1 M Tris buffer (pH 8.5). Cyclization was allowed to occur overnight at RT. The solvent mixture was then purified by first diluting 2-fold with water and then loaded onto a reversed-phase HPLC system (Luna C18 support, 10u, 100A, mobile phase A: water containing 0.1% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA, gradient starting at 5% B and changing to 50% B over 60 min at a flow rate of 15 ml / min). Fractions containing pure product were then freeze-dried on a lyophilizer.

[0309] purification Analytical reversed-phase high performance liquid chromatography (HPLC) was performed on a Gemini C18 column (4.6 mm x 250 mm) (Phenomenex). Semi-preparative reversed-phase HPLC was performed on a Gemini 10 μm C18 column (22 mm x 250 mm) (Phenomenex) or a Jupiter 10 μm, 300A° C18 column (21.2 mm x 250 mm) (Phenomenex). Separation was achieved using a linear gradient of B in buffer A (mobile phase A: water containing 0.15% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA) at flow rates of 1 mL / min (analytical) and 15 mL / min (preparative). Separation was achieved using a linear gradient of B in buffer A (mobile phase A: water containing 0.15% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA) at flow rates of 1 mL / min (analytical) and 15 mL / min (preparative).

[0310] Example 1A Representative synthesis of additional peptide monomers Peptide monomers of the invention were synthesized using standard Fmoc solid phase synthesis techniques on a CEM Liberty Blue™ microwave peptide synthesizer. Peptides were assembled using Oxyma / DIC (ethyl cyanohydroxyiminoacetate / diisopropylcarbodiimide) with microwave heating. Rink Amide-MBHA resin (100-200 mesh, 0.66 mmol / g) was used for peptides with C-terminal amides and Wang resin preloaded with N-α-Fmoc protected amino acids was used for peptides with C-terminal acids. Oxyma was prepared as a 1 M solution in DMF containing 0.1 M DIEA. DIC was prepared as a 0.5 M solution in DMF. Amino acids were prepared at 200 mM. Peptide inhibitors of the invention were identified based on medicinal chemistry optimization and / or phage display and screened to identify those with superior binding and / or inhibitory properties.

[0311] set The peptides were made using the standard CEM Liberty Blue™ protocol. The peptide sequence was assembled as follows: the resin (400 mg, 0.25 mmol) was suspended in 10 ml of 50 / 50 DMF / DCM. The resin was then transferred to a reaction vessel in a microwave cavity. Repeated Fmoc deprotection and Oxyma / DIC coupling cycles were used to assemble the peptides. For deprotection, 20% 4-methylpiperidine in DMF was added to the reaction vessel and heated to 90° C. for 65 seconds. The deprotection solution was drained and the resin was washed three times with DMF. For most amino acids, 5 equivalents of the amino acid, Oxyma and DIC were then added to the reaction vessel and the reaction mixture was rapidly heated to 90° C. for 4 minutes by microwave irradiation. For arginine and histidine residues, milder conditions were used to prevent racemization using temperatures of 75 and 50° C. for 10 minutes, respectively. Rare and expensive amino acids were often coupled manually at room temperature overnight using only 1.5-2 equivalents of reagents. Difficult couplings were often performed as 2 x 4 min double couplings at 90 °C. After coupling, the resin was washed with DMF and the entire cycle was repeated until assembly of the desired peptide was complete.

[0312] Ring-closing metathesis to form olefins The resin (100 μmol) was washed with 2 ml of DCM (3 × 1 min), then with 2 ml of DCE (3 × 1 min), followed by addition of Grubbs Catalyst® 1st generation (4.94 mg ml -1 The resin was treated with 2 ml of a 6 mM solution of 20 mol% with respect to resin substitution. The solution was refluxed overnight (12 h) under nitrogen and then drained. The resin was washed three times with DMF (4 ml each), DCM (4 ml), then dried and cleaved.

[0313] Disconnect After peptide assembly was complete, the peptide was then cleaved from the resin by treatment with a standard cleavage cocktail of 91:5:2:2 TFA / HO / TIPS / DODT for 2 h. If more than one Arg(pbf) residue was present, cleavage was allowed to proceed for an additional hour.

[0314] The cleaved peptide was precipitated in cold diethyl ether. The filtrate was decanted, a second aliquot of cold ether was added, and the procedure was repeated. The quality of the linear peptide was then verified using electrospray ionization mass spectrometry (ESI-MS) (Waters® Micromass® ZQ™) before purification.

[0315] Oxidation-mediated disulfide bond formation Peptides containing a free thiol (eg, diPen) were assembled on Rink Amide-MBHA resin following general Fmoc solid phase synthesis, cleavage and isolation as described above.

[0316] Crude cleaved thiol-containing peptides bearing either Cys, Pen, hCys, (D)Pen, (D)Cys or (D)hCys were dissolved in 50 / 50 acetonitrile / water at approximately 2mg / ml. Saturated iodine in acetic acid was then added dropwise with stirring until the yellow color persisted. The solution was stirred for several minutes and the reaction was monitored using analytical HPLC and LCMS. When the reaction was complete, solid ascorbic acid was added until the solution was clear. The solvent mixture was then purified by first diluting with water and then loading onto a reverse-phase HPLC column (Luna® C18 support, 10u, 100A, mobile phase A: water containing 0.1% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA, gradient starting at 15% B and changing to 50% B over 60 minutes at a flow rate of 15ml / min). Fractions containing pure product were then freeze-dried on a lyophilizer.

[0317] Thioether bond formation Peptides containing free thiols (e.g., Cys) and hSer(OTBDMS) were assembled on Rink Amide-MBHA resin following the general Fmoc-SPPS procedure. Chlorination was carried out by treating the resin with dichlorotriphenylphosphorane (5 equiv., 0.5 M) containing pinene (0.875 M) and thioanisole (0.375 M) scavengers for 2 h at room temperature. The chloro-peptides were cleaved from the resin and precipitated as described above.

[0318] Crude peptides bearing free thiols (e.g., Cys, Pen, hCys, (D)Pen, (D)Cys or (D)hCys) and alkyl halides (hSer(Cl)) were dissolved 1:1 in ACN / water and diluted with 1 volume of 0.2 M Tris buffer (pH 8.4). Cyclization was carried out overnight at room temperature. The reaction mixture was then purified by first diluting 1x with water and then loaded onto a reversed-phase HPLC column (Luna® C18 support, 10u, 100A, mobile phase A: water containing 0.1% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA, gradient starting at 15% B and changing to 50% B over 60 min at a flow rate of 20 ml / min). Fractions containing pure product as determined by RPHPLC were then freeze-dried on a lyophilizer.

[0319] purification Analytical reversed-phase high performance liquid chromatography (HPLC) was performed on a Gemini® C18 column (4.6 mm x 250 mm) (Phenomenex). Semi-preparative reversed-phase HPLC was performed on a Gemini® 10 μm C18 column (22 mm x 250 mm) (Phenomenex) or a Jupiter® 10 μm, 300A° C18 column (21.2 mm x 250 mm) (Phenomenex). Separation was achieved using a linear gradient of B in buffer A (mobile phase A: water containing 0.15% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA) at flow rates of 1 mL / min (analytical) and 20 mL / min (preparative).

[0320] Example 1B Representative synthesis of additional peptide monomers Synthesis of peptide Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-NH2 (SEQ ID NO: 252) (Peptide #252) The acetate salt of peptide #252 was synthesized on a 6.66 mmol scale. Upon completion, 3.24 g of 97% pure peptide #252 was isolated as a white powder, representing an overall yield of approximately 25%.

[0321] The peptide #252 was assembled on Rink Amide MBHA resin using standard FMOC protection synthesis conditions. The assembled peptide was isolated from the resin and protecting groups by cleavage with strong acid followed by precipitation. The crude precipitate was then purified by RP-HPLC and counterion exchange. Lyophilization of the pure fractions afforded the final product peptide #252.

[0322] Resin Swelling: 10 g of Rink Amide MBHA solid phase resin (0.66 mmol / g loading) was transferred to a 250 ml peptide vessel with a filter frit, ground glass joint and vacuum side arm. The resin was washed 3 times with DMF.

[0323] Step 1: Coupling of FMOC-d-Lys(Boc)-OH: Deprotection of the FMOC group was achieved by adding 2 resin bed volumes of 20% 4-methylpiperidine in DMF to the swollen resin, shaking for 3-5 min, then draining, and adding a second, 2 resin bed volumes of 4-methylpiperidine solution and shaking for an additional 20-30 min. After deprotection, the resin was washed three times with DMF with shaking. FMOC-d-Lys(boc)-OH (3 eq, 9.3 g) was dissolved in 100 ml of DMF along with Oxyma (4.5 eq, 4.22 g). Preactivation of the acid was achieved by addition of DIC (3.9 eq, 4 ml) and shaking for 15 min before adding to the deprotected resin. An additional aliquot of DIC (2.6 eq, 2.65 ml) was added after approximately 15 min of coupling. The progress of the coupling reaction was monitored by a colorimetric Kaiser test. Once the reaction was deemed complete, the resin was washed with 3× DMF with shaking before starting the next deprotection / coupling cycle.

[0324] Step 2: Coupling of FMOC-Asn(Trt)-OH: FMOC deprotection was again achieved by adding two sequential, two resin bed volumes of 20% 4-methyl-piperidine / DMF, one for 3-5 min and one for 20-30 min, draining between treatments. The resin was then washed three times before coupling the protected asparagine. FMOC-Asn(Trt)-OH (3 eq, 11.8 g) was dissolved in DMF along with Oxyma (4.5 eq, 4.22 g). After a 15 min preactivation with DIC (3.9 eq, 4 ml), it was added to the d-Lys-Rink-Amide resin. After 15 min, an additional aliquot of DIC (2.6 eq, 2.65 ml) was added to the reaction. Once the reaction was complete as determined by the Kaiser test, the resin was again washed three times with DMF before starting the next deprotection / coupling cycle.

[0325] Step 3: Coupling of FMOC-Lys(Ac)-OH: FMOC was removed from the N-terminus of the resin-bound asparagine as previously described and the resin was washed. FMOC-Lys(Ac)-OH (2 eq., 5.42 g) was dissolved in 100 ml of DMF along with Oxyma (3 eq., 2.81 g). DIC (2.6 eq., 2.65 ml) was added for approximately 15 min to preactivate the acid and then added to the Asn-dLys-Rink-Amide resin. After approximately 15 min, an additional aliquot of DIC (1.4 eq., 1.43 ml) was added to the reaction. Once the reaction was complete as determined by the Kaiser test, the resin was washed again three times with DMF before starting the next deprotection / coupling cycle.

[0326] Step 4: Coupling of FMOC-α-Me-Lys(Boc)-OH: FMOC was removed from the N-terminus of resin-bound acetyl lysine as described previously and the resin was washed. FMOC-α-Me-Lys(Boc)-OH (2 eq., 6.27 g) was dissolved in 100 ml of DMF along with Oxyma (3 eq., 2.81 g). DIC (2.6 eq., 2.65 ml) was added for approximately 15 min for preactivation of the acid and then added to the Lys(Ac)-Asn-dLys-Rink-Amide resin. After approximately 15 min, an additional aliquot of DIC (1.4 eq., 1.43 ml) was added to the reaction. Once the reaction was complete as determined by the Kaiser test, the resin was washed again three times with DMF before starting the next deprotection / coupling cycle.

[0327] Step 5: Coupling of FMOC-L-Ala(2-naphthyl)-OH: FMOC was removed from the N-terminus of the resin-bound peptide as previously described and the resin was washed. FMOC-L-Ala(2-naphthyl)-OH (3 eq, 8.66 g) was dissolved in 100 ml of DMF along with Oxyma (4.5 eq, 4.22 g). DIC (3.9 eq, 4 ml) was added for approximately 15 min for preactivation of the acid and then added to the αMeLys-Lys(Ac)-Asn-dLys-Rink-Amide resin. After approximately 15 min, an additional aliquot of DIC (2.6 eq, 2.65 ml) was added to the reaction. Once the reaction was complete as determined by the Kaiser test, the resin was washed again three times with DMF before starting the next deprotection / coupling cycle.

[0328] Step 6: Coupling of FMOC-4-[2-(boc-amino-ethoxy)]-L-phenylalanine: FMOC was removed from the N-terminus of the resin-bound peptide as previously described and the resin was washed. FMOC-4-[2-(boc-amino-ethoxy)]-L-phenylalanine (3 eq, 10.8 g) was dissolved in 100 ml of DMF along with Oxyma (4.5 eq, 4.22 g). DIC (3.9 eq, 4 ml) was added for approximately 15 min for preactivation of the acid and then added to the 2Nal-αMeLys-Lys(Ac)-Asn-dLys-Rink-Amide resin. After approximately 15 min, an additional aliquot of DIC (2.6 eq, 2.65 ml) was added to the reaction. Once the reaction was complete as determined by the Kaiser test, the resin was washed again three times with DMF before starting the next deprotection / coupling cycle.

[0329] Step 7: Coupling of FMOC-L-Pen(Trt)-OH: FMOC was removed from the N-terminus of the resin-bound peptide as described previously and the resin was washed. FMOC-L-Pen(Trt)-OH (3 eq., 12.14 g) was dissolved in 100 ml of DMF along with Oxyma (4.5 eq., 4.22 g). DIC (3.9 eq., 4 ml) was added for approximately 15 min for preactivation of the acid and then added to the AEF-2Nal-αMeLys-Lys(Ac)-Asn-dLys-Rink-Amide resin. After approximately 15 min, an additional aliquot of DIC (2.6 eq., 2.65 ml) was added to the reaction. Once the reaction was complete as determined by the Kaiser test, the resin was washed again three times with DMF before starting the next deprotection / coupling cycle.

[0330] Step 8: Coupling of FMOC-Lys(Ac)-OH: FMOC was removed from the N-terminus of the resin-bound peptide as described previously and the resin was washed. FMOC-Lys(Ac)-OH (2 eq., 5.4 g) was dissolved in 100 ml of DMF along with Oxyma (3 eq., 2.81 g). DIC (2.6 eq., 2.65 ml) was added for approximately 15 min to preactivate the acid and then added to the Pen-AEF-2Nal-αMeLys-Lys(Ac)-Asn-dLys-Rink-Amide resin. After approximately 15 min, an additional aliquot of DIC (1.4 eq., 1.43 ml) was added to the reaction. Once the reaction was complete as determined by the Kaiser test, the resin was washed again three times with DMF before starting the next deprotection / coupling cycle.

[0331] Step 9: Coupling of FMOC-7-Me-Trp-OH: FMOC was removed from the N-terminus of the resin-bound peptide as described previously and the resin was washed. FMOC-7-Me-Trp-OH (2 eq., 5.81 g) was dissolved in 100 ml of DMF along with Oxyma (3 eq., 2.81 g). DIC (2.6 eq., 2.65 ml) was added for approximately 15 min to preactivate the acid and then added to the Lys(Ac)-Pen-AEF-2Nal-αMeLys-Lys(Ac)-Asn-dLys-Rink-Amide resin. After approximately 15 min, an additional aliquot of DIC (1.4 eq., 1.43 ml) was added to the reaction. Once the reaction was complete as determined by the Kaiser test, the resin was washed again three times with DMF before starting the next deprotection / coupling cycle.

[0332] Step 10: Coupling of FMOC-Thr(tBu)-OH: FMOC was removed from the N-terminus of the resin-bound peptide as described previously and the resin was washed. FMOC-Thr(tBu)-OH (4 eq., 10.5 g) was dissolved in 100 ml of DMF along with Oxyma (6 eq., 5.62 g). DIC (5.2 eq., 5.3 ml) was added for approximately 15 min for preactivation of the acid and then added to the 7MeTrp-Lys(Ac)-Pen-AEF-2Nal-αMeLys-Lys(Ac)-Asn-dLys-Rink-Amide resin. After approximately 15 min, an additional aliquot of DIC (2.6 eq., 2.65 ml) was added to the reaction. Once the reaction was complete as determined by the Kaiser test, the resin was washed again three times with DMF before starting the next deprotection / coupling cycle.

[0333] Step 11: Coupling of FMOC-Asn(Trt)-OH: FMOC was removed from the N-terminus of the resin-bound peptide as described previously and the resin was washed. FMOC-Asn(Trt)-OH (4 eq., 15.8 g) was dissolved in 100 ml of DMF along with Oxyma (6 eq., 5.62 g). DIC (5.2 eq., 5.3 ml) was added for approximately 15 min to preactivate the acid and then added to the Thr-7MeTrp-Lys(Ac)-Pen-AEF-2Nal-αMeLys-Lys(Ac)-Asn-dLys-Rink-Amide resin. After approximately 15 min, an additional aliquot of DIC (2.6 eq., 2.65 ml) was added to the reaction. Once the reaction was complete as determined by the Kaiser test, the resin was washed again three times with DMF before starting the next deprotection / coupling cycle.

[0334] Step 12: Coupling of FMOC-L-Pen(Trt)-OH: FMOC was removed from the N-terminus of the resin-bound peptide as previously described and the resin was washed. FMOC-L-Pen(Trt)-OH (2 eq., 8.1 g) was dissolved in 100 ml of DMF along with Oxyma (3 eq., 2.81 g). DIC (2.6 eq., 2.65 ml) was added for approximately 15 min for preactivation of the acid and then added to the Asn-Thr-7MeTrp-Lys(Ac)-Pen-AEF-2Nal-αMeLys-Lys(Ac)-Asn-dLys-Rink-Amide resin. After approximately 15 min, an additional aliquot of DIC (2.6 eq., 2.65 ml) was added to the reaction. Once the reaction was complete as determined by the Kaiser test, the resin was washed again three times with DMF before the final deprotection and acetic acid capping of the assembled peptide.

[0335] Step 13: Acetyl Capping: FMOC was removed from the N-terminus of the resin-bound peptide as previously described and the resin was washed. 150 ml of capping reagent A (THF / acetic anhydride / pyridine, 80:10:10) was added to the assembled Pen-Asn-Thr-7MeTrp-Lys(Ac)-Pen-AEF-2Nal-αMeLys-Lys(Ac)-Asn-dLys-Rink-Amide resin and shaken for 30 min. The resin was washed three times with DMF followed by three times with DCM. The resin was divided into 5-50 ml centrifuge tubes and placed under vacuum for 1.5 h before cleavage using TFA.

[0336] Step 14: TFA cleavage and ether precipitation: 200 ml of TFA cleavage cocktail (90 / 5 / 2.5 / 2.5 TFA / water / Tips / DODT) was prepared. 40 ml of cleavage cocktail was added to each of the five tubes containing the protected resin-bound peptide and shaken for 2 h. The spent resin was filtered off and the filtrate was divided equally between 18 and 50 ml centrifuge tubes for precipitation. Cold diethyl ether was added to each to form a white precipitate, which was then centrifuged. The ether was decanted and discarded, and two more ether washes of the precipitate were performed. The resulting white precipitate cake was dried overnight in the hood to give approximately 10.4 g of crude reduced peptide.

[0337] Step 15: Oxidation of disulfides: The crude peptide was oxidized in four batches. Approximately 2.5 g of crude peptide was dissolved in 50 ml of 50 / 50 acetonitrile / water and diluted to 1 L of 20% ACN / water. A saturated solution of iodine in acetic acid / methanol was added dropwise to the 1 L peptide solution with swirling until the yellow / brown color of I2 remained and did not disappear. The slightly colored solution was left for 5 minutes and then excess I2 was quenched with a pinch of ascorbic acid.

[0338] Step 16: RP-HPLC purification: RP-HPLC purification was performed in four batches immediately after I2 oxidation. A preparative purification column (Phenomenex, Luna, C18(2), 100A, 250x50mm) was equilibrated at 70ml / min with 5% MPB in MPA (MPA=0.1% TFA / water, MPB=0.1% TFA in ACN). 1L of quenched oxidized peptide was loaded onto the equilibrated column at 70ml / min. After the solvent front eluted, an elution gradient of 20-38% MPB over 60 min at 70ml / min was performed. The desired oxidized peptide eluted at approximately 26% MPB. Pure fractions were combined from all four purifications and lyophilized to give 3.83g of purified TFA salt ready for counterion exchange.

[0339] Step 17: Counterion exchange to acetate: The same preparative RP-HPLC column was equilibrated with 5% MPB in MPA (MPA=0.3% AcOH in water, MPB=0.3% AcOH in ACN, MPC=0.5M NHOAc in water) at 70 ml / min. A total of 3.83 g of purified peptide was dissolved in 50 / 50 ACN / water and diluted to 15% ACN (approximately 50 ml total). The solution was loaded onto the equilibrated column at 70 ml / min and the solvent front was eluted. The captured peptide was washed with 5% MPB in MPA for 5 min. The captured peptide was then washed with 5% MPB in MPC for 40 min at 70 ml / min to exchange the counterion from TFA to acetate. The captured peptide was then washed with 5% MPB in MPA for 10 min at 70 ml / min to clear any NHOAc form system. Finally, peptides were eluted using a steep gradient of 5-70% MPB in MPA over 60 min.

[0340] Step 18: Final lyophilization and analysis: Collected fractions were analyzed by analytical RP-HPLC and all fractions with purity >95% were combined. Lyophilization of the combined fractions gave 3.24 g of peptide #252 as a white powder with 97% purity. Low resolution LC / MS of purified peptide #252 gave three charge states of the peptide, M+3 / 3 of 621.8, M+2 / 2 of 932.1 and a molecular ion of 1863.5. The experimental mass is in agreement with the theoretical mass of 1863.3 da.

[0341] Example 2 Peptide inhibition of interleukin-23 binding to the interleukin-23 receptor Peptide optimization was performed to obtain peptides at low concentrations (e.g., IC 50 We identified peptide inhibitors of IL-23 signaling that are active at IL-23R binding sites (<10 nM). Peptides were tested to identify peptides that inhibit IL-23 binding to human IL-23R and inhibit IL-23 / IL-23R functional activity, as described below.

[0342] Assays were performed to determine peptide activity as described below, and the results of these assays are provided in Tables E1-E3. Human ELISA refers to the IL23-IL23R competitive binding assay described below, rat ELISA refers to the rat IL-23R competitive binding ELISA assay described below, and pStat3HTRF refers to the DB cell IL-23R pSTAT3 cell assay described below. The peptides depicted in Table E1 are cyclized via a disulfide bridge formed between the two Pen residues in these peptides. The peptides depicted in Table E2 are cyclized via a thioether bond between the indicated amino acid residues. Table E2 provides an illustrative structure depicting a thioether cyclization, which is indicated in the table by the term "cyclo", with the cyclic region enclosed in square brackets immediately following the term "cyclo". For certain peptides, the residue Abu is present where indicated, while in other embodiments, e.g., those relating to the non-cyclized forms, Abu may be referred to as a hSer(Cl) or homoSer residue.

[0343] IL23-IL23R competitive binding ELISA Immulon® 4HBX plates were coated with 50ng / well IL23R_huFC and incubated overnight at 4°C. Wells were washed 4 times with PBST, blocked with PBS containing 3% skim milk for 1 hour at room temperature, and washed again 4 times with PBST. Test peptides at a final concentration of 2nM and serial dilutions of IL-23 diluted in assay buffer (PBS containing 1% skim milk) were added to each well and incubated for 2 hours at room temperature. After washing the wells, bound IL-23 was detected by incubation with 50ng / well goat anti-p40 polyclonal antibody (R&D Systems #AF309) diluted in assay buffer for 1 hour at room temperature. Wells were washed again 4 times with PBST. Secondary antibody, HRP-conjugated donkey anti-goat IgG (Jackson ImmunoResearch Laboratories #705-035-147) diluted 1:5000 in assay buffer was then added and incubated for 30 minutes at room temperature. The plates were finally washed as above. Signals were visualized using TMB One Component HRP Membrane Substrate, quenched with 2 M sulfuric acid, and read spectrophotometrically at 450 nm. The IC values ​​of the various test peptides were determined from these data. 50 The values ​​are shown in Tables E1 to E3.

[0344] Rat IL-23R competitive binding ELISA Assay plates were coated with 300ng / well rat IL-23R_huFC and incubated overnight at 4°C. Wells were washed, blocked, and washed again. Serial dilutions of test peptides and IL-23 at a final concentration of 7nM were added to each well and incubated for 2 hours at room temperature. After washing the wells, bound IL-23 was detected using a goat anti-p40 polyclonal antibody followed by HRP-conjugated donkey anti-goat IgG. Signals were visualized using TMB One Component HRP Membrane Substrate and quenched with 2M sulfuric acid. IC values ​​of various test peptides determined from these data 50 The values ​​are shown in Tables E1 to E3.

[0345] DB cell IL23R pSTAT3 cell assay IL-23 plays a central role in supporting and maintaining Th17 differentiation in vivo. This process is thought to be mediated primarily through signal transducer and activator of transcription 3 (STAT3), whose phosphorylation (resulting in pSTAT3) leads to RORC and upregulation of proinflammatory IL-17. This cellular assay examines the levels of pSTAT3 in IL-23R-expressing DB cells upon stimulation with IL-23 in the presence of test compounds. Serial dilutions of test peptides and IL-23 (Humanzyme #HZ-1261) at a final concentration of 0.5 nM were added to each well in a 96-well tissue culture plate (Corning #CLS3894). DB cells (ATCC #CRL-2289) cultured in RPMI-1640 medium (Thermo Scientific #11875093) supplemented with 10% FBS were added at 5 x 10E5 cells / well and incubated at 37°C in a 5% CO2 humidified incubator for 30 minutes. Changes in phospho-STAT3 levels in cell lysates were detected using the Cisbio HTRF pSTAT3(Tyr705) Cellular Assay Kit (Cisbio #62AT3PEH) according to the manufacturer's Two Plate Assay protocol. The IC 50Values ​​are shown in Tables E1, E2, and E3. *=<1 nM; **=1 nM-10 nM; ***=10 nM-100 nM; ****=>100 nM. If not shown, data was undetermined. [Table 22-1] [Table 22-2] [Table 23] [Table 24-1] [Table 24-2] [Table 24-3] [Table 24-4] [Table 24-5] [Table 24-6] [Table 24-7] [Table 24-8] [Table 24-9]

[0346] Example 3 NK cell-based assays Natural killer (NK) cells purified from human peripheral blood of healthy donors by negative selection (Miltenyi Biotech, Cat # 130-092-657) were cultured in complete medium (RPMI 1640 containing 10% FBS, L-glutamine and penicillin-streptomycin) in the presence of 25 ng / mL IL-2 (RnD, Cat # 202-IL-010 / CF). After 7 days, cells were centrifuged and resuspended in complete medium at 1E6 cells / mL. The previously determined EC 50 ~EC 75 Recombinant IL-23 and 10 ng / mL IL-18 (RnD, Cat # B003-5) were mixed with various concentrations of peptides and added to NK cells seeded at 1E5 cells / well. After 20-24 hours, IFNγ was quantified in the supernatants using a Quantikine ELISA (RnD, Cat # DIF50). [Table 25-1] [Table 25-2]

[0347] Example 4 Stability of peptide inhibitors in simulated intestinal fluid (SIF), simulated gastric fluid (SGF) and redox conditions Studies in simulated intestinal fluid (SIF) and simulated gastric fluid (SGF) were performed to assess the gastric stability of the peptide inhibitors of the present invention. Additionally, studies were performed to assess the redox stability of the peptide inhibitors of the present invention.

[0348] SIF was prepared by adding 6.8 g of monobasic potassium phosphate and 10.0 g of pancreatin to 1.0 L of water. After dissolution, the pH was adjusted to 6.8 using NaOH. DMSO stocks (2 mM) were first prepared for the test compounds. Aliquots of the DMSO solution were placed into six individual tubes, each containing 0.5 mL of SIF, pre-warmed to 37° C. The final test compound concentration was 20 μM. The vials were kept in a benchtop Thermomixer® for the duration of the experiment. At each time point (0, 5, 10, 20, 40, 60, or 360 minutes or 24 hours), the reaction was terminated by adding 1.0 mL of acetonitrile containing 1% formic acid to one vial. Samples were stored at 4° C. until the end of the experiment. After sampling at the final time point, the tubes were mixed and then centrifuged at 3,000 rpm for 10 minutes. An aliquot of the supernatant was removed, diluted 1:1 in distilled water containing an internal standard, and analyzed by LCMS / MS. The percent remaining at each time point was calculated based on the peak area response ratio of the test to compound relative to the internal standard. Time point 0 was set to 100% and all subsequent time points were calculated relative to time point 0. Half-life was calculated by fitting to a first-order exponential decay equation using Graphpad. Stability in the SIF assay is shown in Tables E9 and E10.

[0349] SGF was prepared by adding 20 mg of NaCl, 32 mg of porcine pepsin (MP Biochemicals, catalog 02102599), and 70 μL of HCl to 10 ml of water (final pH=2). Aliquots of SGF (0.5 ml each) were added to 37 oThe mixture was pre-warmed to 37°C. To initiate the reaction, 1 μl of peptide stock solution (10 mM in DMSO) was added to 0.5 ml of SGF and mixed thoroughly to give a final peptide concentration of 20 μM. The reaction was incubated at 37°C with gentle shaking. At each time point (0, 15, 30, 60 min), a 50 μl aliquot was removed and added to 200 ul of acetonitrile containing 0.1% formic acid to quench the reaction. Samples were stored at 4°C until the end of the experiment and centrifuged at 10,000 rpm for 5 min. An aliquot of the supernatant was removed, diluted 1:1 in distilled water containing an internal standard, and analyzed by LCMS / MS. The percentage remaining at each time point was calculated based on the peak area response ratio of the test compound to the internal standard. Time point 0 was set to 100% and all subsequent time points were calculated relative to time point 0. Half-life was calculated by fitting to a first-order exponential decay equation using Graphpad. Stability in the SGF assay is shown in Table E5. [Table 26-1] [Table 26-2]

[0350] Example 5 Stability of peptide inhibitors in human and cynomolgus monkey (CYNOMLOGUS) feces. Studies in human or cynomolgus monkey fecal homogenates were carried out to assess the gastrointestinal stability of the peptide inhibitors of the present invention.

[0351] Fecal homogenates (20%) were prepared by adding 4 mL of growth medium (1 L contains 2 g peptone water powder, 2 g yeast extract, 0.1 g NaCl, 0.04 g KH2PO4, 0.01 g CaCl2·6H2O, 0.01 g MgSO4·7H2O, 2 mL Tween 80, 0.5 g bile salts, 0.5 g L-cysteine ​​HCl, 2 g NaHCO3, and 10 μL vitamin K, pH adjusted to 6.8, and sterilized by filtration through a 0.22 μm filter) per gram of feces (freshly collected human or cynomolgus monkey feces were pooled). The suspension was vortexed to break up large aggregates and homogenized using a bead mill homogenizer. The homogenates were centrifuged at 2800 × g for 15 min. The supernatant was collected and used for incubation. DMSO stocks (10 mM) were initially prepared for the test compounds. Incubations were performed in an anaerobic chamber conditioned at 37°C. Aliquots of DMSO solution were placed in 1.0 mL aliquots of 20% fecal homogenate pre-warmed to 37°C. The final test compound concentration was 20 μM. At each time point (0, 20 min, 1, 3, 6, or 24 h), 100 μL aliquots of each incubation mixture were taken and added to separate tubes containing 300 μL of 50% acetonitrile / 50% methanol and an internal standard to terminate the reaction. Samples were removed from the anaerobic chamber and stored at 4°C until the end of the experiment. After sampling at the final time point, the tubes were mixed and then centrifuged at 3,000 rpm for 10 min. An aliquot of the supernatant was removed and diluted 1:1 in distilled water containing 0.1% formic acid and analyzed by LC / MS / MS. The percent remaining at each time point was calculated based on the peak area response ratio of the test compound relative to the internal standard. Time point 0 was set to 100% and all subsequent time points were calculated relative to time point 0. Half-life was calculated by fitting to a first-order exponential decay equation using Graphpad or Excel. Stability in the fecal homogenate assay is shown in the table.

[0352] Example 6 Stability of peptide inhibitors in rat plasma Peptides of interest (20 μM) were incubated with rat plasma (SD rats, mixed gender pool, EDTA, filtered through 0.22 μm, BioreclamationIVT) pre-warmed to 37° C. Aliquots were taken at various time points up to 24 h (e.g., 0, 0.25, 1, 3, 6 and 24 h) and immediately quenched with 4 volumes of organic solvent (acetonitrile / methanol (1:1) and 0.1% formic acid, containing 1 μM internal standard). Quenched samples were stored at 4° C. until the end of the experiment and centrifuged at 4,000 rpm for 10 min. Supernatants were diluted 1:1 with deionized water and analyzed using LC-MS. Percentages remaining at each time point were calculated based on peak area ratios (analyte to internal standard) compared to initial levels at time point 0. Half-lives were calculated by fitting to a first-order exponential decay equation using Graphpad. [Table 27-1] [Table 27-2] [Table 27-3]

[0353] All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referenced herein and / or listed in the Application Data Sheets are hereby incorporated by reference in their entireties.

[0354] It will be appreciated from the foregoing that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications can be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims. The present invention provides, for example, the following items. (Item 1) Formula (I): X7-X8-X9-X10-X11(I) or a pharma- ceutically acceptable salt or solvate thereof, wherein the peptide inhibitor of the interleukin-23 receptor comprises an amino acid sequence of X7 is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X8 is Gln, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp; X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen or Pen(sulfoxide); X10 is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, with the proviso that i) at least one of X7 and X11 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; ii) X7 is other than a 5-F substituted Trp, and iii) when X7 is unsubstituted Trp, or Trp substituted with 1-Me, ​​5-OH or 6-Cl, then X9 is other than Cys; and The peptide inhibitor inhibits the binding of interleukin-23 (IL-23) to the IL-23 receptor. A peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof. (Item 2) The peptide inhibitor has the formula (II): X4-X5-X6-X7-X8-X9-X10-X11(II) wherein the amino acid sequence is X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X5 is Cit, Glu, Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, Asp, or Cys; and X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp; X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); when X4 is Abu, X9 is Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); and when X9 is Abu, X4 is Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X10 is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with halo, alkyl, haloalkyl, hydroxy, or alkoxy; The peptide inhibitor is cyclized via the bond between X4 and X9, provided that: i) at least one of X7 and X11 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; ii) X7 is other than a 5-F substituted Trp, and iii) when X7 is unsubstituted Trp, or Trp substituted with 1-Me, ​​5-OH or 6-Cl, then X9 is other than Cys; and The peptide inhibitor inhibits the binding of interleukin-23 (IL-23) to the IL-23 receptor. Item 2. A peptide inhibitor according to item 1, or a pharma- ceutically acceptable salt or solvate thereof. (Item 3) The peptide inhibitor of item 2, or a pharma- ceutically acceptable salt or solvate thereof, wherein X4 or X9 is Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen, and the bond between X4 and X9 is a disulfide bond. (Item 4) The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 2 to 3, wherein X4 is Cys, (D)Cys, or alpha-MeCys. (Item 5) The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 2 to 3, wherein X4 is (D)Pen, or Pen, or X4 is Pen(sulfoxide). (Item 6) 4. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 2 to 3, wherein X4 is Pen. (Item 7) 7. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 1 to 6, wherein X9 is Cys, (D)Cys, or alpha-MeCys. (Item 8) The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 1 to 6, wherein X9 is Pen or (D)Pen. (Item 9) 7. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 1 to 6, wherein X9 is Pen. (Item 10) 3. The peptide inhibitor according to item 2, or a pharma- ceutically acceptable salt or solvate thereof, wherein X4 is Pen and X9 is Pen, and the bond is a disulfide bond. (Item 11) 3. The peptide inhibitor according to item 2, or a pharma- ceutically acceptable salt or solvate thereof, wherein X4 or X9 is Abu and the bond between X4 and X9 is a thioether bond. (Item 12) 12. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any of items 2 or 11, wherein X4 is Abu. (Item 13) 13. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 2, 11-12, wherein X9 is Cys, (D)Cys, or alpha-MeCys. (Item 14) 13. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 2, 11 to 12, wherein X9 is Pen or (D)Pen. (Item 15) 13. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 2, 11-12, wherein X9 is Pen. (Item 16) 13. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 2, 11-12, wherein X9 is Cys. (Item 17) 13. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 2, 11 to 12, wherein X4 is Abu, and X9 is Cys or Pen, and the bond is a thioether bond. (Item 18) 13. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 2, 11 to 12, wherein X4 is Abu and X9 is Cys and the bond is a thioether bond. (Item 19) The peptide inhibitor has the formula (IIa), (IIb), or (IIc): Pen-X5-X6-X7-X8-Pen-X10-X11(IIa), Abu-X5-X6-X7-X8-Cys-X10-X11(IIb), or Abu-X5-X6-X7-X8-Pen-X10-X11(IIc) wherein the amino acid sequence is represented by formula (IIa), (IIb), and (IIc): The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to item 1, wherein X5 to X8 and X10 to X11 are as described in item 2, and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or the peptide inhibitor is cyclized via an Abu-Cys or Abu-Pen thioether bond. (Item 20) 20. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 2 to 19, wherein X5 is Asn, Gln, or Glu. (Item 21) 20. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 2 to 19, wherein X5 is Asn, or Gln. (Item 22) 20. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 2 to 19, wherein X5 is Asn. (Item 23) The peptide inhibitor has formula (IIIa), (IIIb), (IIIc), or (IIId): Pen-Asn-X6-X7-X8-Pen-X10-X11(IIIa), Pen-Gln-X6-X7-X8-Pen-X10-X11(IIIb), Abu-Asn-X6-X7-X8-Cys-X10-X11(IIIc), or Abu-Gln-X6-X7-X8-Pen-X10-X11(IIId) wherein in formula (IIIa), (IIIb), (IIIc), and (IIId): X6 to X8 and X10 to X11 are as described in item 2, and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or an Abu-Cys or Abu-Pen thioether bond; Item 2. A peptide inhibitor according to item 1, or a pharma- ceutically acceptable salt or solvate thereof. (Item 24) 24. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 2 to 23, wherein X6 is Thr. (Item 25) The peptide inhibitor has the formula (IVa), (IVb), (IVc), or (IVd): Pen-Asn-Thr-X7-X8-Pen-X10-X11(IVa), Pen-Gln-Thr-X7-X8-Pen-X10-X11(IVb), Abu-Asn-Thr-X7-X8-Cys-X10-X11(IVc), or Abu-Gln-Thr-X7-X8-Pen-X10-X11(IVd) wherein X7 to X8 and X10 to X11 in formulas (IVa), (IVb), (IVc), and (IVd) are as described in item 2, and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or an Abu-Cys or Abu-Pen thioether bond. 2. The peptide inhibitor according to item 1, or a pharma- ceutically acceptable salt or solvate thereof. (Item 26) 26. The peptide inhibitor according to any one of items 1 to 25, or a pharma- ceutically acceptable salt or solvate thereof, wherein X8 is Gln, alpha-Me-Lys, alpha-MeLys(Ac), or Glu. (Item 27) 26. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 1 to 25, wherein X8 is Gln. (Item 28) The peptide inhibitor has the formula (Va), (Vb), (Vc), or (Vd): Pen-Asn-Thr-X7-Gln-Pen-X10-X11(Va), Pen-Gln-Thr-X7-Gln-Pen-X10-X11(Vb), Abu-Asn-Thr-X7-Gln-Cys-X10-X11(Vc), or Abu-Gln-Thr-X7-Gln-Pen-X10-X11(Vd) wherein in formula (Va), (Vb), (Vc), and (Vd): X7-X8 and X10-X11 are as described in item 2, and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or an Abu-Cys or Abu-Pen thioether bond; 2. The peptide inhibitor according to item 1, or a pharma- ceutically acceptable salt or solvate thereof. (Item 29) X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], or Phe(4-CONH 2 29. The peptide inhibitor according to any one of items 1 to 28, or a pharma- ceutically acceptable salt or solvate thereof, wherein (Item 30) 29. The peptide inhibitor according to any one of items 1 to 28, wherein X10 is Phe[4-(2-aminoethoxy)], or Phe[4-(2-acetylaminoethoxy)], or a pharma- ceutically acceptable salt or solvate thereof. (Item 31) The peptide inhibitor has the formula (VIa), (VIb), (VIc), or (VId): Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11(VIa), Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11(VIb), Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11(VIc), or Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11(VId) wherein in formulas (VIa), (VIb), (VIc), and (VId), X7 and X11 are as described in item 2, [F(4-2ae)] is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or an Abu-Cys or Abu-Pen thioether bond, or a pharma- ceutically acceptable salt or solvate thereof. (Item 32) The peptide inhibitor has the formula (II'): X7-X8-X9-X10-X11-X12-X13-X14-X15(II') and wherein the amino acid sequence is X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, or cyclohexyl Ala, Lys, or Aib; X13 is Aib, Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys, or X13 is Lys, pegylated Lys, b-homoGlu, or Lys(Y2-Ac), where Y2 is an amino acid; X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Ala, (D)Ala, beta-Ala, His, Thr, n-Leu, Gln, Ser, (D)Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Leu, Aib, (D)Leu, beta-Ala, Cit, Gln, Asp, alpha-MeGln, alpha-MeAsn, Lys(Ac), (D)Lys, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), or homo-Lys(Ac), or absent; 32. The peptide inhibitor according to any one of items 2 to 31, or a pharma- ceutically acceptable salt or solvate thereof. (Item 33) The peptide inhibitor has formula (VIIa), (VIIb), or (VIIc): Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15(VIIa), Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-X12-X13-X14-X15(VIIb), or Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15(VIIc) wherein in formula (VIIa), (VIIb), and (VIIc): X7 and X11 are as described in item 2, X12 to X15 are as described in item 32, and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or an Abu-Cys or Abu-Pen thioether bond; 33. The peptide inhibitor according to item 32, or a pharma- ceutically acceptable salt or solvate thereof. (Item 34) 34. The peptide inhibitor according to item 33, or a pharma- ceutically acceptable salt or solvate thereof, wherein X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, Ala, cyclohexyl Ala, Lys, or Aib. (Item 35) 34. The peptide inhibitor according to item 33, or a pharma- ceutically acceptable salt or solvate thereof, wherein X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, or alpha-MeLeu. (Item 36) 34. The peptide inhibitor according to item 33, or a pharma- ceutically acceptable salt or solvate thereof, wherein X12 is alpha-MeLeu. (Item 37) 37. The peptide inhibitor according to any one of items 32 to 36, or a pharma- ceutically acceptable salt or solvate thereof, wherein X13 is Glu, Gln, Lys(Ac), or Lys. (Item 38) 37. The peptide inhibitor according to any one of items 32 to 36, or a pharma- ceutically acceptable salt or solvate thereof, wherein X13 is Gln, Lys(Ac), or Lys. (Item 39) 37. The peptide inhibitor according to any one of items 32 to 36, wherein X13 is Lys(Ac), or Lys, or a pharma- ceutically acceptable salt or solvate thereof. (Item 40) 37. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 32 to 36, wherein X13 is Lys(Ac). (Item 41) The peptide inhibitor has formula (VIIIa), (VIIIb) or (VIIIc): Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-aMeLeu-K(Ac)-X14-X15(VIIIa), Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-aMeLeu-K(Ac)-X14-X15(VIIIb), or Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-aMeLeu-K(Ac)-X14-X15(VIIIc) wherein in formula (VIIIa), (VIIIb) and (VIIIc): X7 and X11 are as described in item 2, X14, and X15 are as described in item 32, and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or an Abu-Cys or Abu-Pen thioether bond; 33. The peptide inhibitor according to item 32, or a pharma- ceutically acceptable salt or solvate thereof. (Item 42) 42. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 32 to 41, wherein X14 is Asn. (Item 43) 43. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 32 to 42, wherein X15 is Asn. (Item 44) The peptide inhibitor has formula (IXa), (IXb), or (IXc): Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-K(Ac)-Asn-Asn(IXa), Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-K(Ac)-Asn-Asn(IXb), or Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-K(Ac)-Asn-Asn(IXc) wherein in formula (IXa), (IXb), and (IXc): X7 and X11 are as described in item 2, and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or an Abu-Cys or Abu-Pen thioether bond; 33. The peptide inhibitor according to item 32, or a pharma- ceutically acceptable salt or solvate thereof. (Item 45) 45. The peptide inhibitor according to any one of items 1 to 44, wherein X7 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, and X11 is as described in item 1, or a pharma- ceutically acceptable salt or solvate thereof. (Item 46) 45. The peptide inhibitor according to any one of items 1 to 44, wherein X11 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, and X7 is as described in item 1, or a pharma- ceutically acceptable salt or solvate thereof. (Item 47) The peptide inhibitor has formula (Xa), (Xb), (Xc), (Xd), (Xe), or (Xf): Pen-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-X11-aMeLeu-K(Ac)-Asn-Asn(Xa), Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-W'-aMeLeu-K(Ac)-Asn-Asn(Xb), Abu-Asn-Thr-W'-Gln-Cys-[F(4-2ae)]-X11-aMeLeu-K(Ac)-Asn-Asn(Xc), Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-W'-aMeLeu-K(Ac)-Asn-Asn(Xd), Abu-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-X11-aMeLeu-K(Ac)-Asn-Asn(Xe), or Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-W'-aMeLeu-K(Ac)-Asn-Asn(Xf) wherein in formula (Xa), (Xb), (Xc), (Xd), (Xe), and (Xf): X7 and X11 are as described in item 2, W' is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or an Abu-Cys or Abu-Pen thioether bond; 33. The peptide inhibitor according to item 32, or a pharma- ceutically acceptable salt or solvate thereof. (Item 48) 48. The peptide inhibitor according to any one of items 1 to 47, wherein X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal, or a pharma- ceutically acceptable salt or solvate thereof. (Item 49) 48. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 1 to 47, wherein X11 is 2-Nal, or 1-Nal. (Item 50) 48. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 1 to 47, wherein X11 is 2-Nal. (Item 51) 48. The peptide inhibitor according to any one of items 1 to 47, or a pharma- ceutically acceptable salt or solvate thereof, wherein X7 is unsubstituted Trp. (Item 52) The peptide inhibitor has formula (XIa), (XIb), (XIc), (XId), (XIe), or (XIf): Pen-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-[2-Nal]-aMeLeu-K(Ac)-Asn-Asn(XIa) (SEQ ID NO: 100), Pen-Asn-Thr-W-Gln-Pen-[F(4-2ae)]-W'-aMeLeu-K(Ac)-Asn-Asn(XIb) (SEQ ID NO: 101), Abu-Asn-Thr-W'-Gln-Cys-[F(4-2ae)]-[2-Nal]-aMeLeu-K(Ac)-Asn-Asn(XIc) (SEQ ID NO: 102), Abu-Asn-Thr-W-Gln-Cys-[F(4-2ae)]-W'-aMeLeu-K(Ac)-Asn-Asn(XId) (SEQ ID NO: 103), Abu-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-[2-Nal]-aMeLeu-K(Ac)-Asn-Asn(XIe) (SEQ ID NO: 104), or Abu-Asn-Thr-W-Gln-Pen-[F(4-2ae)]-W'-aMeLeu-K(Ac)-Asn-Asn(XIf) (SEQ ID NO: 105) wherein in formula (XIa), (XIb), (XIc), (XId), (XIe), and (XIf): W' is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or an Abu-Cys or Abu-Pen thioether bond; 2. The peptide inhibitor according to item 1, or a pharma- ceutically acceptable salt or solvate thereof. (Item 53) The peptide inhibitor has the formula (Z): R 1 -XR 2 (Z) or a pharma- ceutically acceptable salt or solvate thereof, wherein: R 1 is a bond, hydrogen, Ac, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl-C1-6 alkyl, C1-C20 alkanoyl, including PEGylated versions of any of the above alone or as a spacer, X is an amino acid sequence of any of Formulas (I), (II)-(XIf), or an amino acid sequence shown in any of Tables E1, E2, or E3, and R 2 is OH or NH 2 That is, 53. The peptide inhibitor according to any one of items 1 to 52, or a pharma- ceutically acceptable salt or solvate thereof. (Item 54) R 1 54. The peptide inhibitor according to item 53, or a pharma- ceutically acceptable salt or solvate thereof, wherein is H or C1-C20 alkanoyl. (Item 55) R 1 54. The peptide inhibitor according to item 53, or a pharma- ceutically acceptable salt or solvate thereof, wherein is H or Ac. (Item 56) R 1 54. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to item 53, wherein is Ac. (Item 57) 57. The peptide inhibitor according to any one of items 47 to 56, or a pharma- ceutically acceptable salt or solvate thereof, wherein W' is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, and the substitution is at the 4, 5, 6, or 7 position. (Item 58) W' is cyano, F, Cl, Br, I, Me, Et, i-Pr, n-Pr, n-Bu, t-Bu, CF 3 57. The peptide inhibitor or a pharma- ceutically acceptable salt or solvate thereof according to any one of items 47 to 56, wherein Trp is substituted with hydroxy, OMe, or OEt, and said substitution is at the 4, 5, 6 or 7 position. (Item 59) 57. The peptide inhibitor according to any one of items 47 to 56, or a pharma- ceutically acceptable salt or solvate thereof, wherein W' is Trp substituted with 5-F, 6-F, 7-F, 5-Cl, 6-Cl, 7-Cl, 5-Me, 6-Me, 7-Me, 5-OH, 6-OH, 7-OH, 5-OMe, 6-OMe, or 7-OMe. (Item 60) 57. The peptide inhibitor according to any one of items 47 to 56, or a pharma- ceutically acceptable salt or solvate thereof, wherein W' is Trp substituted with 7-Me, 5-F, 7-F, 6-Cl, 6-Me, 4-OMe, 5-OMe, or 5-Br. (Item 61) 57. The peptide inhibitor according to any one of items 47 to 56, or a pharma- ceutically acceptable salt or solvate thereof, wherein W' is Trp substituted with 7-Me, 6-Me, 4-OMe, or 6-Cl. (Item 62) 57. The peptide inhibitor according to any one of items 47 to 56, or a pharma- ceutically acceptable salt or solvate thereof, wherein W' is Trp substituted with 7-Me. (Item 63) below: Ac-[Pen]-NT-[W(7-Me)]-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH 2 (SEQ ID NO: 6), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 201), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 227), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 242), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 (SEQ ID NO: 245), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-H-NH 2 (SEQ ID NO: 248), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Cit]-NH 2 (SEQ ID NO: 249), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Val]-NH 2 (SEQ ID NO: 251), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-NH 2 (SEQ ID NO: 252), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Arg]-NH 2 (SEQ ID NO: 256), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Phe]-NH 2 (SEQ ID NO: 258), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Tyr]-NH 2 (SEQ ID NO: 259), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NS-NH 2 (SEQ ID NO: 260), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Ser]-NH 2 (SEQ ID NO: 261), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Thr]-NH 2 (SEQ ID NO: 263), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Aib]-NH 2 (SEQ ID NO: 264), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-[N-MeAla]-NH 2 (SEQ ID NO: 265), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 267), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Achc]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 274), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[DiethylGly]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 276), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acbc]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 277), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeOrn]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 278), Ac-[Pen]-NT-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 (SEQ ID NO: 284), Ac-[Pen]-NT-[W(7-n-Pr)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 (SEQ ID NO: 285), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 (SEQ ID NO: 320), or Ac-[Pen]-NT-[W(7-Me)]-[Lys(Aib)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 (SEQ ID NO:322) or a pharma- ceutically acceptable salt or solvate thereof, wherein said peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or an Abu-C thioether bond. (Item 64) The peptide is Ac-[Pen]-NT-[W(4-OMe)]-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH 2 (SEQ ID NO: 4), Ac-[Pen]-NT-[W(6-Me)]-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH 2 (SEQ ID NO:5), Ac-[Pen]-NTW-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-W(6-Cl)-[α-MeLeu]-[Lys(Ac)]-NN-NH 2 (SEQ ID NO: 13), Ac-[Pen]-NTW-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-W(6-Me)-[α-MeLeu]-[Lys(Ac)]-NN-NH 2 (SEQ ID NO: 16), Ac-[Pen]-NTW-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-W(5-Br)-[α-MeLeu]-[Lys(Ac)]-NN-NH 2 (SEQ ID NO: 22), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 202), Ac-[(D)Arg]-Abu-QT-[W(7-Me)]-QC-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[bA]-NH 2 (SEQ ID NO: 203), Ac-Abu-QT-[W(7-Me)]-QC-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[bA]-NH 2 (SEQ ID NO: 204), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-G-[bA]-NH 2 (SEQ ID NO: 205), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-A-[bA]-NH 2 (SEQ ID NO: 207), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-L-[bA]-NH 2 (SEQ ID NO: 208), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-[(D)Ala]-[bA]-NH 2 (SEQ ID NO: 209), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-H-[bA]-NH 2 (SEQ ID NO: 214), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-[(D)His]-[bA]-NH 2 (SEQ ID NO: 215), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-T-[bA]-NH 2 (SEQ ID NO: 217), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-S-[bA]-NH 2 (SEQ ID NO: 221), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-[(D)Ser]-[bA]-NH 2 (SEQ ID NO: 222), Ac-[Pen]-NT-[W(4-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 231), Ac-[Pen]-NT-[W(1-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 232), Ac-[Pen]-NT-[W(7-Me)]-[a-MeLys]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 234), Ac-[Pen]-NT-[W(7-Me)]-[a-MeLeu]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 235), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Aib]-N-[bA]-NH 2 (SEQ ID NO: 236), Ac-[Pen]-QT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 237), Ac-[Pen]-[Cit]-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 238), Ac-[Pen]-[Lys(Ac)]-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 239), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-R-NH 2 (SEQ ID NO: 243), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-L-NH 2 (SEQ ID NO: 244), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[NMeArg]-NH 2 (SEQ ID NO: 246), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bhPhe]-NH 2 (SEQ ID NO: 247), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-V-NH 2 (SEQ ID NO: 250), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-P-NH 2 (SEQ ID NO: 253), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Pro]-NH 2 (SEQ ID NO: 254), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NI-NH 2 (SEQ ID NO: 255), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Phe]-NH 2 (SEQ ID NO: 257), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-[bA]-[bA]-NH 2 (SEQ ID NO: 268), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-L-[bA]-NH 2 (SEQ ID NO: 269), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-[bA]-[bA]-NH 2 (SEQ ID NO: 270), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-S-[bA]-NH 2 (SEQ ID NO: 271), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-H-[bA]-NH 2 (SEQ ID NO: 272), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-E-[bA]-[bA]-NH 2 (SEQ ID NO: 273), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Spiral_Pip]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 275), Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Cit]-[bA]-[bA]-NH 2 (SEQ ID NO: 279), Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-E-N-[bA]-NH 2 (SEQ ID NO: 282), Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[W(1-Me)]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 283), Ac-[Pen]-N-T-[W(7-i-Pr)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 (SEQ ID NO: 286), Ac-[Pen]-N-T-[W(7-OMe)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2(SEQ ID NO: 288), Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[2-Nal]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 (SEQ ID NO: 289), Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-H-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 (SEQ ID NO: 290), Ac-[Pen]-N-T-[W(7-OMe)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-NH 2 (SEQ ID NO: 297), Ac-[Pen]-N-T-[W(7-OMe)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-NH 2 (SEQ ID NO: 299), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ala)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 (SEQ ID NO: 314), Ac-[Pen]-NT-[W(7-Me)]-[Lys(IVA)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 (SEQ ID NO: 315), Ac-[Pen]-NT-[W(7-Me)]-[Lys(cyclohexanoic acid)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 ; (SEQ ID NO: 316), Ac-[Pen]-NT-[W(7-Me)]-[Lys(bAla)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 ; (SEQ ID NO: 321), Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH 2 (SEQ ID NO: 323), or Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 ;(SEQ ID NO:325) and The peptide inhibitor is cyclized via a Pen-Pen disulfide bond. 64. The peptide inhibitor according to item 63, or a pharma- ceutically acceptable salt or solvate thereof. (Item 65) The peptide is Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-NH 2 (SEQ ID NO:27), Ac-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-NH 2 (SEQ ID NO:28), Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NN-NH 2 (SEQ ID NO:29), or Ac-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NN-NH 2 (SEQ ID NO:30) and The peptide inhibitor is cyclized via an Abu-C thioether bond. 64. The peptide inhibitor according to item 63, or a pharma- ceutically acceptable salt or solvate thereof. (Item 66) A peptide inhibitor of the interleukin-23 receptor, the peptide having an amino acid sequence shown in any of Table E1, Table E2, or Table E3, or a pharma- ceutically acceptable salt or solvate thereof. (Item 67) The peptide is Ac-[Pen]-NT-[W(5-F)]-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH 2 2. The peptide inhibitor according to item 1, wherein the peptide inhibitor is (SEQ ID NO: 7) or a pharma- ceutically acceptable salt or solvate thereof. (Item 68) The peptide is Ac-[Pen]-[Cit]-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO:238)

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Claims

1. A peptide or a pharma- ceutically acceptable salt or solvate thereof, The peptide has the formula (II): X4-X5-X6-X7-X8-X9-X10-X11 (II) wherein the amino acid sequence is X4 is Abu; X5 is Cit, Glu, Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, Asp, or Cys; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is Trp substituted with alkyl; X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp; X9 is Cys or Pen; X10 is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with halo, alkyl, haloalkyl, hydroxy, or alkoxy; The peptide is cyclized via a thioether bond between X4 and X9, provided that: when X7 is Trp substituted with 1-Me, ​​X9 is other than Cys; and The peptide inhibits the binding of interleukin-23 (IL-23) to the IL-23 receptor. A peptide or a pharma- ceutically acceptable salt or solvate thereof.

2. 2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein X4 is Abu and X9 is Cys and the bond is a thioether bond.

3. The peptide comprises an amino acid sequence of formula (IIb) or (IIc), Abu-X5-X6-X7-X8-Cys-X10-X11 (IIb) Abu-X5-X6-X7-X8-Pen-X10-X11 (IIc) the peptide is cyclized via an Abu-Cys or Abu-Pen thioether bond; 2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

4. 2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein X5 is Asn, Gln, or Glu.

5. The peptide comprises an amino acid sequence of formula (IIIc) or (IIId): Abu-Asn-X6-X7-X8-Cys-X10-X11 (IIIc) Abu-Gln-X6-X7-X8-Pen-X10-X11 (IIId) The peptide is cyclized via an Abu-Cys or Abu-Pen thioether bond.

2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

6. 2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein X6 is Thr.

7. The peptide comprises an amino acid sequence of formula (IVc) or (IVd), Abu-Asn-Thr-X7-X8-Cys-X10-X11 (IVc) Abu-Gln-Thr-X7-X8-Pen-X10-X11 (IVd) the peptide is cyclized via an Abu-Cys or Abu-Pen thioether bond; 2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

8. 2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein X8 is Gln, alpha-Me-Lys, alpha-MeLys(Ac), or Glu.

9. The peptide comprises an amino acid sequence of formula (Vc) or (Vd), Abu-Asn-Thr-X7-Gln-Cys-X10-X11 (Vc) Abu-Gln-Thr-X7-Gln-Pen-X10-X11 (Vd) The peptide is cyclized via an Abu-Cys or Abu-Pen thioether bond.

2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

10. X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], or Phe(4-CONH ２ 2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

11. The peptide comprises an amino acid sequence of formula (VIc) or (VId), Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11(VIc) Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11(VId) 2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein [F(4-2ae)] is Phe[4-(2-aminoethoxy)] and the peptide is cyclized via an Abu-Cys or Abu-Pen thioether bond.

12. The peptide has the formula (II'): X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15 (II') and wherein the amino acid sequence is represented by the formula (II'): X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, or cyclohexylAla, Lys, or Aib; X13 is Aib, Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac) or Lys, or X13 is pegylated Lys or b-homoGlu; X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Ala, (D)Ala, beta-Ala, His, Thr, n-Leu, Gln, Ser, (D)Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Leu, Aib, (D)Leu, beta-Ala, Cit, Gln, Asp, alpha-MeGln, alpha-MeAsn, Lys(Ac), (D)Lys, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), or homo-Lys(Ac), or absent; 2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

13. The peptide comprises an amino acid sequence of formula (VIIb) or (VIIc), Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-X12-X13-X14-X15 (VIIb) Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15 (VIIc) The peptide is cyclized via an Abu-Cys or Abu-Pen thioether bond.

13. The peptide of claim 12, or a pharma- ceutically acceptable salt or solvate thereof.

14. 14. The peptide of claim 13, or a pharma- ceutically acceptable salt or solvate thereof, wherein X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, Ala, cyclohexylAla, Lys, or Aib.

15. 13. The peptide of claim 12, or a pharma- ceutically acceptable salt or solvate thereof, wherein X13 is GIu, Gln, Lys(Ac), or Lys.

16. The peptide comprises an amino acid sequence of formula (VIIIb) or (VIIIc), Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-aMeLeu-K(Ac)-X14-X15(VIIIb) Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-aMeLeu-K(Ac)-X14-X15(VIIIc) The peptide is cyclized via an Abu-Cys or Abu-Pen thioether bond.

13. The peptide of claim 12, or a pharma- ceutically acceptable salt or solvate thereof.

17. 13. The peptide of claim 12, or a pharma- ceutically acceptable salt or solvate thereof, wherein X14 is Asn.

18. 13. The peptide of claim 12, or a pharma- ceutically acceptable salt or solvate thereof, wherein X15 is Asn.

19. 2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein X7 is Trp substituted with methyl, ethyl, n-propyl, or isopropyl.

20. 2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein X11 is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy.

21. The peptide comprises an amino acid sequence of formula (Xc), (Xd), (Xe), or (Xf), Abu-Asn-Thr-W'-Gln-Cys-[F(4-2ae)]-X11-aMeLeu-K(Ac)-Asn-Asn(Xc) Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-W'-aMeLeu-K(Ac)-Asn-Asn(Xd) Abu-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-X11-aMeLeu-K(Ac)-Asn-Asn(Xe) Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-W'-aMeLeu-K(Ac)-Asn-Asn(Xf) W' is an alkyl-substituted Trp, and the peptide is cyclized via an Abu-Cys or Abu-Pen thioether bond; 13. The peptide of claim 12, or a pharma- ceutically acceptable salt or solvate thereof.

22. 2. The peptide according to claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal.

23. The peptide comprises an amino acid sequence of formula (XIc), (XId), or (XIe), Abu-Asn-Thr-W'-Gln-Cys-[F(4-2ae)]-[2-Nal]-aMeLeu-K(Ac)-Asn-Asn(XIc) (SEQ ID NO: 102) Abu-Asn-Thr-W-Gln-Cys-[F(4-2ae)]-W'-aMeLeu-K(Ac)-Asn-Asn(XId) (SEQ ID NO: 103) Abu-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-[2-Nal]-aMeLeu-K(Ac)-Asn-Asn(XIe) (SEQ ID NO: 104) W' is an alkyl-substituted Trp, and the peptide is cyclized via an Abu-Cys or Abu-Pen thioether bond; 2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

24. The peptide has the formula (Z): R １ -X-R ２ (Z) or a pharma- ceutically acceptable salt or solvate thereof, wherein: R １ is a bond, hydrogen, Ac, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl-C1-6 alkyl, C1-C20 alkanoyl, including PEGylated versions of any of the above alone or as a spacer, X is an amino acid sequence of formula (II), and R ２ is OH or NH ２ That is, 2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

25. 22. The peptide of claim 21, or a pharma- ceutically acceptable salt or solvate thereof, wherein W' is Trp substituted with alkyl, and said substitution is at the 4, 5, 6, or 7 position.

26. 2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, further comprising a conjugated chemical substituent selected from a lipophilic substituent and a polymer moiety.

27. The conjugated chemical substituents are Ac, Palm, gamaGlu-Palm, isoGlu-Palm, PEG having a molecular weight of 400 Da to 40,000 Da, PEG2-Ac, PEG4-isoGlu-Palm, (PEG) ５ 27. The peptide of claim 26, or a pharma- ceutically acceptable salt or solvate thereof, wherein the peptide is -Palm, succinic acid, glutaric acid, pyroglutaric acid, benzoic acid, IVA, octanoic acid, 1,4 diaminobutane, isobutyl, or biotin.

28. A pharmaceutical composition comprising the peptide according to any one of claims 1 to 27, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier, excipient, or diluent.

29. The pharmaceutical composition described in claim 28, which inhibits the binding of interleukin-23 (IL-23) to the IL-23 receptor.

30. 30. The pharmaceutical composition of claim 28 or 29, further comprising an enteric coating.

31. 28. The method of claim 1, further comprising administering to a subject a therapeutically effective amount of a peptide according to claim 1 or a pharmacologic agent or a medicament for the treatment of inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation or chemotherapy, colitis associated with disorders of innate immunity such as in leukocyte adhesion deficiency type 1, In one embodiment, the pharmaceutical composition is for treating colitis resulting from rectal resection and ileoanal anastomosis, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich syndrome, pouchitis resulting from proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, or graft versus host disease.

32. 32. The pharmaceutical composition of claim 31, wherein the pharmaceutical composition is provided to the subject by an oral, parenteral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization, sublingual, buccal, parenteral, rectal, intraocular, inhalation, topical, vaginal, or external route of administration.

33. 32. The pharmaceutical composition of claim 31 for treating inflammatory bowel disease (IBD), ulcerative colitis, or Crohn's disease, wherein the pharmaceutical composition is provided orally to the subject.

34. 32. The pharmaceutical composition of claim 31 for treating psoriasis, wherein the pharmaceutical composition is provided to the subject orally, topically, parenterally, intravenously, subcutaneously, peritoneally, or intravenously.

35. The peptide is Ac-[(D)Arg]-Abu-Q-T-[W(7-Me)]-Q-C-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[bA]-NH ２ (SEQ ID NO: 203), Ac-Abu-Q-T-[W(7-Me)]-Q-C-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[bA]-NH ２ (SEQ ID NO: 204), Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sar]-NH ２ ; (SEQ ID NO: 323), Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH ２ ; (SEQ ID NO: 325) Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-NH ２ (SEQ ID NO:27), Ac-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-NH ２ (SEQ ID NO:28), Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NN-NH ２ (SEQ ID NO:29), or Ac-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NN-NH ２ (SEQ ID NO: 30) and The peptide is cyclized via an Abu-Cys thioether bond.

2. The peptide of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

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