Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases

Abstract

To provide a novel therapeutic agent targeting the interleukin-23 (IL-23) pathway, which may be used to treat and prevent IL-23-associated diseases.SOLUTION: Provided are novel peptide inhibitors of the interleukin-23 receptor (IL-23R), as well as related compositions and methods of using these peptide inhibitors for treating or preventing various diseases and disorders, including inflammatory bowel disease. In one aspect, provided are monocyclic peptide inhibitors of the IL-23R, or pharmaceutically acceptable salts or solvates thereof, which comprise a specific amino acid sequence and inhibit the binding of IL-23 to the IL-23 receptor.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application is a continuation of U.S. Provisional Patent Application No. 62 / 961,618, filed January 15, 2020. Priority is claimed on all aspects of the present invention, which is incorporated herein by reference in its entirety for all purposes. It is incorporated into the detailed text.

[0002] (Sequence Listing) This application has been filed electronically via EFS-Web and is available electronically in .txt format. The .txt file containing the submitted sequence listing was created on January 14, 2021, and is approximately 2 "056365_514001WO_Sequence" has a size of 30 KB This .txt file contains a sequence listing entitled "_Listing_ST25.txt". The sequence listing contained in is part of the present specification and is incorporated herein by reference in its entirety. .

[0003] FIELD OF THE INVENTION The present invention relates to novel peptide inhibitors of interleukin-23 receptor (IL-23R), as well as and to treat a variety of diseases and disorders, including inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis. and its use for the treatment or prevention of [Background technology]

[0004] Interleukin-23 (IL-23) cytokines play a key role in multiple sclerosis, asthma, and arthritis. Euthanasia, psoriasis, and inflammatory bowel disease (IBD), e.g., ulcers In the pathogenesis of autoimmune inflammation and related diseases and disorders, such as ulcerative colitis and Crohn's disease Studies in acute and chronic mouse models of IBD This highlights the key role of IL-23R and downstream effector cytokines in disease pathogenesis. IL-23R is involved in the expression of Th17 cells, γδT cells, and IL-23R is involved in the expression of Th17 cells, which are abundant in the intestine. cells, natural killer (NK) cells, dendritic cells, macrophages, and It is expressed in various adaptive and innate immune cells, including intestinal and innate lymphoid cells. It was found that gene expression and protein levels of IL-23R are increased at mucosal surfaces. IL-23 is a cytotoxic inhibitor of IL-6, IL-17, and tumor necrosis factor (TNF). Pathogenic CD4 producing tumor necrosis factor (TNF) + By promoting the development of T cell populations , which is thought to mediate this effect.

[0005] IL-23 is produced in large amounts in the intestine, where it acts as a regulator of T-helper 1 (Th1) and and Th17-associated cytokines, thereby enhancing the T cell-dependent and T cell-mediated mechanisms of intestinal inflammation. In addition to controlling the balance between tolerance and immunity through a mitochondrial-independent pathway, It is thought to play an important role in suppressing the regulatory T cell response in the intestine. Polymorphisms in the IL-23 receptor (IL-23R) may influence susceptibility to inflammatory bowel disease (IBD). has been associated with morbidity, thereby contributing to the role of IL-23 in intestinal homeostasis. The important role of the road was further established.

[0006] Psoriasis, a chronic skin disease that affects approximately 2% to 3% of the general population, is a T-cell inflammation of the body. IL-23 has been shown to be mediated by the interleukin-1 response mechanism. Chronic autoimmune inflammation through induction of inflammatory cytokines (e.g., inflammatory bowel disease), regulation of T memory cells, and activation of macrophages It is believed that the mechanism of psoriasis pathogenesis is mainly due to the maintenance of It is one of several interleukins that are involved in the expression of IL-23 and IL-23R. It has been shown to be elevated in tissues of psoriasis patients, and antibodies that neutralize IL-23 demonstrated IL-23-dependent inhibition of psoriasis development in an animal model of psoriasis.

[0007] IL-23 has a unique p19 subunit and a p19 subunit that encodes interferon-γ (IFN-γ) production. Raw T helper 1 (T H 1) It is shared with IL-12, a cytokine involved in cell development. It is a heterodimer composed of the p40 subunit and the p40 subunit. Although both contain the p40 subunit, they have different phenotypic properties. Animals lacking IL-12 are prone to inflammatory autoimmune diseases, whereas IL-23-deficient animals The immune system is resistant to IL-23, possibly due to the role of IL-6, IL-1 in the CNS of IL-23-deficient animals. -17, and TNF-producing CD4 + This is due to a decrease in the number of T cells. I is a heterodimeric receptor composed of IL-12Rβ1 and IL-23R subunits. Binding of IL-23 to IL-23R induces Jak-stat Signal transduction molecules, Jak2, Tyk2, and Stat1, Stat3, Stat4, and Stat5 are activated, but compared with IL-12, Stat4 activation is substantially The IL-23 complex is weakly expressed and a distinct DNA-binding Stat complex is formed in response to IL-23. 23R associates constitutively with Jak2 and ligand-dependently with Stat3. In contrast to IL-12, which acts primarily on naive CD4(+) T cells, IL-23 acts primarily on naive CD4(+) T cells. It acts preferentially on CD4(+) T cells.

[0008] IL-23 pathway inhibitors for use in the treatment of IL-23-associated diseases and disorders Attempts have been made to identify therapeutic moieties for moderate to severe fetal psoriasis, active psoriatic arthritis, and arthritis, moderately to severely active Crohn's disease, and moderately to severely active ulcerative colitis Urokinase, an antibody that binds to the p40 subunit of IL-23, has been approved for treatment. A number of antibodies that bind to IL-23 or IL-23R have been identified, including stekinumab. More recently, it has been reported that IL-23 binds to IL-23R and inhibits the binding of IL-23 to IL-23R. Polypeptide inhibitors have been identified (see, e.g., U.S. Patent Application Publication No. 2013 / 002299). (See issue 9907). Briakinumab (also targets the common p40 subunit) , as well as tildrakizumab, guselkumab, MEDI2070, and BI-655066 Clinical improvement of Crohn's disease or psoriasis by targeting the unique p19 subunit of IL-23 Clinical trials highlight the potential of blocking IL-23 signaling in the treatment of human inflammatory diseases. Although these findings are encouraging, the clinical significance of these drugs in patients with Crohn's disease, ulcerative colitis, and related conditions remains unclear. Intestinal IL-1 receptors can be used to treat intestinal diseases such as enteritis, including disorders that cause 23 Challenges remain regarding the identification of stable and selective agents that preferentially target the pathway. Summary of the Invention

[0009] Apparently, treating IL-23-associated diseases, including those associated with autoimmune inflammation in the intestinal tract New therapeutic agents targeting the IL-23 pathway have been developed that can be used to treat and prevent There remains a need in the art for methods to deliver IL-2 from the luminal side of the intestine. Compounds and methods for specifically targeting 3R I are useful in treating intestinal tissue suffering from local inflammation. The present invention provides a method for the treatment of BD patients by binding to IL-23R and inhibiting IL-2 We present a novel peptide inhibitor that inhibits the binding and signal transduction of 3 and is suitable for oral administration. We address these needs by providing

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

[0011] In a first aspect, the present invention provides monocyclic peptide inhibitors of the interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor has the formula: I) comprising or consisting of the amino acid sequence X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X1 4-X15-X16(I) During the ceremony, X3 is absent or any amino acid; each X4, X5, and X6 is independently any amino acid; X7 is unsubstituted Trp, or cyano, halo, alkyl, haloalkyl, hydroxy , alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. is a substituted Trp, X8: Gln, alpha-MeLys, alpha-MeLeu, alpha-MeLy s(Ac), beta-homoGln, Cit, Glu, Phe, Paf(Ac), Phe4 NH2Ac, Asn, Thr, Val, Aib, alpha-MeGln, alpha-Me Asn, 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, Pe n, or Pen(sulfoxide); X10 is unsubstituted Phe, or halo, alkyl, haloalkyl, hydroxy, alkoxy hydroxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy Toxi, AEF, AEF(Ac), AEF(BH), AEF(Boc), AEF(Me) 2, bMeRPhe, Phe42ae-ethyl, Phe42aeSMSB, Phe4Pi Phe substituted with p, X11 is 6 amide 2Nal, 6OMe2Nal, bMe2Nal(2S,3R), r bMe2Nal, 2-Nal, aMe(2-Nal), Phe(2-Me), Phe(3 -Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted T rp, or cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy is a substituted Trp, X12 is 4diFAchx, Achx, Acpx, AmeK(Boc), 4-amino -4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha- MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha Alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexyl cyclohexyl Ala, 1-aminocyclohexyl Ala (Achc), Acvc, Lys, or Aib, X13 and X14 are independently any amino acid; i) X16 is absent, and X15 is His, Phe-tetraF, Phe_3OH, ameF, Aib, THP, Phe, substituted Phe, substituted (D)Phe, a-MePhe, Substituted a-MePhe, Trp, Substituted Trp, 1-Nal, aMe(1-Nal), Substituted 1 -Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted Asn There is, However, the peptide inhibitor Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4 -(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac) ]-N-[Aib]-NH2 (SEQ ID NO: 151) or Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac )]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aM eLys]-[Lys(Ac)]-N-[a-MePhe]-NH2 (SEQ ID NO: 201) or ii) X16 is paf, Aib, 3Pal, Phe, substituted Phe, substituted (D)Phe , substituted or unsubstituted Tyr, unsubstituted (D)Tyr, a-MePhe, substituted a-MePh e, b-hPhe, 1-Nal, aMe(1-Nal), substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted Asn, and X15 is any Although it is an amino acid, However, the peptide inhibitor Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[ 4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac )]-N-[Aib]-[(D)Tyr]-NH2 (SEQ ID NO: 202) The conditions are: or iii) the peptide is Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[3-Quin]-[α-MeLys]-[L ys(Ac)]-N-[(D)Leu)]-NH2 (SEQ ID NO: 1), Ac-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[(D)Lys]-NH2 (SEQ ID NO: 64), Ac-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 65), Ac-[Pen]-N-[(D)Dap]-[W(7-Me)]-[Lys(Ac)] -[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeL Lys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 72), Ac-[Pen]-N-[(D)Lys]-[W(7-Me)]-[Lys(Ac)] -[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeL Lys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 73), Ac-[Pen]-N-[(D)Asp]-[W(7-Me)]-[Lys(Ac)] -[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeL Lys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 74), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[Aib-Ahx]-NH2 (SEQ ID NO: 70), [Propionic acid]-[(D)Arg]-[Pen]-QTWQ-[Pen]-P he[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[NM e-bAla]-NH2 (SEQ ID NO: 8), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[N-Me-bAla ]-NH2 (SEQ ID NO: 14), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-[aM eTyr]-NH2 (SEQ ID NO: 44), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-[αMeGlu]-N-[αMeTyr]-NH2 (SEQ ID NOs: 150, 44), or Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[aMeTyr]-NH2 (SEQ ID NO: 151); and, The peptide inhibitors are either Abu-Cys thioether bonds or Pen-Pen disulfides. cyclized via a bond, and, X4 and X9 form a disulfide bond or a thioether bond, and, The peptide inhibitor binds to the IL-23 receptor of interleukin-23 (IL-23). a peptide inhibitor, or a pharmaceutically acceptable salt or solvate thereof, which inhibits the binding of provide.

[0012] In a second aspect, the present invention provides monocyclic peptide inhibitors of the interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor has the formula: II) comprising or consisting of the amino acid sequence X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X 15-X16(II) wherein X7 to X16 are as described for formula (I); X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pe n, or Pen(sulfoxide); X5: Cit, Glu, Gly, Leu, Ile, beta-Ala, Ala, Lys , Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLe u, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab( Ac), Dap(Ac), homo-Lys(Ac), Gln, Asp, or Cys; X6: Thr, Alb, Asp, Dab, Gly, Pro, Ser, Alpha-Me Gln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha alpha-MeThr, alpha-MeSer, or Val, The peptide inhibitor is cyclized via the bond between X4 and X9, Peptide inhibitors inhibit the binding of interleukin-23 (IL-23) to the IL-23 receptor. This hinders integration.

[0013] In certain embodiments, X15 is selected from His, Phe_tetraF, Phe_3OH, a meF, Aib, THP, Phe, substituted Phe, substituted (D)Phe, a-MePhe, substituted Substituted a-MePhe, Trp, Substituted Trp, 1-Nal, aMe(1-Nal), Substituted 1- Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted Asn Therefore, X16 does not exist.

[0014] In certain embodiments, X15 is any amino acid and X16 is paf, Aib, 3Pal, Phe, substituted Phe, substituted (D)Phe, substituted or unsubstituted Tyr, unsubstituted (D)Tyr, a-MePhe, substituted a-MePhe, b-hPhe, 1-Nal, aM e(1-Nal), substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Na l, or N-substituted Asn.

[0015] In certain embodiments, X15 is any amino acid and X16 is Aib, 3Pal , Phe, substituted Phe, substituted (D)Phe, substituted or unsubstituted Tyr, unsubstituted (D)T yr, a-MePhe, substituted a-MePhe, b-hPhe, 1-Nal, aMe(1- Nal), substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or It is N-substituted Asn.

[0016] In certain embodiments, N-substituted Asn is (N-Me)Asn, (N-Et)Asn, (Nn-Pr)Asn, (N-iPr)Asn, (N-iBu)Asn, (N-nBu )Asn, (N-tBu)Asn, (N-benzyl)Asn, (N-Ph)Asn, (N -2-aminophenyl)Asn, (N-3-aminophenyl)Asn, (N-4-amino (phenyl)Asn, (N-pyr)Asn, (N-3-Pyz)Asn, (N-4-Py z) Asn, (N-pip)Asn, (N-5-indolyl)Asn, (N-propyla (N-imidazo-2-yl)Asn, or (N-imidazo-2-yl)Asn.

[0017] In certain embodiments, X5 is selected from the group consisting of Cit, Glu, Gly, Lys, Asn, Pro, and As. Alpha-MeGln, Alpha-MeLys, Alpha-MeLeu, Alpha-MeA sn, 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.

[0018] In certain embodiments, X8 is Gln, alpha-Me-Lys, alpha-MeLe u, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, P af(Ac), Phe4NH2Ac, Asn, Thr, Val, Aib, alpha-Me Gln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Da b(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or T In certain embodiments, X8 is Gln, alpha-Me-Lys, alpha -MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Paf(Ac), Phe4NH2Ac, Asn, Thr, Val, Aib, Al alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap( Homo-Lys(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp.

[0019] In one embodiment, X4 is Abu and X9 is Cys, (D)Cys, alpha- In another embodiment, X4 is Cys, (D)Pen, or Pen. D) Cys, alpha-MeCys, (D) Pen, or Pen, and X9 is Abu In another embodiment, each X4 and X9 is independently Cys, (D)Cys, In another embodiment, each of X and X is selected from the group consisting of (D)-MeCys, (D)Pen, or Pen. 9 is Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen .

[0020] In a specific embodiment, the present invention provides monocyclic peptide inhibitors of the interleukin-23 receptor. or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is represented by the formula comprising or consisting of the amino acid sequence of (XIa) or (XIb), Pen-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-[2-Na l]-aMeLeu-K(Ac)-Asn-X15-X16(XIa) (SEQ ID NO: 323 ) or Pen-Asn-Thr-W-Gln-Pen-[F(4-2ae)]-W'-aMe Leu-K(Ac)-Asn-X15-X16(XIb) (SEQ ID NO: 324) wherein X15 and X16 are as defined herein; W' is cyano, halo, a Trp substituted with alkyl, haloalkyl, hydroxy, or alkoxy; The inhibitor is cyclized via a Pen-Pen disulfide bond.

[0021] In another specific embodiment, the present invention provides monocyclic peptide inhibitors of the interleukin-23 receptor. or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is , comprising or consisting of an amino acid sequence of formula (XIc) or (XId), Abu-Asn-Thr-W'-Gln-Cys-[F(4-2ae)]-[2-Na l]-aMeLeu-K(Ac)-Asn-X15-X16(XIc) (SEQ ID NO: 325 ) or Abu-Asn-Thr-W-Gln-Cys-[F(4-2ae)]-W'-aMe Leu-K(Ac)-Asn-X15-X16(XId) (SEQ ID NO: 326) wherein X15 and X16 are as defined herein; W' is cyano, halo, a Trp substituted with alkyl, haloalkyl, hydroxy, or alkoxy; The inhibitor is cyclized via an Abu-Cys thioether bond.

[0022] In another specific embodiment, the present invention provides monocyclic peptide inhibitors of the interleukin-23 receptor. or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is , comprising or consisting of an amino acid sequence of formula (XIe) or (XIf), Abu-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-[2-Na l]-aMeLeu-K(Ac)-Asn-X15-X16(XIe) (SEQ ID NO: 327 ) or Abu-Asn-Thr-W-Gln-Pen-[F(4-2ae)]-W'-aMe Leu-K(Ac)-Asn-X15-X16(XIf) (SEQ ID NO: 328) wherein X15 and X16 are as defined herein; W' is cyano, halo, a Trp substituted with alkyl, haloalkyl, hydroxy, or alkoxy; The inhibitor is cyclized via an Abu-Pen thioether bond.

[0023] In another specific embodiment, the present invention provides monocyclic peptide inhibitors of the interleukin-23 receptor. or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is , an amino acid sequence of formula (Z): R 1 -XR 2 (Z) Also, a peptide comprising or consisting of a pharmaceutically acceptable salt or solvate thereof. or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 alkanoyl, either alone or in combination with any of the foregoing. PEGylated versions of any of the spacers, and X is a group represented by the formula (I), formula (II) to (X If), or an amino acid sequence listed in Table E1, and R 2 is OH or NH 2).

[0024] The presently disclosed peptide inhibitors include those comprising the amino acid sequences of formulas (I) to (XIf). In specific embodiments of any of the peptide inhibitors provided herein, X4 is Pen; X9 is Pen and the bond is a disulfide bond.

[0025] In specific embodiments, any of the peptide inhibitors described herein is a peptide inhibitor one or more half-life extending moieties and / or one or more In a specific embodiment, the half-life extending moiety comprises one or more linker moieties. It is conjugated to a peptide inhibitor via an anchor moiety.

[0026] In specific embodiments, any of the peptide inhibitors described herein is a conjugate chemically substituted In specific embodiments, the conjugated chemical substituent further comprises a lipophilic substituent or a polymer moiety. Minutes, e.g., Ac, Palm, gamaGlu-Palm, isoGlu-Palm, P EG2-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 the form, the conjugated chemical substituents are polyethylene having a molecular weight of 400 Da to 40,000 Da. In a specific embodiment, the peptide is conjugated at X8. In a specific embodiment, the peptide is conjugated at X9. The thiols are conjugated at X10.

[0027] In a related aspect, the present invention provides peptide dimeric inhibitors of the interleukin-23 receptor. wherein the peptide dimeric inhibitor is connected via one or more linker moieties. and each peptide monomer subunit has the formula ( I), (II) to (XIf), or any other sequence or structure described herein. In certain embodiments, one or both peptide monomer subunits comprise X and X 9. In certain embodiments, one or both of the intramolecular The bond is a disulfide bond or a thioether bond. In certain embodiments, the linker is any of those shown in Table 2 or described herein. The linker part is a diethylene glycol linker, iminodiacetic acid acid (IDA) linker, β-Ala-iminodiacetic acid (β-Ala-IDA) linker, or a PEG linker. In a specific embodiment, the N of each peptide monomer subunit The termini are connected by a linker moiety. In a specific embodiment, each peptide monomer subunit The C-termini of the subunits are connected by a linker moiety. The peptides are synthesized by combining at least one internal amino acid residue of a peptide monomer subunit with another peptide. The amino acid residues are attached to the N-terminus, C-terminus, or internal amino acid residue of the monomelic subunit.

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

[0029] In another aspect, the present invention provides a method for treating a patient with a peptide inhibitor or peptide dimer inhibitor of the present invention, comprising administering to a patient a therapeutically effective amount of a compound selected from the group consisting of acetaminophen, benzodiazepine, benzodiazepine, benzophenone ...phenone, benzodiazepine, benzophenone, and a physiologically acceptable carrier, excipient, or diluent. In certain embodiments, the pharmaceutical composition comprises an enteric coating. The coating protects and releases the pharmaceutical composition within the subject's lower digestive system.

[0030] In another aspect, the present invention provides a method for treating inflammatory bowel disease (IBD), ulcerative colitis, cholangitis, and urinary tract infections in a subject. Enteropathy associated with seronegative arthropathy, microscopic Colitis, collagen colitis, eosinophilic gastroenteritis, radiation- or chemotherapy-related colitis, white Colitis, chronic granulomatous disease, associated with impaired innate immunity, such as hemocyte adhesion deficiency-1, 1b Glycogen storage disease type 2, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiss syndrome Cott-Aldrich syndrome, pouchitis after proctocolectomy and ileoanal anastomosis, digestive Cancer of the kidney, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholecititis, chronic tracheitis These include, but are not limited to, rhinosinusitis, chronic sinusitis, asthma, psoriasis, or graft-versus-host disease. 1. A method for treating or preventing a disease associated with impaired IL-23 signaling, comprising administering an effective amount of The present invention also includes methods comprising providing a peptide inhibitor or pharmaceutical composition of the present invention to a subject. In certain embodiments, the inflammatory bowel disease is ulcerative colitis or Crohn's disease. In some embodiments, the peptide inhibitor or peptide dimer inhibitor inhibits interleukin-23 (IL-23). -23) to the interleukin-23 receptor (IL-23R). In embodiments, the pharmaceutical composition is administered orally, intravenously, intraperitoneally, intradermally, subcutaneously, intramuscularly, intrathecally, by inhalation, Ingestion, vaporization, spray, sublingual, buccal, parenteral, rectal, ocular, inhalation, vaginal, or topical routes of administration In a specific embodiment, the pharmaceutical composition is provided to a subject by D) is administered orally to treat ulcerative colitis and Crohn's disease. The pharmaceutical composition may be administered topically, parenterally, intravenously, subcutaneously, intraperitoneally, or intravenously to treat psoriasis. or provided intravenously to the subject. DETAILED DESCRIPTION OF THE INVENTION

[0031] definition Unless otherwise defined herein, scientific and technical terms used in this application are understood by those skilled in the art. Generally, the chemistry described herein, Molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and proteins and nucleic acids The nomenclature used in connection with chemistry and the techniques thereof are well known and commonly used in the art. It is being used in a practical way.

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

[0033] Throughout this specification, the terms "comprise" and "comprises" or Variations such as "comprising" refer to the specified integer (or component) or integers (or (component), but any other integer (or component) or group of integers (or components) It is understood to mean not excluding.

[0034] Unless the context clearly dictates, the singular forms "a," "an," and "the" , which contains multiple referents.

[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 may refer to a human or non-human These terms include humans, primates, and domestic animals (e.g., animals (e.g., dogs, cats), and rodents (e.g., mice, pigs). This includes mammals such as mice, rats, and mice.

[0037] As used herein, the term "peptide" refers to a molecule that is joined together by a peptide bond. It broadly refers to a sequence of two or more amino acids joined together. The term refers to a specific length of amino acids. It does not mean a polymer, but rather that the polypeptide is synthesized by recombinant techniques, chemically or enzymatically. It is not intended to mean or distinguish between compounds produced using synthetic methods and those that occur naturally. It should be understood that the term peptide includes cyclic peptides.

[0038] As used herein, "sequence identity," "percent identity," "percent homology" and "sequence identity" are used interchangeably. Statements including "a sequence identical to" or, for example, "a sequence 50% identical to" indicate that the sequence is within the comparison window. It refers to the degree of identity at the nucleotide or amino acid level across a sequence. The term "percent sequence identity" refers to the percentage of sequence identity between two optimally aligned sequences. Compare across the window and find the number of identical nucleobases (e.g. A, T, C, G, I) or identical amino acid residues (e.g., Ala, Pro, Ser, Th r, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, Hi positions that are present in both sequences (asp, Asp, Glu, Asn, Gln, Cys, and Met) The number of matched positions is calculated and the number of matched positions is compared with the total number of positions in the window (i.e., the window by dividing by the number of nucleotides (number of nucleotides) and multiplying the result by 100 to obtain the percent sequence identity. It can be calculated.

[0039] Sequence similarity or sequence identity between sequences (these terms are used interchangeably herein) The calculation of ) can be performed as follows: To determine percent identity of sequences, align these sequences for optimal comparison. (e.g., by adjusting the first and second amino acids or nucleic acids for optimal alignment) Gaps may be introduced into one or both of the sequences, allowing non-homologous sequences to be ignored for comparison purposes. In certain embodiments, the length of the reference sequence to be aligned for comparison purposes may be The length is at least 30%, preferably at least 40%, more preferably at least 50%, of the length of the reference sequence. is at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100%. Then, the amino acid at the corresponding amino acid position or nucleotide position Residues or nucleotides are compared. A position in the first sequence is compared to the corresponding position in the second sequence. Molecules are identical at a position when it is occupied by the same amino acid residue or nucleotide. is.

[0040] The percent identity between two sequences is introduced to optimally align the two sequences. The sequences share identical sequences, taking into account the number of gaps that need to be is a function of the number of positions.

[0041] The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In some embodiments, the identity pattern between two amino acid sequences can be achieved by The metric is based on the Ne The algorithm of Edleman and Wunsch (1970, J. Mol. Biol. 4 8:444-453) and Blossum 62 matrix or PAM250 matrix. Any of the following: Use a gap weight and a length weight of 1, 2, 3, 4, 5, or 6 In yet another preferred embodiment, the identity pattern between two nucleotide sequences is determined as The company uses the GAP program in the GCG software package to dna.CMP matrix and gap weights of 40, 50, 60, 70, or 80 , and length weights of 1, 2, 3, 4, 5, or 6. The meter set is a gap penalty of 12, a gap extension penalty of 4, and a frame Includes a Blossum62 scoring matrix with a shift gap penalty of 5. The percent identity between two amino acid or nucleotide sequences can be calculated using the ALIGN program ( The algorithm of E. Meyers and W. Miller is incorporated in the (1989, Cabios, 4:11-17) using the PAM120 weight residue table. , a gap length penalty of 12, and a gap penalty of 4.

[0042] The peptide sequences described herein may be used to identify, for example, other family members or related sequences. used as a "query sequence" to perform a search against public databases to identify Such an algorithm is described in Altschul, et al., 990, J. Mol. Biol., 215:403-10) This can be done using the NBLAST program (version 2.0). Perform a BLAST nucleotide search using argin, score=100, word length=12. Nucleotide sequences homologous to the nucleic acid molecules of the present invention can be obtained by XBLAST. Perform a BLAST protein search using the program, score = 50, word length = 3 For comparison purposes, amino acid sequences homologous to the protein molecules of the present invention can be obtained. To obtain gapped alignments, Altschul et al. As described in Biochemical Acids Res. 25:3389-3402, 1997), G Gapped BLAST is available. When using ST programs, please refer to the respective programs (e.g., XBLAST and NB The default parameters (LAST) may be used.

[0043] As used herein, the term "conservative substitution" refers to a substitution of one or more amino acids. This means that the acid is replaced by another biologically similar residue. Similar characteristics, e.g., small amino acids, acidic amino acids, polar amino acids, basic amino acids, hydrophobicity Substitution of amino acid residues with amino acids and aromatic amino acids is also possible. For example, In some embodiments of the invention, one or more Met residues However, norleucine, a bioisostere of Met, is not readily oxidized in contrast to Met. It is substituted with Nle, a nucleotide not normally found in endogenous mammalian peptides and proteins. Other examples of conservative substitutions of amino acids with amino acids such as ornithine, canavanine, aminoethylsilyl, Conservative substitution of Arg or Lys with SEQ ID NO: 1 or another basic amino acid. In some embodiments, one or more cysteines of the peptide analogs of the invention are replaced by serine. Phenotypically silencing peptides and proteins can be achieved by substituting other residues such as α- and β-amino acids. For more information on suitable substitutions, see, e.g., Bowie et al. Science See ce 247, 1306-1310, 1990. In the following scheme, Conservative amino acid substitutions are grouped by physicochemical properties: I: neutral, hydrophilic, II: acids and amides, III: basics, IV: hydrophobic, V: aromatic, bulky amino acids.

[0044] [Table 1]

[0045] In the scheme below, conservative amino acid substitutions are grouped by physicochemical properties. VI: Neutral or hydrophobic, VII: Acidic, VIII: Basic, IX: Polar, X: Aromatic Tribe.

[0046] [Table 2]

[0047] As used herein, the term "amino acid" or "any amino acid" refers to a naturally occurring amino acids present in the This refers to all amino acids, including D- and L-amino acids, as well as unnatural amino acids. Natural amino acids include, for example, the amino acids that combine to form peptide chains and have a vast array of It contains naturally occurring amino acids, such as the 23 amino acids that form the building blocks of proteins. These are primarily L stereoisomers, but are present in bacterial envelopes and some antibiotics. There are several D-amino acids. The 20 "standard" naturally occurring amino acids are listed in the table above. "Non-standard" naturally occurring amino acids are pyrrolidine (from methanogens and other selenocysteine ​​(found in many non-eukaryotes and most eukaryotes) and selenocysteine ​​(found in many non-eukaryotes and most eukaryotes). N-formylmethionine (present in bacteria, mitochondria, and chloroplasts) and N-formylmethionine (present in bacteria, mitochondria, and chloroplasts) "Non-naturally occurring" or "unnatural" Amino acids are non-proteinogenic amino acids (amino acids) that are naturally occurring or chemically synthesized. (i.e., not naturally encoded or found in the genetic code). Over 140 unnatural amino acids are known, with thousands of additional combinations possible. Examples of "unnatural" amino acids include β-amino acids (β 3 and β 2 ), Homoami acid, proline and pyruvic acid derivatives, 3-substituted alanine derivatives, glycine derivatives, cyclic Modified phenylalanine and tyrosine derivatives, linear core amino acids, diamino acids, D-amino acids , alpha-methyl amino acids, and N-methyl amino acids. Unnatural amino acids also include modified amino acids. "Modified" amino acids are amino acids that have been modified with a natural amino acid. Amino acids that have been chemically modified to include groups or chemical moieties not found in natural According to certain embodiments, the peptide inhibitor comprises a hydroxyl group (amino acid) present in the peptide inhibitor. The amino acid residues that form the bond are intimately connected to each other. It is understood that the properties of the molecules change slightly when they are bound to each other compared to when they are not bound to each other. Reference to a specific amino acid refers to that amino acid in both its unbound and bound state. For example, the amino acid residue homoserine (hSe) in its unbound form is meant to encompass r) or homoserine (Cl), when involved in an intramolecular bond according to the present invention, is 2-aminobutyric acid. The present invention relates to peptide inhibitors containing a bridge between X4 and X9. and a peptide inhibitor that does not include a bridge between X4 and X9, e.g., a peptide inhibitor before forming the bridge. Therefore, the names hSer and Abu refer to the same amino acid. are intended to be used interchangeably.

[0048] In most cases, the naturally occurring and non-naturally occurring amino acids used herein The names of acyl residues are listed in "Nomenclature of α-Amino Acids" (Recommendations, 1974)” Biochemistry, 14(2) ), (1975) Nomenclature of Organi c Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature in IUPAC Co In this specification and the appended claims, To the extent that the names and abbreviations of the amino acids and aminoacyl residues used differ from those proposed, Some of the techniques useful in explaining the present invention will become clear to the reader. Abbreviations are defined in Table 1 below.

[0049] [Table 3-1]

[0050] [Table 3-2]

[0051] [Table 3-3]

[0052] [Table 3-4]

[0053] [Table 3-5]

[0054] [Table 3-6]

[0055] [Table 3-7]

[0056] [Table 3-8]

[0057] [Table 3-9]

[0058] [Table 3-10]

[0059] Throughout this specification, naturally occurring amino acids are referred to by their full names (e.g., alanine, alanine, If not referred to by their conventional three-letter or one-letter abbreviations (e.g., Arginine, etc.), Ala or A for lanine, Arg or R for arginine, etc. Unless otherwise indicated, the three-letter and one-letter abbreviations of amino acids refer to the amino acid in question. As used herein, the term "L-amino acid" refers to the L-isomer form. The term "D-amino acid" refers to the "L" isomeric form of a peptide, and conversely, the term "D-amino acid" refers to the "D" isomeric form of a peptide. "Isomeric forms (e.g., Dasp, (D)Asp, or D-Asp; Dphe, (D)P Any L-Phe is also acceptable as long as the peptide retains the desired function. An amino acid residue may be substituted with an amino acid residue in its D isomeric form. When referred to using the abbreviation, it may be conventionally presented in lower case.

[0060] For less common or non-naturally occurring amino acids, the full name (e.g. Unless otherwise specified by Sar or Sarc (sarcosine, ornithine, etc.), Cosine (i.e., N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2 ,4-diaminobutanoic acid), Dapa (2,3-diaminopropanoic acid), γ-Glu (γ -glutamic acid), GABA (γ-aminobutanoic acid), β-Pro (pyrrolidine-3-carboxylate carboxylic acid), and 8Ado (8-amino-3,6-dioxaoctanoic acid), Abu(2- aminobutyric acid), βhPro (β-homoproline), βhPhe (β-homophenylalanine) (β,β-diphenylalanine), and Bip (β,β-diphenylalanine), and Ida (iminodiacetic acid), The frequently used three-letter or four-letter code for the residue is used.

[0061] As will be apparent to one of skill in the art, the peptide sequences disclosed herein are read from left to right. The left end of the sequence is the N-terminus of the peptide, and the right end of the sequence is the C-terminus of the peptide. Some of the sequences disclosed herein have a "Hy-" at the amino terminus (N-terminus) of the sequence. The carboxyl terminus (C-terminus) of the sequence is either an "-OH" or an "-NH2" moiety. In such cases, unless otherwise indicated, The "Hy-" moiety at the end corresponds to the presence of a free primary or secondary amino group at the N-terminus. indicates a hydrogen atom at the C-terminus of the sequence, while an "-OH" or "-NH" moiety at the C-terminus of the sequence indicates a hydrogen atom at the C-terminus of the sequence. A hydroxyl group or an amide group corresponding to the presence of an amide (CONH2) group at the C-terminus, respectively. In each sequence of the present invention, the C-terminal "-NH2" moiety is replaced with the C-terminal "-OH " portion may be substituted, and vice versa.

[0062] Those skilled in the art will appreciate that certain amino acids and other chemical moieties are modified when attached to another molecule. For example, an amino acid side chain may form an intramolecular bridge with another amino acid side chain. For example, one or more hydrogen atoms may be removed by bonding. Thus, as used herein, a group (e.g., a group at the X4 position or at the X 9) Reference to amino acids or modified amino acids present in the peptide dimers of the invention is , such amino acids or modifications present in the peptide both before and after forming the intramolecular bond. It is meant to include amino acid forms.

[0063] As used herein, the term "dimer" broadly refers to a group of two or more monomeric subunits. A particular dimer refers to a peptide comprising a dimer of formula (I) or a sequence described herein. The dimers of the present invention include homodimers and heterodimers. The monomeric subunits of the dimer may be linked at their C-terminus or N-terminus, or may be internally linked. Each monomer subunit of the dimer may be linked via an amino acid residue. Although they may be linked via different sites (e.g., C-terminal, N-terminal, or internal sites), They may be linked together.

[0064] As used herein, the term "NH2" refers to the amino acid at the amino terminus of a polypeptide. As used herein, the term "OH" may refer to a free amino group present in a phenyl group. It may also refer to the free carboxy group present at the carboxy terminus of a peptide. When used herein, the term "Ac" refers to acylation through acylation of the C- or N-terminus of a polypeptide. In certain peptides shown herein, the cetyl protection is located at the C-terminus of the peptide. NH2 represents an amino group.

[0065] As used herein, the term "carboxy" refers to -CO2H.

[0066] As used herein, the term "isosteric substitution" refers to a substitution that is similar to the specified amino acid. It refers to any amino acid or other analogous moiety that has certain chemical and / or structural characteristics. In embodiments, an isosteric substitution is a conservative substitution or analog of the specified amino acid.

[0067] As used herein, the term "cyclization" refers to the formation of a disulfide bridge or a thioether. A part of a polypeptide molecule is attached to another part of the polypeptide molecule, such as by forming a bond. It refers to a closed ring formed by linking a moiety to a heterocyclic group.

[0068] As used herein, the term "subunit" refers to a dimeric peptide composition. It refers to one of a pair of polypeptide monomers that are joined to form a

[0069] As used herein, the term "linker moiety" broadly refers to a linker moiety that connects two peptide units. It refers to a chemical structure that can link or join dimeric subunits to form a dimer.

[0070] As used herein, the term "pharmaceutically acceptable salt" refers to a compound that is soluble in water or oil. and the like. , suitable for treating diseases without excessive toxicity, irritation, and allergic responses, and reasonable The risk / benefit ratio is commensurate with the intended use and is effective. It can be prepared during isolation and purification or separately by reacting the amino group with a suitable acid. Typical acid addition salts include acetate, adipate, alginate, and citrate. Acid salts, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, sulphates Unosate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate , heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, iodide Peritone, 2-hydroxyethanesulfonate (isethionate), lactate, maleate , mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinic acid Salt, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3 -phenylpropionate, picrate, pivalate, propionate, succinate, Tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate The compounds of the present invention include salts of toluenesulfonic acid, para-toluenesulfonic acid, and undecanoic acid. The amino groups in the compound can be quaternized with: methyl, ethyl, Phenyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides and bromides; and iodides; and benzyl and phenethyl bromides, forming therapeutically acceptable addition salts. Examples of acids that can be used to form the hydroxybenzoate include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Pharmaceutically acceptable salts are preferably selected from, for example, acid addition salts and basic salts. Examples of acid addition salts include chloride salts, citrate salts, and acetate salts. Examples of basic salts include those in which the cation is a sodium or potassium ion. Alkali metal cations, alkaline earth metal cations such as calcium or magnesium ions on, and N(R1)(R2)(R3)(R4)+ (where R1, R2, R3, and R 4 is independently typically hydrogen, optionally substituted C1-6 alkyl, or optionally Selectively substituted C2-6 alkenyl (showing the type of ion, such as substituted ammonium) Examples of related C alkyl groups include salts selected from the following: Examples include methyl, ethyl, 1-propyl, and 2-propyl groups. Examples of C2-6 alkenyl groups include ethenyl, 1-propenyl, and 2-propenyl. Other examples of pharmaceutically acceptable salts include those listed in "Remington's Pharmaceuticals" Maceutical Sciences”, 17th edition, Alfonso R.Genn aro (ed.), Mark Publishing Company, Easton, PA. ,USA,1985 (and its newer editions), "Encyclopaedia of "Pharmaceutical Technology", 3rd edition, James Swa rbrick (ed.), Informa Healthcare USA (Inc.),N Y, USA, 2007, and J. Pharm. Sci. 66:2 (1977) For a review of suitable salts, see the Handbook of Pharmaceutical Sciences. rmaceutical Salts:Properties,Selection,a nd Use by Stahl and Wermuth(Wiley-VCH,20 Suitable base salts are formed from bases which form non-toxic salts. Typical examples include aluminum, arginine, benzathine, calcium, choline, and dietary fiber. Aminomethylamine, Diolamine, Glycine, Lysine, Magnesium, Meglumine, Olamine, Potassium Hemi-salts of acids and bases, e.g. In some cases, hemisulfate and hemicalcium salts may be formed.

[0071] As used herein, the term "N(alpha) methylation" generally refers to N-methylated This paper describes the methylation of the alpha amine of an amino acid, also known as methylation.

[0072] As used herein, "sym methylation" or "Arg-Me-sym" The term describes the symmetric methylation of the two nitrogens of the guanidine group of arginine. The term "sym methylation" or "Arg-Me-asym" refers to the guanidinium methylation of arginine. Explain the methylation of one nitrogen of the methyl group.

[0073] As used herein, the term "acylated organic compound" refers to an acylated organic compound that forms a C-terminal dimer. Before synthesis, amino acids or monomers or dimers, for example, the N-terminus of a monomer subunit, are added. Acylation refers to a variety of compounds with a carboxylic acid functional group that can be used to acylate. Non-limiting examples of organic compounds include cyclopropylacetic acid, 4-fluorobenzoic acid, 4-fluorobenzoic acid, Fluorophenylacetic acid, 3-phenylpropionic acid, succinic acid, glutaric acid, cyclopentaacetic acid carboxylic acid, 3,3,3-trifluoropropionic acid, 3-fluoromethylbutyric acid, tetrafluoroethylene rahelo-2H-pyran-4-carboxylic acid.

[0074] The term "alkyl" refers to straight or branched chain, acyclic alkyl groups containing 1 to 24 carbon atoms. Representative saturated linear alkyls include, but are not limited to, However, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, etc. while saturated branched alkyls include, but are not limited to, isopropyl, sec- Examples include butyl, isobutyl, tert-butyl, and isopentyl. Cyclic alkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, while the unsaturated cyclic alkyl includes, but is not limited to, Examples include cyclopentenyl and cyclohexenyl.

[0075] "Halo" or "halogen" means bromo (Br), chloro (Cl), fluoro (F), or refers to an iodo(I) substituent.

[0076] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen has been replaced with a halogen atom. Certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms include alkyl groups. In the formula, all halogen atoms are identical to each other. Two or more hydrogen atoms are replaced by halogen atoms. In other embodiments provided, the halogen atoms are not all the same as one another.

[0077] An "alkoxy" group refers to an (alkyl)O- group, where alkyl is as defined herein. (This refers to the street).

[0078] An "aryloxy" group refers to an (aryl)O- group, where aryl is defined herein. This refers to the way things are (as they are).

[0079] "Carboxy" means the radical --C(O)OH.

[0080] "Aminocarbonyl" or "carboxamide" refers to the -CONH2 radical.

[0081] "2-aminoethoxy" refers to the -OCH2CH2-NH2 radical.

[0082] "2-acetylaminoethoxy" is -OCH2CH2-N(H)C(O)Me radical Refers to the rule.

[0083] The term "mammal" includes humans, mice, rats, dogs, cats, hamsters, guinea pigs, and the like. This refers to any mammal species, such as rats, rabbits, domestic animals, etc.

[0084] As used herein, a "therapeutically effective amount" of a peptide inhibitor of the present invention is defined herein as IL-23 / IL-23R, including but not limited to any of the diseases and disorders described A sufficient amount of pe to treat the associated disease (e.g., to reduce inflammation associated with IBD) In a specific embodiment, a therapeutically effective amount is any It will achieve the desired benefit-risk ratio applicable to any medical treatment.

[0085] "Analogs" of amino acids, e.g., "Phe analogs" or "Tyr analogs," are referred to. Various amino acid analogs, including Phe and Tyr analogs, are , are known and available in the art. In certain embodiments, amino acids Analogs, e.g., Phe analogs or Tyr analogs, have a higher affinity than Phe or Tyr, respectively. In certain embodiments, the substitutions include one, two, three, four, or five substitutions. In certain embodiments, the Phe analog has the structure Phe(R 2 )( In the formula, R 2 are Hy, OH, CH3, CO2H, CONH2, CONH2OCH2CH2 NH2, t-Bu, OCH2CH2NH2, Phenoxy, OCH3, Oallyl, Br, C 1, F, NH, N, or guanadino. 2 teeth , CONH2OCH2CH2NH2, OCH3, CONH2, OCH3, or CO2H Examples of Phe analogs include hPhe, Phe(4-OMe), and α-Me-Phe. , hPhe(3,4-dimethoxy), Phe(4-CONH2), Phe(4-phenoxy) Phe(4-tBu), Phe(4-CN), Phe(4-tBu), Phe(4-CN), Phe (4-Br), Phe(4-OBzl), Phe(4-NH2), BhPhe(4-F) , Phe(4-F), Phe(3,5 DiF), Phe(CH2CO2H), Phe( Penta-F), Phe(3,4-Cl2), Phe(3,4-F2), Phe(4-CF 3), ββ-diPheAla, Phe(4-N3), Phe[4-(2-aminoethoxy) )], 4-phenylbenzylalanine, Phe(4-CONH2), Phe(3,4-di methoxy), Phe(4-CF3), Phe(2,3-Cl2), and Phe(2,3- F2) Examples of Tyr analogs include, but are not limited to, hTyr, Examples include N-Me-Tyr, Tyr(3-tBu), Tyr(4-N3), and βhTyr. Examples include, but are not limited to:

[0086] Peptide inhibitors of IL-23R In genome-wide association studies (GWAS), I Significant association between the IL-23 receptor (IL-23R) gene and inflammatory bowel disease (IBD) has been demonstrated This suggests that disruption of IL-23 signaling may contribute to the pathogenesis of this disease as well as other inflammatory diseases and The present invention suggests that IL-23R antagonism may be involved in the pathogenesis of IL-23R disorders. The present invention provides compositions and methods for modulating the IL-23 pathway through

[0087] The present invention generally relates to IL-23R antigens, including both peptide monomers and peptide dimers. In a particular embodiment, the present invention relates to peptides having IL-2 antagonist activity. for treating IBD and other diseases and disorders by oral delivery of antagonists of 3 This demonstrates a new paradigm: IBD presents with local inflammation of the intestinal tissue, thus favoring The therapeutic agent acts from the luminal side of the intestine, resulting in high drug concentrations in the affected tissues and systemic absorption. Improved efficacy and safety compared to systemic approaches with minimal irritation Oral administration of the compounds of the present invention provides a therapeutic effect while limiting circulating drug concentrations. This maximizes drug levels in affected intestinal tissue, thereby improving the efficacy of IBD as well as other diseases and Provides effective, safe, sustained delivery for lifelong treatment of cancer and disorders It is expected that...

[0088] In certain embodiments, the present invention provides a method for forming a cyclized structure via a disulfide or other bond. Various peptides or peptide dimers containing hetero- or homo-monomeric subunits are available. In certain embodiments, the disulfide or other bond is an intramolecular bond. The cyclization structure of the monomeric subunits of the peptide monomeric inhibitors and peptide dimeric inhibitors is In certain embodiments, peptides have been shown to increase the potency and selectivity of inhibitors. Dimeric peptide inhibitors link two monomeric peptide subunits within a peptide dimeric inhibitor. One or more intramolecular bonds, e.g., one within each peptide monomer subunit. The structure may include an intermolecular bridge between two Pen residues.

[0089] The present invention provides peptide inhibitors that bind to IL-23R, which are monomeric. In a specific embodiment, the peptide inhibitor is a dimer of IL-23. In certain embodiments, IL-23R inhibits binding to human IL-23. R and the IL-23 is human IL-23. In certain embodiments, the peptides of the invention The inhibitors attenuated the binding of IL-23 to IL-23R compared to the negative control peptide. 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%. Methods for this are known in the art and include the ELISA assays described in the accompanying Examples. include.

[0090] In certain embodiments, peptide inhibitors of the invention are directed to, for example, the IL-23R of IL-23. (e.g., human IL-23 and human IL-23R) >1 mM; <1mM, 500nM~1000nM, <500nM, <250nM, <100nM, < I of 50 nM, <25 nM, <10 nM, <5 nM, <2 nM, <1 nM, or <5 mM Methods for determining activity are known in the art and are described in the accompanying Examples. This includes any of the items listed above.

[0091] In certain embodiments, the peptide inhibitors of the present invention inhibit the activity of simulated intestinal fluid compared to a control peptide. (stimulated intestinal fluid, SIF) or simulated gastric fluid (S Increased stability in HCl (e.g., HCl-1000), HCl-1000, ... In certain embodiments, the control peptide The control peptide is an unrelated peptide of the same or similar length. The peptide inhibitors are those with amino acid sequences identical or highly related (e.g., >90% sequence identity) to the peptide inhibitors. In a specific embodiment, the control peptide is a peptide having a peptide blocker. have the same or highly related amino acid sequence (e.g., >90% sequence identity) as the cytotoxic agent, For example, a cyclized structure formed via an intramolecular bond between two amino acid residues in a reference peptide The peptide is free of dimerization or dimerization or does not contain a stabilizing conjugate. In a specific embodiment, the only difference between the peptide inhibitor and the control peptide is the peptide The inhibitor may be one or more peptides that introduce one or more amino acid residues into the peptide inhibitor. The amino acid substitutions described above are included, and the introduced amino acid residue is not a substitute for another amino acid in the peptide inhibitor. The formation of intramolecular disulfide or thioether bonds with acid residues. An example of a control for a peptide dimeric inhibitor is the monomeric subunit present in the peptide dimeric inhibitor. A control example of a peptide inhibitor containing a conjugate is a monomer having the same sequence as one of the is a peptide having the same sequence but without the conjugated moiety. The reference peptide is a peptide corresponding to the region of IL-23 that binds to IL-23R (e.g., It is a naturally occurring peptide.

[0092] Methods for determining peptide stability are known in the art. In certain embodiments, The stability of peptide inhibitors can be assessed using the SIF assay, e.g., as described in Example 3. In certain embodiments, the stability of the peptide inhibitor is determined, for example, as described in Example 3. In a specific embodiment, peptide inhibitors are determined using the SGF assay as described above. The agent exhibits a cytotoxic effect when exposed to SIF or SGF or DTT for 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 given conditions have a half-life (e.g., in SIF or SGF or DTT) under a certain temperature (e.g., temperature) In certain embodiments, the temperature is about 25° C., about 4° C., or about 37° C., and the pH is physiological. The pH is approximately 7.4.

[0093] In some embodiments, the half-life can be determined using any suitable method known in the art. For example, in some embodiments, the stability of the peptides of the invention is measured in vitro using The peptides were incubated with pre-warmed human serum (Sigma) at 37°C. Typically, samples are taken at various time points up to 24 hours and the peptide Alternatively, peptide dimers can be separated from serum proteins and then isolated using LC-MS to identify the desired peptides. Analyze the stability of the sample by analyzing for the presence of peptides or peptide dimers do.

[0094] In some embodiments, the peptide inhibitors of the present invention inhibit lysis compared to a control peptide. The solubility may be measured by any suitable method known in the art. In some embodiments, the solubility can be determined by a method such as Suitable methods known in the art include the use of various buffers (acetic acid pH 4.0, acetic acid pH 5.0, Phosphoric acid / citric acid pH 5.0, Phosphoric acid / citric acid pH 6.0, Phosphoric acid pH 6.0, Phosphate pH 7.0, Phosphate 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 Incubate the peptide in a known pH range (or other pH range) and use standard techniques to detect aggregation or These include testing for surface hydrophobicity and for example agglomeration. Visual precipitation, dynamic light scattering, circular dichroism, and fluorescent dyes for detecting aggregation or fibrillation are included. In some embodiments, improved solubility includes, but is not limited to, This means that the peptide is more soluble in a given liquid than the control peptide. In embodiments, reduced aggregation refers to the ability of a peptide to aggregate more readily under a given set of conditions than a control peptide. This means that it has less clumping in a given liquid.

[0095] Certain implementations are advantageous for achieving high compound concentrations in intestinal tissue when delivered orally. In this form, the peptide inhibitors of the present invention are stable in the gastrointestinal (GI) environment. Protein degradation in the GI tract is achieved by secreting or printing proteins from the pancreas into the lumen. Enzymes produced as nucleoside enzymes (peptin, trypsin, chymotrypsin, elastase , aminopeptidases, and carboxypeptidases A / B) Proteases typically cleave peptides and proteins with a wide range of conformations. In the reducing environment of intestinal fluid, disulfide bonds are broken, resulting in linear peptides and rapid This luminal redox environment is dominated by Cys / CySS acids. In the intestinal cell, the relevant activities include CYP450 and UDP-glucuronyl-transferase. Later, 10 10 ~10 12 Bacteria present in the large intestine at concentrations in the CFU / ml range are different from other bacteria. In certain embodiments, the peptide inhibitors are capable of blocking the gastric barrier (pH 1.5-1.9). ) to a strong acidic tendency in the small intestine (pH 6-7.5), then to a basic tendency in the colon Such peptide inhibitors are stable over a wide range of pH, from weakly acidic (pH 5-7). The process of toxicity is estimated to take 3-4 hours in the intestine and 6-48 hours in the colon. It is stable during transit through the various GI compartments.

[0096] In some embodiments, the peptide inhibitors of the present invention may be administered in a variety of ways, e.g., over a period of time. Less degradation (i.e., more stable degradation), e.g., about 10% more than the control peptide less, about 20% or more less, about 30% or more less, about 40% or more less, or about 50% or more less In some embodiments, the degradation stability is greater than any known in the art. Determination may be via any suitable method. In some embodiments, the degradation is enzymatic degradation. For example, in certain embodiments, the peptide inhibitor is a trypsin, chymotrypsin, or ellagase inhibitor. In some embodiments, the protein has reduced susceptibility to degradation by proteases. Suitable methods known in the art for determining sex include those described by Hawe et al., JP Harm Sci, VOL. 101, No. 3, 2012, pp. 895-913 The present invention includes methods, which are incorporated herein by reference in their entirety. In an embodiment, it is used to select potent peptide sequences with extended shelf life. In specific embodiments, peptide stability is assessed using methods such as those described in, for example, WO 2016 / 011208. It is determined using the SIF assay or the SGF assay as described in.

[0097] In certain embodiments, the peptide inhibitors of the present invention inhibit or reduce IL-23 mediated inflammation. In a related embodiment, the peptide inhibitors of the invention reduce, for example, IL-1 on the cell surface. IL-23-mediated activation of one or more cytokines by binding to IL-23R. Inhibits or reduces secretion, thereby inhibiting IL-23 binding to cells. In embodiments, the peptide inhibitors of the present invention are selected from the group consisting of Jak2, Tyk2, Stat1, Stat inhibits or reduces IL-23-mediated activation of Stat3, Stat4, or Stat5. Methods for determining inhibition of kine secretion and inhibition of signaling molecules are known in the art. For example, inhibition of IL-23 / IL-23R signaling has been reported in, for example, international publications. As described in Patent Publication No. 2016 / 011208, phospho-Sta in cell lysates This can be determined by measuring the inhibition of t3 levels.

[0098] In certain embodiments, the peptide inhibitor exhibits increased redox activity compared to a control peptide. Various assays that can be used to determine redox stability include Any of these may be used to implement the present invention. The redox stability of the peptide inhibitors can be determined.

[0099] In certain embodiments, the present invention provides a method for disrupting or blocking the binding between IL-23 and IL-23R. To isolate IL-23R, various peptides that bind to or associate with IL-23R in vitro or in vivo were analyzed. In certain embodiments, the peptide inhibitors bind human IL-23R. In certain embodiments, the peptide inhibitors inhibit and / or inhibit the expression of the ATPase inhibitors in both humans and rodents. In certain embodiments, the peptide inhibitor binds to and / or inhibits human IL-23R. In certain embodiments, the peptide inhibitors inhibit both human and rat IL-23R. The inhibitor binds human IL-23R, rat IL-23R, and cynomolgus monkey IL-23R. In specific embodiments, the peptide inhibitors are, for example, those described herein. As determined by the assays described above, rat IL-23R and / or cynomolgus IL- 23R at least 50%, at least 60%, at least 70%, at least 80% In addition to inhibiting human IL-23R by at least 90%, or at least 95%, In certain embodiments, the peptide inhibitor binds to or inhibits the activity of a peptide relative to murine IL-23R. and human IL-23R and / or rat IL-23R and / or cynomolgus monkey IL-2 In a specific embodiment, the peptide inhibitor preferentially binds to and / or inhibits the 3R. Preferentially binds to rat IL-23R compared to mouse IL-23R. In this state, peptide inhibitors preferentially bind to the human IL-23R compared to the murine IL-23R. In a specific embodiment, the peptide inhibitor binds to mouse IL-23R. In certain embodiments, the peptide inhibitors preferentially bind to cynomolgus monkey IL-23R. Binding of the same peptide inhibitors to the human IL-23R and / or rat IL-23R was also observed. less than 75%, less than 50% of binding to IL-23R and / or cynomolgus IL-23R; Less than 40%, less than 30%, less than 20%, or less than 10% compared to mouse IL-23R Compared to human IL-23R and / or rat IL-23R and / or cynomolgus IL-2 In certain embodiments of peptide inhibitors that preferentially bind and / or inhibit 3R, the peptide The inhibitor is present in mouse IL-23R but not in human IL-23R or rat IL-23 or is disrupted by the presence of additional amino acids not present in cynomolgus IL-23R. In certain embodiments, the IL-23R domain binds to an additional IL-23R domain present in mouse IL-23R. The amino acids are from about amino acid residue 315 to about amino acid residue 3 of the mouse IL23R protein. 40, e.g., the amino acid region NWQPWSSPFVHQTSQETGKR (SEQ ID NO: 322). In a specific embodiment, the peptide inhibitor is located at about amino acid 23 It binds to the region of human IL-23R from amino acid residue 0 to approximately 370.

[0100] In certain embodiments, the peptide inhibitors exhibit localization restricted to the GI following oral administration. In specific embodiments, greater than 50%, greater than 60%, or greater than 70% of orally administered peptide inhibitors In particular embodiments, more than 80%, or more than 90% of the total IgG is localized in the gastrointestinal organs and tissues. Plasma levels of orally administered peptide inhibitors were found in the small intestinal mucosa, colonic mucosa, or proximal colon. Less than 20%, less than 10%, less than 5%, less than 2%, less than 1% of the level of peptide inhibitors , or less than 0.5%.

[0101] The various peptide inhibitors of the present invention may be constructed exclusively from natural amino acids. The tide inhibitors include unnatural amino acids, including but not limited to modified amino acids. In certain embodiments, the modified amino acid may have a group or chemical structure that is not naturally occurring in an amino acid. The peptide inhibitors of the present invention include naturally occurring amino acids that have been chemically modified to include an amino acid moiety. Furthermore, the peptide inhibitors of the present invention may further comprise one or more D-amino acids. may include amino acid analogs.

[0102] In certain embodiments, the peptide inhibitors of the present invention comprise one or more modified or In some embodiments of the invention, the peptide inhibitor comprises an unnatural amino acid. In certain embodiments, the peptides of the invention comprise one or more unnatural amino acids as set forth in The tide inhibitors may be selected from the group consisting of an amino acid sequence or peptide shown in any one of the tables herein. Inhibitor structures, including but not limited to, any of those described herein This includes any of the following:

[0103] The present invention also includes any of the peptide inhibitors described herein in free or salt form. Thus, any embodiment of the peptide inhibitors described herein (and related thereto) The methods of use include pharmaceutically acceptable salts of the peptide inhibitors.

[0104] The present invention also relates to any of the compounds comprising a sequence shown in any one of the tables herein. A variant of any of the peptide inhibitors described herein, including but not limited to: wherein one or more L-amino acid residues are present in the D isomeric form of the amino acid residue. For example, L-Ala is replaced with D-Ala.

[0105] The peptide inhibitors described herein include isotopically labeled peptide inhibitors. In exemplary embodiments, the present disclosure provides compounds having the various formulas and structures presented herein or in the sequence. The present invention provides a peptide inhibitor identical to any of those listed above, but which in fact may be one or more of the above. The atoms above have atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the present compounds include , isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, e.g., 2 H, 3 H , 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Cl is an example. Certain isotopically labeled compounds described herein, e.g., 3 H and 14 C, etc. Radioisotopes incorporated are effective in drug and / or substrate tissue distribution assays. Furthermore, for example, deuterium, i.e. 2 Substitution with isotopes such as H can improve metabolic stability. more qualitative, e.g., longer in vivo half-life or lower dosage requirements Certain therapeutic advantages can be obtained due to this.

[0106] The present invention also provides linker molecules comprising any of the specific linker moieties described herein. The present invention also includes any of the peptide monomeric inhibitors described herein linked to a - moiety. In embodiments, the linker is attached to the N-terminal or C-terminal amino acid, while in other embodiments, The linker is attached to an internal amino acid. In a specific embodiment, the linker is attached to two internal amino acids. amino acids, e.g., internal amino acids in each of the two monomeric subunits that form the dimer In some embodiments of the invention, the peptide inhibitor is one or more of the peptides shown Two or more linker moieties are attached.

[0107] The present invention also relates to a peptide inhibitor comprising a peptide sequence as described herein and a peptide sequence which is at least 90% identical to the peptide sequence of the peptide inhibitor described herein. , pairs having at least 95%, at least 98%, or at least 99% sequence identity. In a specific embodiment, the peptides of the present invention include peptides and peptide dimers. Tide inhibitors consist of a core peptide sequence and one or more N-terminal and / or C-terminal modifications ( For example, Ac and NH2) and / or one or more conjugated linker moieties and / or half-chains. As used herein, a core peptide sequence includes such modifications. The amino acid sequence of the peptide without decorations or conjugates.

[0108] In certain embodiments, the peptide inhibitors or monomeric subunits of the peptide inhibitors of the present invention The amino acid sequences are 7 to 35 amino acid residues, 8 to 35 amino acid residues, and 9 to 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, 7-20 amino acid residues 8-20 amino acid residues, 9-20 amino acid residues, 10-20 amino acid residues Group, 7-18 amino acid residues, 8-18 amino acid residues, 9-18 amino acid residues or 10-18 amino acid residues and, optionally, a conjugated chemical moiety, e.g., PE and one or more additional non-amino acid moieties, such as a G or a linker moiety, In specific embodiments, any of Formula I The peptide inhibitors of the present invention (or monomers thereof), including but not limited to those of the embodiments, Subunits) 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, for example, 35 to 50 amino acids. , the peptide inhibitor (or its monomeric subunit) is 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 a specific embodiment, the monomeric portion of a peptide inhibitor (or peptide monomeric inhibitor) The units are 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, 3 Specific examples include those containing or consisting of 2, 33, 34, or 35 amino acid residues. In embodiments, the monomeric subunits of the peptide inhibitors of the present invention comprise 10 to 23 amino acids. residue and, optionally, one or more conjugated chemical moieties, such as PEG or a linker moiety. and two or more additional non-amino acid moieties. The monomeric subunits are those with 7 to 35 amino acid residues, those with 7 to 20 amino acid residues, 8 to 20 amino acid residues, 9 to 20 amino acid residues, 10 to 20 amino acid residues, 8-18 amino acid residues, 8-19 amino acid residues, 8-18 amino acid residues, 9 containing up to 18 amino acid residues, or 10 to 18 amino acid residues, or consisting of these. In specific embodiments of any of the various formulas described herein.

[0109] Certain exemplary peptide inhibitors described herein contain 12 or more amino acid residues. However, the present invention also provides a method for preparing a nucleotide sequence having 7, 8, 9, 10, or 11 amino acid residues. Peptides comprising fragments of any of the peptide sequences described herein, including peptide inhibitors For example, the peptide inhibitors of the present invention include X4-X9, X4-X10, X4- X11, X4-X12, X4-X13, X4-X14, or X4-X15, or It includes peptides consisting of them.

[0110] In a specific embodiment of the invention, the amino acid sequence of the peptide inhibitor is not present in the antibody. Squid or antibody V H or V L Not present in the region.

[0111] Peptide inhibitors The peptide inhibitors of the present invention may comprise any of the amino acid sequences described herein. or a peptide consisting thereof, a compound comprising any of the peptide sequences described herein. Compounds having any of the structures described herein, including peptides and compounds such as Exemplary peptides of the present invention include those listed in any of the accompanying tables. The amino acid sequence or structure may be any of the following:

[0112] In certain embodiments, the present invention provides monocyclic peptide inhibition of the interleukin-23 receptor. or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is represented by the formula (I) comprising or consisting of the amino acid sequence X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X1 4-X15-X16(I) During the ceremony, X3 is absent or any amino acid; each X4, X5, and X6 is independently any amino acid; X7 is unsubstituted Trp, Trp-psi, or cyano, halo, alkyl, haloal alkyl, hydroxy, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl-substituted Trp; X8: Gln, alpha-MeLys, alpha-MeLeu, alpha-MeLy s(Ac), beta-homoGln, Cit, Glu, Phe, Paf(Ac), Phe4 NH2Ac, Asn, Thr, Val, Aib, alpha-MeGln, alpha-Me Asn, 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, Pe n, or Pen(sulfoxide); X10 is unsubstituted Phe, or halo, alkyl, haloalkyl, hydroxy, alkoxy hydroxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy Toxi, AEF, AEF(Ac), AEF(BH), AEF(Boc), AEF(Me) 2, bMeRPhe, Phe42ae-ethyl, Phe42aeSMSB, Phe4Pi Phe substituted with p, X11 is 6 amide 2Nal, 6OMe2Nal, bMe2Nal(2S,3R), r bMe2Nal, 2-Nal, aMe(2-Nal), Phe(2-Me), Phe(3 -Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted T rp, or cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy is a substituted Trp, X12 is 4diFAchx, Achx, Acpx, AmeK(Boc), 4-amino -4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha- MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha Alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexyl cyclohexyl Ala, 1-aminocyclohexyl Ala (Achc), Acvc, Lys, or Aib, X13 and X14 are independently any amino acid; i) X16 is absent, and X15 is His, Phe_tetraF, Phe_3OH, ameF, Aib, THP, Phe, substituted Phe, substituted (D)Phe, a-MePhe, Substituted a-MePhe, Trp, Substituted Trp, 1-Nal, aMe(1-Nal), Substituted 1 -Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted Asn There is, However, the peptide inhibitor Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4 -(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac) ]-N-[Aib]-NH2 (SEQ ID NO: 151) or Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac )]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aM eLys]-[Lys(Ac)]-N-[a-MePhe]-NH2 (SEQ ID NO: 201) or ii) X16 is paf, Aib, 3Pal, Phe, substituted Phe, substituted (D)Phe , substituted or unsubstituted Tyr, unsubstituted (D)Tyr, a-MePhe, substituted a-MePh e, b-hPhe, 1-Nal, aMe(1-Nal), substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted Asn, and X15 is any Although it is an amino acid, However, the peptide inhibitor Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[ 4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac )]-N-[Aib]-[(D)Tyr]-NH2 (SEQ ID NO: 202) The conditions are: or iii) the peptide is Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[3-Quin]-[α-MeLys]-[L ys(Ac)]-N-[(D)Leu)]-NH2 (SEQ ID NO: 1), Ac-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[(D)Lys]-NH2 (SEQ ID NO: 64), Ac-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 65), Ac-[Pen]-N-[(D)Dap]-[W(7-Me)]-[Lys(Ac)] -[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeL Lys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 72), Ac-[Pen]-N-[(D)Lys]-[W(7-Me)]-[Lys(Ac)] -[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeL Lys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 73), Ac-[Pen]-N-[(D)Asp]-[W(7-Me)]-[Lys(Ac)] -[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeL Lys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 74), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[Aib-Ahx]-NH2 (SEQ ID NO: 70), [Propionic acid]-[(D)Arg]-[Pen]-QTWQ-[Pen]-P he[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[NM e-bAla]-NH2 (SEQ ID NO: 8), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[N-Me-bAla ]-NH2 (SEQ ID NO: 14), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-[aM eTyr]-NH2 (SEQ ID NO: 44), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-[αMeGlu]-N-[αMeTyr]-NH2 (SEQ ID NO: 150), or Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[aMeTyr]-NH2 (SEQ ID NO: 151); and, The peptides are linked via an Abu-Cys thioether bond or a Pen-Pen disulfide bond. is cyclized via and, X4 and X9 form a disulfide bond or a thioether bond, and, The peptide inhibitor binds to the IL-23 receptor of interleukin-23 (IL-23). inhibits the binding of

[0113] In certain embodiments, the present invention provides monocyclic peptide inhibition of the interleukin-23 receptor. or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is represented by the formula (I) comprising or consisting of the amino acid sequence X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X1 4-X15-X16(I) During the ceremony, X3 is absent or any amino acid; each X4, X5, and X6 is independently any amino acid; X7 is unsubstituted Trp, or cyano, halo, alkyl, haloalkyl, hydroxy , alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. is a substituted Trp, X8: Gln, alpha-MeLys, alpha-MeLeu, alpha-MeLy s(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 the law of nature, X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pe n, or Pen(sulfoxide); X10 is unsubstituted Phe, or halo, alkyl, haloalkyl, hydroxy, alkoxy hydroxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy is Phe substituted with thionyl; X11 is 2-Nal, aMe(2-Nal), Phe(2-Me), Phe(3-M e), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp or substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy It is Trp, X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha- MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAsn, Alpha-MeT yr, Ala, cyclohexyl Ala, 1-aminocyclohexyl Ala (Achc), Acvc, Lys, or Aib; X13 and X14 are independently any amino acid; i) X16 is absent and X15 is His, Aib, THP, Phe, substituted Phe, or substituted Substituted (D)Phe, a-MePhe, Substituted a-MePhe, Trp, Substituted Trp, 1-Na l, aMe(1-Nal), substitution 1-Nal, 2-Nal, aMe(2-Nal), substitution 2-Nal or N-substituted Asn, However, the peptide inhibitor Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4 -(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac) ]-N-[Aib]-NH2 (SEQ ID NO: 151) or Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac )]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aM eLys]-[Lys(Ac)]-N-[a-MePhe]-NH2 (SEQ ID NO: 201) or ii) X16 is Aib, 3Pal, Phe, substituted Phe, substituted (D)Phe, substituted or or unsubstituted Tyr, unsubstituted (D)Tyr, a-MePhe, substituted a-MePhe, b- hPhe, 1-Nal, aMe(1-Nal), substituted 1-Nal, 2-Nal, aMe( 2-Nal), substituted 2-Nal, or N-substituted Asn, and X15 is any amino acid However, However, the peptide inhibitor Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[ 4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac )]-N-[Aib]-[(D)Tyr]-NH2 (SEQ ID NO: 202) The conditions are: or iii) the peptide is Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[3-Quin]-[α-MeLys]-[L ys(Ac)]-N-[(D)Leu)]-NH2 (SEQ ID NO: 1), Ac-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[(D)Lys]-NH2 (SEQ ID NO: 64), Ac-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 65), Ac-[Pen]-N-[(D)Dap]-[W(7-Me)]-[Lys(Ac)] -[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeL Lys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 72), Ac-[Pen]-N-[(D)Lys]-[W(7-Me)]-[Lys(Ac)] -[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeL Lys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 73), Ac-[Pen]-N-[(D)Asp]-[W(7-Me)]-[Lys(Ac)] -[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeL Lys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 74), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[Aib-Ahx]-NH2 (SEQ ID NO: 70), [Propionic acid]-[(D)Arg]-[Pen]-QTWQ-[Pen]-P he[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[NM e-bAla]-NH2 (SEQ ID NO: 8), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[N-Me-bAla ]-NH2 (SEQ ID NO: 14), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-[aM eTyr]-NH2 (SEQ ID NO: 44), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-[αMeGlu]-N-[αMeTyr]-NH2 (SEQ ID NO: 150), or Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[aMeTyr]-NH2 (SEQ ID NO: 151); and, The peptides are linked via an Abu-Cys thioether bond or a Pen-Pen disulfide bond. is cyclized via and, X4 and X9 form a disulfide bond or a thioether bond, and, The peptide inhibitor binds to the IL-23 receptor of interleukin-23 (IL-23). inhibits the binding of

[0114] In one embodiment, X3 is any amino acid. In certain embodiments, X3 is (D ) Arg. In a specific embodiment, X3 is absent.

[0115] In a related embodiment, the present invention provides monocyclic peptide inhibitors of the interleukin-23 receptor. or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor comprises: comprising or consisting of an amino acid sequence of formula (I), X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X 15-X16(II) During the ceremony, X7 to X16 are as described for formula (I), X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pe n, or Pen(sulfoxide); X5: Cit, Glu, Gly, Leu, Ile, beta-Ala, Ala, Lys , Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLe u, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab( Ac), Dap(Ac), homo-Lys(Ac), Gln, Asp, or Cys; X6: Thr, Alb, Asp, Dab, Gly, Pro, Ser, Alpha-Me Gln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha alpha-MeThr, alpha-MeSer, or Val, The peptide inhibitor is cyclized via the bond between X4 and X9, Peptide inhibitors inhibit the binding of interleukin-23 (IL-23) to the IL-23 receptor. This hinders integration.

[0116] In certain embodiments, X15 is selected from His, Phe_tetraF, Phe_3OH, a meF, Aib, THP, Phe, substituted Phe, substituted (D)Phe, a-MePhe, substituted Substituted a-MePhe, Trp, Substituted Trp, 1-Nal, aMe(1-Nal), Substituted 1- Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted Asn Therefore, X16 does not exist.

[0117] In certain embodiments, X15 is selected from His, Aib, THP, Phe, substituted Phe, substituted (D)Phe, a-MePhe, substituted a-MePhe, Trp, substituted Trp, 1-Nal , aMe(1-Nal), substitution 1-Nal, 2-Nal, aMe(2-Nal), substitution 2 -Nal, or N-substituted Asn, and X16 is absent.

[0118] In certain embodiments, X15 is any amino acid and X16 is paf, Aib, 3Pal, Phe, substituted Phe, substituted (D)Phe, substituted or unsubstituted Tyr, unsubstituted (D)Tyr, a-MePhe, substituted a-MePhe, b-hPhe, 1-Nal, aM e(1-Nal), substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Na l, or N-substituted Asn.

[0119] In certain embodiments, X15 is any amino acid and X16 is Aib, 3Pal , Phe, substituted Phe, substituted (D)Phe, substituted or unsubstituted Tyr, unsubstituted (D)T yr, a-MePhe, substituted a-MePhe, b-hPhe, 1-Nal, aMe(1- Nal), substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or It is N-substituted Asn.

[0120] In certain embodiments, N-substituted Asn is (N-Me)Asn, (N-Et)Asn, (Nn-Pr)Asn, (N-iPr)Asn, (N-iBu)Asn, (N-nBu )Asn, (N-tBu)Asn, (N-benzyl)Asn, (N-Ph)Asn, (N -2-aminophenyl)Asn, (N-3-aminophenyl)Asn, (N-4-amino (phenyl)Asn, (N-pyr)Asn, (N-3-Pyz)Asn, (N-4-Py z) Asn, (N-pip)Asn, (N-5-indolyl)Asn, (N-propyla (N-imidazo-2-yl)Asn, or (N-imidazo-2-yl)Asn.

[0121] In certain embodiments, X13 is selected from Aib, Glu, Cit, Gln, Lys(Ac), Orn(COMe), alpha-MeArg, alpha-MeGlu, alpha-MeL eu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac) , Dab(Ac), Dap(Ac), Homo-Lys(Ac), Lys(COR3), Ly s(SO2R3), or Lys, or X13 is Lys, PEGylated Lys, b-homoGlu or Lys(Y2-Ac), where Y2 is an amino acid, and R3 are Me, Et, n-Pr, i-Pr, CF3, n-pentyl, cyclopropyl, tB u, or O-allyl.

[0122] In certain embodiments, X14 is selected from the group consisting of Asn, 2-Nap, Aib, Arg, Cit, As p, Phe, Gly, Lys, Leu, Ala, (D)Ala, Beta-Ala, His , Thr, n-Leu, Gln, Ser, (D)Ser, Tic, Trp, alpha-M eGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), D ap(Ac), homo-Lys(Ac), or Lys(Ac).

[0123] 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. do.

[0124] In certain embodiments, X4 is Cys, (D)Cys, or alpha-MeCys. do.

[0125] In certain embodiments, X4 is (D)Pen, Pen, or Pen(sulfoxide). be.

[0126] In certain embodiments, X4 is Pen.

[0127] In certain embodiments, X9 is Cys, (D)Cys, or alpha-MeCys. do.

[0128] In certain embodiments, X9 is Pen or (D)Pen.

[0129] In certain embodiments, X9 is Pen.

[0130] In certain embodiments, X4 is Pen, X9 is Pen, and the bond is a disulfide bond. It is a fid bond.

[0131] In certain embodiments, X4 is Pen, X9 is Cys, and the bond is a disulfide bond. It is a fid bond.

[0132] In certain embodiments, X4 or X9 is Abu and the bond between X4 and X9 is Thi It is an ether bond.

[0133] In certain embodiments, X4 is Abu and X9 is Cys, (D)Cys, or Abu. In certain embodiments, X9 is Pen or (D)Pen. In a specific embodiment, X9 is Pen. In a more specific embodiment, X9 is In the most specific embodiment, X4 is Abu and X9 is Cys. be.

[0134] In certain embodiments, X4 is Abu, X9 is Cys or Pen, and the bond is a thioether bond.

[0135] In certain embodiments, X4 is Abu, X9 is Cys, and the linkage is a thioe It is a ether bond.

[0136] In certain embodiments, the peptide inhibitor is represented by formula (IIa), (IIb), or (IIc or comprising a sequence of formula (IIa), (IIb), or (IIc): , Pen-X5-X6-X7-X8-Pen-X10-X11-X12-X13-X14 -X15-X16(IIa) Abu-X5-X6-X7-X8-Cys-X10-X11-X12-X13-X14 -X15-X16(IIb), or Abu-X5-X6-X7-X8-Pen-X10-X11-X12-X13-X14 -X15-X16(IIc) X7 to X16 are as described for formula (I), and the peptide inhibitor is Pen-P en disulfide bond, Abu-Cys thioether bond, or Abu-Pen thioether bond It is cyclized via a tert-bond.

[0137] In certain embodiments, X5 is Asn, Gln, or Glu.

[0138] In certain embodiments, X5 is Asn or Gln.

[0139] In certain embodiments, X5 is Asn.

[0140] In certain embodiments, the peptide inhibitor is represented by formula (IIIa), (IIIb), (IIIc), ), or (IIId), or according to formula (IIIa), (IIIb), ( IIIc), or (IIId), Pen-Asn-X6-X7-X8-Pen-X10-X11-X12-X13-X1 4-X15-X16(IIIa) Pen-Gln-X6-X7-X8-Pen-X10-X11-X12-X13-X1 4-X15-X16(IIIb) Abu-Asn-X6-X7-X8-Cys-X10-X11-X12-X13-X1 4-X15-X16(IIIc), or Abu-Gln-X6-X7-X8-Pen-X10-X11-X12-X13-X1 4-X15-X16(IIId) In the formula, X6 is as described for formula (II), and X7 to X16 are as described for formula (I). The peptide inhibitors are as described above, and the peptide inhibitors are Pen-Pen disulfide bonds, Abu- It is cyclized via a Cys thioether bond or an Abu-Pen thioether bond.

[0141] In certain embodiments, X6 is Thr.

[0142] In certain embodiments, the peptide inhibitor is represented by formula (IVa), (IVb), (IVc), or or (IVd), or according to formula (IVa), (IVb), (IVc), or or (IVd), Pen-Asn-Thr-X7-X8-Pen-X10-X11-X12-X13-X 14-X15-X16(IVa) Pen-Gln-Thr-X7-X8-Pen-X10-X11-X12-X13-X 14-X15-X16(IVb) Abu-Asn-Thr-X7-X8-Cys-X10-X11-X12-X13-X 14-X15-X16(IVc), or Abu-Gln-Thr-X7-X8-Pen-X10-X11-X12-X13-X 14-X15-X16(IVd) X7 to X16 are as described for formula (I), and the peptide inhibitor is Pen-P en disulfide bond, Abu-Cys thioether bond, or Abu-Pen thioether bond It is cyclized via a tert-bond.

[0143] In certain embodiments, X8 is Gln, alpha-Me-Lys, alpha-MeLy s(Ac), Lys(Ac), Paf(Ac), Phe4NH2Ac, or Glu .

[0144] In certain embodiments, X8 is Gln. In certain embodiments, X8 is Cit. In certain embodiments, X8 is Lys(Ac).

[0145] In certain embodiments, the peptide inhibitor has the formula (Va), (Vb), (Vc), or (Vd) or according to formula (Va), (Vb), (Vc), or (Vd) contains an array of Pen-Asn-Thr-X7-Gln-Pen-X10-X11-X12-X13- X14-X15-X16(Va), Pen-Gln-Thr-X7-Gln-Pen-X10-X11-X12-X13- X14-X15-X16(Vb), Abu-Asn-Thr-X7-Gln-Cys-X10-X11-X12-X13- X14-X15-X16(Vc) (SEQ ID NO: 330), or Abu-Gln-Thr-X7-Gln-Pen-X10-X11-X12-X13- X14-X15-X16(Vd) X7 to X16 are as described for formula (I), and the peptide inhibitor is Pen-P en disulfide bond, Abu-Cys thioether bond, or Abu-Pen thioether bond It is cyclized via a tert-bond.

[0146] In certain embodiments, X10 is Phe, Phe[4-(2-aminoethoxy)][F (4-2ae)], Phe[4-(2-acetylaminoethoxy)], AEF, AEF( Ac), AEF(BH), AEF(Boc), AEF(Me)2, bMeRPhe, Ph e42ae-ethyl, Phe42aeSMSB, Phe4Pip, or Phe(4-CO NH2).

[0147] In certain embodiments, the peptide inhibitor has the formula (Va), (Vb), (Vc), or (Vd) or according to formula (Va), (Vb), (Vc), or (Vd) contains an array of Pen-Asn-Thr-X7-Gln-Pen-X10-X11-X12-X13- X14-X15-X16(Va), Pen-Gln-Thr-X7-Gln-Pen-X10-X11-X12-X13- X14-X15-X16(Vb), Abu-Asn-Thr-X7-Gln-Cys-X10-X11-X12-X13- X14-X15-X16(Vc) (SEQ ID NO: 331), or Abu-Gln-Thr-X7-Gln-Pen-X10-X11-X12-X13- X14-X15-X16(Vd) X7 to X16 are as described for formula (I), and the peptide inhibitor is Pen-P en disulfide bond, Abu-Cys thioether bond, or Abu-Pen thioether bond It is cyclized via a tert-bond.

[0148] In certain embodiments, X10 is Phe, Phe[4-(2-aminoethoxy)][F (4-2ae)], Phe[4-(2-acetylaminoethoxy)], or Phe(4- CONH2).

[0149] In certain embodiments, X10 is Phe[4-(2-aminoethoxy)] or Phe[ 4-(2-acetylaminoethoxy)].

[0150] In certain embodiments, the peptide inhibitor is represented by formula (VIa), (VIb), (VIc), or or (VId), or according to formula (VIa), (VIb), (VIc), or or (VId), Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X 12-X13-X14-X15-X16(VIa) (SEQ ID NO: 332), Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X 12-X13-X14-X15-X16(VIb) (SEQ ID NO: 333), Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-X 12-X13-X14-X15-X16(VIc) (SEQ ID NO: 334), or Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X 12-X13-X14-X15-X16(VId) (SEQ ID NO: 335) X7 to X16 are as described for formula (I), and [F(4-2ae)] is Ph e[4-(2-aminoethoxy)], and the peptide inhibitor is Pen-Pen disulfide. via a peptide bond, an Abu-Cys thioether bond, or an Abu-Pen thioether bond and cyclized.

[0151] In certain embodiments, the peptide inhibitor comprises the amino acid sequence of formula (I): X7-X8-X9-X10-X11-X12-X13-X14-X15-X16(I) During the ceremony, X15 is His, Phe_tetraF, Phe_3OH, ameF, THP, Ph e, substituted Phe, (D)Phe, substituted (D)Phe, a-MePhe, bhPhe, Tr p, substituted Trp, 1-Nal, aMe(1-Nal), substituted 1-Nal, 2-Nal, a Me(2-Nal), substituted 2-Nal, N(NMe), N(NEt), N(NiPr), N(NBu), N(NiBu), N(Nchx), N(Ncpx), N(NBzl), N (NtBu), N(NAnil), N(N2AmAnil), N(N3AmAnil), N(N4AmAnil), N(Npip), or N(NAmbu), and X16 is present. Does not exist.

[0152] In certain embodiments, the peptide inhibitor comprises the amino acid sequence of formula (I): X7-X8-X9-X10-X11-X12-X13-X14-X15-X16(I) During the ceremony, X15 is His, THP, Phe, substituted Phe, (D)Phe, substituted (D)Phe, a-MePhe, bhPhe, Trp, substituted Trp, 1-Nal, aMe(1-Nal) , substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, N(NMe) , N(NEt), N(NiPr), N(NBu), N(NiBu), N(Nchx), N (Ncpx), N(NBzl), N(NtBu), N(NAnil), N(N2AmAn il), N(N3AmAnil), N(N4AmAnil), N(Npip), or N( NAmbu) and X16 does not exist.

[0153] In certain embodiments, the peptide inhibitor comprises the amino acid sequence of formula (I): X7-X8-X9-X10-X11-X12-X13-X14-X15-X16(I) In the formula, X15 is any amino acid, and X16 is paf, Aib, 3Pal, Ph e, substituted Phe, substituted (D)Phe, substituted or unsubstituted Tyr, unsubstituted (D)Tyr, a-MePhe, substituted a-MePhe, b-hPhe, 1-Nal, aMe(1-Nal ), substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted The conversion is Asn.

[0154] In certain embodiments, the peptide inhibitor comprises the amino acid sequence of formula (I): X7-X8-X9-X10-X11-X12-X13-X14-X15-X16(I) In the formula, X15 is any amino acid, and X16 is Aib, 3Pal, Phe, or a substituted Phe, substituted (D)Phe, substituted or unsubstituted Tyr, unsubstituted (D)Tyr, a-Me Phe, substituted a-MePhe, b-hPhe, 1-Nal, aMe(1-Nal), substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted Asn is.

[0155] In certain embodiments, the peptide inhibitor is represented by formula (VIIa), (VIIb), or (VIIc). VIIc) or according to formula (VIIa), (VIIb), or (VII c) the sequence of Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X 12-X13-X14-X15-X16(VIIa) (SEQ ID NO: 336), Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-X 12-X13-X14-X15-X16(VIIb) (SEQ ID NO: 337), or Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X 12-X13-X14-X15-X16(VIIc) (SEQ ID NO: 338) wherein X7 and X11 are as described for formula (I), and X12 is 4diFA chx, Achx, Acpx, AmeK(Boc), 4-amino-4-carboxy-tet α-MeLys, α-MeLeu, α- MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, Alpha-MeAsn, alpha-MeTyr, Ala, cyclohexyl Ala, 1-amino cyclohexyl Ala (Achc), Acvc, Lys, or Aib; X13 is Aib, Glu, Cit, Gln, Lys(Ac), Orn(COMe), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-Me Lys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), D ap(Ac), homo-Lys(Ac), Lys(COR3), Lys(SO2R3), young or Lys, or X13 is Lys, PEGylated Lys, b-homoGlu, or Lys(Y2-Ac), where Y2 is an amino acid and R3 is Me, Et, n-Pr , i-Pr, CF3, n-pentyl, cyclopropyl, t-Bu, or O-allyl , 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 His, Phe_tetraF, Phe_3OH, ameF, THP, Ph e, substituted Phe, (D)Phe, substituted (D)Phe, a-MePhe, Trp, substituted Tr p, 1-Nal, aMe(1-Nal), substituted 1-Nal, 2-Nal, aMe(2-N al), substituted 2-Nal, and N-substituted Asn is (N-Me)Asn, (N-Et) Asn, (Nn-Pr)Asn, (N-iPr)Asn, (N-iBu)Asn, (N -nBu)Asn, (N-tBu)Asn, (N-benzyl)Asn, (N-Ph)As n, (N-2-aminophenyl)Asn, (N-3-aminophenyl)Asn, (N-4 -aminophenyl)Asn, (N-pyr)Asn, (N-3-Pyz)Asn, (N- 4-Pyz)Asn, (N-pip)Asn, (N-5-indolyl)Asn, (N-plot (N-imidazo-2-yl)Asn, or (N-imidazo-2-yl)Asn, and X16 is present Or not, or X15 is any amino acid, and X16 is paf, Aib, 3Pal, Phe, Substituted Phe, substituted (D)Phe, substituted or unsubstituted Tyr, unsubstituted (D)Tyr, aM ePhe, substituted a-MePhe, b-hPhe, 1-Nal, aMe(1-Nal), substituted Substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted As n, The peptide inhibitors are either cyclized via a Pen-Pen disulfide bond or The thioether bond is then cyclized to form a thiol-peptide inhibitor. can be.

[0156] In certain embodiments, the peptide inhibitor is represented by formula (VIIa), (VIIb), or (VIIc). VIIc) or according to formula (VIIa), (VIIb), or (VII c) the sequence of Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X 12-X13-X14-X15-X16(VIIa) (SEQ ID NO: 339), Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-X 12-X13-X14-X15-X16(VIIb) (SEQ ID NO: 340), or Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X 12-X13-X14-X15-X16(VIIc) (SEQ ID NO: 341) wherein X7 and X11 are as described for formula (I), and X12 is 4diFA chx, Achx, Acpx, AmeK(Boc), 4-amino-4-carboxy-tet α-MeLys, α-MeLeu, α- MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, Alpha-MeAsn, alpha-MeTyr, Ala, cyclohexyl Ala, 1-amino cyclohexyl Ala (Achc), Lys, or Aib; X13 is Aib, Glu, Cit, Gln, Lys(Ac), Orn(COMe), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-Me Lys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), D ap(Ac), homo-Lys(Ac), Lys(COR3), Lys(SO2R3), young or Lys, or X13 is Lys, PEGylated Lys, b-homoGlu, or Lys(Y2-Ac), where Y2 is an amino acid and R3 is Me, Et, n-Pr , i-Pr, CF3, n-pentyl, cyclopropyl, t-Bu, or O-allyl , 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 His, THP, Phe, substituted Phe, (D)Phe, substituted (D)Phe, a-MePhe, Trp, substituted Trp, 1-Nal, aMe(1-Nal), substituted 1-N al, 2-Nal, aMe(2-Nal), substituted 2-Nal, and N-substituted Asn is (N-Me)Asn, (N-Et)Asn, (Nn-Pr)Asn, (N-iPr)A sn, (N-iBu)Asn, (N-nBu)Asn, (N-tBu)Asn, (N-vehicle) (N-phenyl)Asn, (N-Ph)Asn, (N-2-aminophenyl)Asn, (N-3- (N-4-aminophenyl)Asn, (N-pyr)Asn, (N-3-Pyz)Asn, (N-4-Pyz)Asn, (N-pip)Asn, (N- 5-indolyl)Asn, (N-propylamido)Asn, or (N-imidazo-2-yl) X16 is absent, or X15 is any amino acid, and X16 is Aib, 3Pal, Phe, or substituted Phe , substituted (D)Phe, substituted or unsubstituted Tyr, unsubstituted (D)Tyr, a-MePhe , substituted a-MePhe, b-hPhe, 1-Nal, aMe(1-Nal), substituted 1-N al, 2-Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted Asn , The peptide inhibitors are either cyclized via a Pen-Pen disulfide bond or The thioether bond is then cyclized to form a thiol-peptide inhibitor. can be.

[0157] In certain embodiments, X15 is selected from His, Phe_tetraF, Phe_3OH, a meF, Asn, Arg, Leu, Val, Pro, (D)Pro, Ile, NMeAr g, Aib, (D)Leu, beta-Ala, Cit, Gln, Asp, alpha-Me Gln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Da b(Ac), Dap(Ac), or homo-Lys(Ac), and X16 is paf, A ib, 3Pal, Phe, substituted Phe, substituted (D)Phe, substituted or unsubstituted Tyr, Unsubstituted (D)Tyr, a-MePhe, substituted a-MePhe, b-hPhe, 1-Nal , aMe(1-Nal), substitution 1-Nal, 2-Nal, aMe(2-Nal), substitution 2 -Nal, or N-substituted Asn.

[0158] In certain embodiments, X15 is selected from His, Asn, Arg, Leu, Val, Pro, (D)Pro, Ile, NMeArg, Aib, (D)Leu, Beta-Ala, Cit , Gln, Asp, alpha-MeGln, alpha-MeAsn, Lys(Ac), Lufa-MeLys(Ac), Dab(Ac), Dap(Ac), or homo-Lys(A c) X16 is Aib, 3Pal, Phe, substituted Phe, substituted (D)Phe, or substituted substituted or unsubstituted Tyr, unsubstituted (D)Tyr, a-MePhe, substituted a-MePhe, b-hPhe, 1-Nal, aMe(1-Nal), substituted 1-Nal, 2-Nal, aM e(2-Nal), substituted 2-Nal, or N-substituted Asn.

[0159] In certain embodiments, each X12, X13, or X14 is independently any amino acid. In one embodiment, the amino acid is a naturally occurring amino acid. is an unnatural amino acid.

[0160] In certain embodiments, X14 is selected from the group consisting of Asn, 2-Nap, Aib, Arg, Cit, As p, 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, As p, Phe, Gly, Lys, Leu, Ala, (D)Ala, Beta-Ala, His , Thr, n-Leu, Gln, Ser, (D)Ser, Tic, Trp, alpha-M eGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), D ap(Ac), homo-Lys(Ac), or Lys(Ac). In certain embodiments, , X14 is Asn.

[0161] In certain embodiments, X15 is THP, Phe, or a-MePhe.

[0162] In certain embodiments, X13 is selected from Glu, Cit, Gln, Lys(Ac), alpha -MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(A c), homo-Lys(Ac), Lys(COR3), Lys(SO2R3), or L or X13 is Lys, PEGylated Lys, b-homoGlu, or Ly s(Y2-Ac), wherein Y2 is an amino acid. In certain embodiments, X13 is A ib, Glu, Cit, Gln, Lys(Ac), Orn(COMe), alpha-Me Arg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha Alpha-Me-Asn, Alpha-MeLys(Ac), Dab(Ac), Dap(Ac), Homo-Lys(Ac), Lys(COR 3 ), Lys(SO2R 3 ), or Lys or X13 is Lys, PEGylated Lys, b-homoGlu, or Lys(Y 2-Ac), Y2 is an amino acid, and R 3 are Me, Et, n-Pr, i-Pr , CF3, n-pentyl, cyclopropyl, t-Bu, or O-allyl.

[0163] In certain embodiments, X12 is selected from the group consisting of 4diFAchx, Achx, Acpx, AmeK( Boc), 4-amino-4-carboxy-tetrahydropyran (THP), alpha-M eLys, alpha-MeLeu, Ala, cyclohexyl Ala, Lys, Acvc, Or Aib.

[0164] In certain embodiments, X12 is selected from the group consisting of 4diFAchx, Achx, Acpx, AmeK( Boc), 4-amino-4-carboxy-tetrahydropyran (THP), alpha-M eLys, alpha-MeLeu, Ala, cyclohexyl Ala, Lys, or Aib is.

[0165] In certain embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran ( THP), alpha-MeLys, or alpha-MeLeu.

[0166] In certain embodiments, X12 is alpha-MeLeu. X12 is alpha-MeLys. In certain embodiments, X12 is 4-amino- 4-carboxy-tetrahydropyran (THP).

[0167] In certain embodiments, X13 is Glu, Gln, Lys(Ac), or Lys. .

[0168] In certain embodiments, X13 is Gln, Lys(Ac), or Lys.

[0169] In certain embodiments, X13 is Lys(Ac) or Lys.

[0170] In certain embodiments, X13 is Lys(Ac).

[0171] In certain embodiments, X13 is Gln. In certain embodiments, X13 is Gl In certain embodiments, X13 is alpha-MeGlu. In certain embodiments, X13 is Aib or OrnCOMe. Lys(COR 3 ) or Lys(SO2R 3 ) and R 3 are Me, Et, n-Pr, It is i-Pr, CF3, n-pentyl, cyclopropyl, t-Bu, or O-allyl.

[0172] In certain embodiments, the peptide inhibitor is represented by formula (VIIIa), (VIIIb), or is according to formula (VIIIc) or according to formula (VIIIa), (VIIIb) or contains the sequence of (VIIIc).

[0173] Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-a MeLeu-K(Ac)-X14-X15-X16(VIIIa) (SEQ ID NO: 339), Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-a MeLeu-K(Ac)-X14-X15(VIIIb) (SEQ ID NO: 340), or Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-a MeLeu-K(Ac)-X14-X15-X16(VIIIc) (SEQ ID NO: 341) wherein X7, X11, X14, X15, and X16 are as described for formula (I). The peptide inhibitors are Pen-Pen disulfide bonds, Abu-Cys thioates, and The cyclization is via a pentoyl bond or an Abu-Pen thioether bond.

[0174] In certain embodiments, X14 is Asn.

[0175] In certain embodiments, the peptide inhibitor is represented by formula (IXa), (IXb), or (IX c) or a sequence of formula (IXa), (IXb) or (IXc) Including, Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[ α-MeLeu]-K(Ac)-Asn-X15-X16(IXa) (SEQ ID NO: 342) , Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[ α-MeLeu]-K(Ac)-Asn-X15-X16(IXb) (SEQ ID NO: 343) , or Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[ α-MeLeu]-K(Ac)-Asn-X15-X16(IXc) (SEQ ID NO: 344) In the formula, X7, X11, and X15 to X16 are as defined for formula (II), Peptide inhibitors are linked via Pen-Pen disulfide bonds and Abu-Cys thioether bonds. , or cyclized via an Abu-Pen thioether bond.

[0176] In certain embodiments, X7 is cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy-substituted Trp-psi-Trp, and X11 is any of the groups described herein. As stated above.

[0177] In certain embodiments, X7 is cyano, halo, alkyl, haloalkyl, hydroxy, or Trp substituted with alkoxy, and X11 is as defined herein.

[0178] In certain embodiments, X11 is cyano, halo, alkyl, haloalkyl, hydroxy or alkoxy-substituted Trp, and X7 is as described herein.

[0179] In certain embodiments, X7 is substituted or unsubstituted aryl, or substituted or unsubstituted Heteroaryl-substituted Trp.

[0180] In certain embodiments, X7 is Trp-psi unsubstituted Trp, Trp5Br, Trp7 Cl, Trp7F, Trp5Me, or Trp7Me.

[0181] In certain embodiments, X7 is unsubstituted Trp.

[0182] In certain embodiments, X7 is Trp substituted with a substituted or unsubstituted phenyl. In certain embodiments, X7 is Trp substituted with substituted or unsubstituted phenyl or thienyl. be.

[0183] In certain embodiments, the peptide inhibitor is represented by formula (Xa), (Xb), (Xc), (Xd): , (Xe), or (Xf), or according to formula (Xa), (Xb), (Xc ), (Xd), (Xe), or (Xf), Pen-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-X11-a MeLeu-K(Ac)-Asn-X15-X16(Xa) (SEQ ID NO: 345), Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-W'-aM eLeu-K(Ac)-Asn-X15-X16(Xb) (SEQ ID NO: 346), Abu-Asn-Thr-W'-Gln-Cys-[F(4-2ae)]-X11-a MeLeu-K(Ac)-Asn-X15-X16(Xc) (SEQ ID NO: 347), Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-W'-aM eLeu-K(Ac)-Asn-X15-X16(Xd) (SEQ ID NO: 348), Abu-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-X11-a MeLeu-K(Ac)-Asn-X15-X16(Xe) (SEQ ID NO: 349), or Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-W'-aM eLeu-K(Ac)-Asn-X15-X16(Xf) (SEQ ID NO: 350) wherein X7, X11, X15, and X16 are as described for formula (I); ' is cyano, halo, alkyl, haloalkyl, hydroxy, phenyl, thienyl, or Alkoxy-substituted Trp, and the peptide inhibitor is Pen-Pen disulfide via bond, Abu-Cys thioether bond, or Abu-Pen thioether bond It is cyclized.

[0184] In certain embodiments, X11 is 6amide 2Nal, 6OMe2Nal, bMe2Na l(2S,3R), rbMe2Nal, 2-Nal, Phe(2-Me), Phe(3- Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal.

[0185] In certain embodiments, X11 is 2-Nal, Phe(2-Me), Phe(3-Me ), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal.

[0186] In certain embodiments, X11 is 2-Nal or 1-Nal.

[0187] In certain embodiments, X11 is 2-Nal.

[0188] In certain embodiments, X7 is unsubstituted Trp, Trp-psi, Trp5Br, Trp 7Cl, Trp7F, Trp5Me, or Trp7Me.

[0189] In certain embodiments, X7 is unsubstituted Trp.

[0190] In certain embodiments, the peptide inhibitor is represented by formula (XIa), (XIb), (XIc), (XId), (XIe), (XIf), (XIg), (XIh), (XIj ... XId), (XIe), or (XIf), or according to formula (XIa) , (XIb), (XIc), (XId), (XIe), or (XIf) , Pen-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-[2-Na l]-aMeLeu-K(Ac)-Asn-X1-X16 5(XIa) (SEQ ID NO: 32 3) Pen-Asn-Thr-W-Gln-Pen-[F(4-2ae)]-W'-aMe Leu-K(Ac)-Asn-X15-X16(XIb) (SEQ ID NO: 324), Abu-Asn-Thr-W'-Gln-Cys-[F(4-2ae)]-[2-Na l]-aMeLeu-K(Ac)-Asn-X15-X16(XIc) (SEQ ID NO: 325 ), Abu-Asn-Thr-W-Gln-Cys-[F(4-2ae)]-W'-aMe Leu-K(Ac)-Asn-X15-X16(XId) (SEQ ID NO: 326), Abu-Asn-Thr-W'-Gln-Pen-[F(4-2ae)]-[2-Na l]-aMeLeu-K(Ac)-Asn-X15-X16(XIe) (SEQ ID NO: 327 ), or Abu-Asn-Thr-W-Gln-Pen-[F(4-2ae)]-W'-aMe Leu-K(Ac)-Asn-X15-X16(XIf) (SEQ ID NO: 328), wherein X X15 and X16 are as described for formula (I), and W' is cyano, halo, alkyl, Trp substituted with aryl, haloalkyl, hydroxy, or alkoxy; The inhibitor can be a Pen-Pen disulfide bond, an Abu-Cys thioether bond, or an Ab It is cyclized via a u-Pen thioether bond.

[0191] In certain embodiments, W' is cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy-substituted Trp. In one embodiment, W' is alkyl-substituted In certain embodiments, W' is Me, Et, n-Pr, or i-Pr. In certain embodiments, W' is Trp substituted with Ph. In certain embodiments, W' is Trp substituted with thienyl.

[0192] In certain embodiments, W' is Trp substituted with 7-Me or 7-Ph.

[0193] In certain embodiments, W' is cyano, halo, alkyl at the 4, 5, 6, or 7 position. and Trp substituted with aryl, haloalkyl, hydroxy, or alkoxy.

[0194] In certain embodiments, W' is cyano, F, Cl, B at the 4, 5, 6, or 7 position. r, I, Me, Et, i-Pr, n-Pr, n-Bu, t-Bu, CF3, hydroxy, In certain embodiments, the substitution is at position 7. do.

[0195] In certain embodiments, W' is 5-F, 6-F, 7-F, 5-Cl, 6-Cl, 7-C l, 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 substituted Trp.

[0196] In certain embodiments, W' is 7-Me, 5-F, 7-F, 6-Cl, 6-Me, 4- In more specific embodiments, Trp is substituted with OMe, 5-OMe, or 5-Br. W' is Trp substituted with 7-Me, 6-Me, 4-OMe, or 6-Cl In a most specific embodiment, W' is Trp substituted with 7-Me.

[0197] In more specific embodiments, W' is unsubstituted Trp.

[0198] In certain embodiments, X15 is THP and X16 is absent. In certain embodiments, X15 is Phe and X16 is absent. is a-MePhe and X16 is absent.

[0199] In certain embodiments, X15 is Trp or a substituted Trp and X16 is absent. In certain embodiments, X15 is Trp substituted with alkyl, aryl, or halo. and X16 is absent. In certain embodiments, X15 is 7-Me, 5-F, or 7-Trp substituted with Ph, X16 is absent.

[0200] In certain embodiments, X15 is Phe or a substituted Phe and X16 is absent. In certain embodiments, X15 is Phe substituted with alkyl, alkoxy, or halo. and X16 is absent. In certain embodiments, X15 is OMe, diOMe, Phe substituted with F or Cl, and X16 is absent.

[0201] In certain embodiments, X15 is 2-Nal or substituted 2-Nal. In this state, X15 is aMe(2-Nal) and X16 is absent.

[0202] In certain embodiments, X15 is His, Phe_tetraF, Phe3OH, or ameF and X16 does not exist.

[0203] In certain embodiments, X15 is Phe-tetraF, Phe3OH, ameF, T HP, Phe, substituted Phe, (D)Phe, substituted (D)Phe, a-MePhe, Trp , substituted Trp, 1-Nal, aMe(1-Nal), substituted 1-Nal, 2-Nal, aM e(2-Nal), substituted 2-Nal, N(NMe), N(NEt), N(NiPr), N (NBu), N(NiBu), N(Nchx), N(Ncpx), N(NBzl), N( NtBu), N(NAnil), N(N2AmAnil), N(N3AmAnil), N (N4AmAnil), N(Npip), or N(NAmbu), and X16 is present do not.

[0204] In certain embodiments, X15 is His, THP, Phe, substituted Phe, (D)Phe , Substituted (D)Phe, a-MePhe, Trp, Substituted Trp, 1-Nal, aMe(1- Nal), substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, N( NMe), N(NEt), N(NiPr), N(NBu), N(NiBu), N(Nch x), N(Ncpx), N(NBzl), N(NtBu), N(NAnil), N(N2 AmAnil), N(N3AmAnil), N(N4AmAnil), N(Npip), Or N(NAmbu), and X16 is not present.

[0205] In certain embodiments, N-substituted Asn is (N-Me)Asn, (N-Et)Asn, (Nn-Pr)Asn, (N-iPr)Asn, (N-iBu)Asn, (N-nBu )Asn, (N-tBu)Asn, (N-benzyl)Asn, (N-Ph)Asn, (N -2-aminophenyl)Asn, (N-3-aminophenyl)Asn, (N-4-amino (phenyl)Asn, (N-pyr)Asn, (N-3-Pyz)Asn, (N-4-Py z) Asn, (N-pip)Asn, (N-5-indolyl)Asn, (N-propyla X16 is absent.

[0206] In certain embodiments, X15 or X16 is an N-substituted Asn, and the N-substituted Asn is The following is the result.

[0207] [ka]

[0208] [Table 4]

[0209] In certain embodiments, X15 is N(NMe), N(NEt), or N(NiPr). Yes, X16 does not exist.

[0210] In certain embodiments, X15 is Aib, Leu, Lys, His, Val, Thr, (D)Leu, (D)Lys, (D)His, (D)Val, or (D)Thr; X16 is substituted or unsubstituted Phe or substituted or unsubstituted (D)Phe.

[0211] In certain embodiments, X15 is Asn, Phe, aMePhe, substituted Phe, or T HP, and X16 is Aib, 3Pal, substituted or unsubstituted Phe, or substituted or unsubstituted Phe. is unsubstituted (D)Phe.

[0212] In a specific embodiment, X15 is any amino acid and X16 is 3Pal.

[0213] In certain embodiments, X15 is any amino acid and X16 is paf, dPhe 4-2ae, or dPhe4OCF3.

[0214] In certain embodiments, X16 is absent, (D)NMeTyr, (D)Tyr, (D)(4-amino)Phe, (D)(3-amino)Phe, (D)Phe, (D)2- Nal, aMePhe, bhPhe, or Aib.

[0215] In certain embodiments, the peptide inhibitor has the structure of formula (Z): R 1 -XR 2 (Z) or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 alkanoyl, either alone or in combination with any of the foregoing. PEGylated versions of any of the spacers, and X is a group represented by the formula (I), formula (II) to (X If), or an amino acid sequence set forth in any of Tables E1, E2, or E3. is the amino acid sequence, and R 2 is OH or NH2.

[0216] In certain embodiments, the peptide inhibitor has the structure of formula (Z'): R 1 -X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 -X14-X15-X16-R 2 (Z') or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 alkanoyl, either alone or in combination with any of the foregoing. PEGylated versions of any of the spacers, and X is a group represented by the formula (I), formula (II) to (X If), or an amino acid sequence set forth in any of Tables E1, E2, or E3. is the amino acid sequence, and R 2 is OH or NH2.

[0217] In certain embodiments, R 1 is H or C1-C 20 It is an alkanoyl.

[0218] In certain embodiments, R 1 is H or Ac.

[0219] In certain embodiments, R 1 is Ac.

[0220] In certain embodiments of peptides of formula Z, X3 is absent or is D(arg). do.

[0221] In certain embodiments of peptides of formula Z, X4 is selected from the group consisting of Abu, Cys, (D)Cys, Al, (D) Pen, Pen, or Pen(sulfoxide).

[0222] In certain embodiments of peptides of formula Z, X4 is selected from Cys, (D)Cys, alpha-M eCys, (D)Pen, or Pen.

[0223] In certain embodiments of peptides of formula Z, X5 is Asn, Gln, or Glu.

[0224] In certain embodiments of peptides of formula Z, X6 is selected from the group consisting of Thr, Aib, Asp, Dab, G ly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-Me Leu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or V al.

[0225] In certain embodiments of peptides of formula Z, X7 is unsubstituted Trp, or cyano, halo , alkyl, Trp-psi, haloalkyl, hydroxy, alkoxy, substituted or unsubstituted Trp substituted with substituted aryl or substituted or unsubstituted heteroaryl.

[0226] In certain embodiments of peptides of formula Z, X7 is selected from the group consisting of unsubstituted Trp, Trp-psi, Tr p5Br, Trp7Cl, Trp7F, Trp5Me, or Trp7Me.

[0227] In certain embodiments of peptides of formula Z, X8 is selected from the group consisting of Gln, alpha-MeLys ... Fa-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Gl u, Phe, Paf(Ac), Phe4NH2Ac, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Da p(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp.

[0228] In certain embodiments of peptides of formula Z, X8 is selected from the group consisting of Gln, alpha-Me-Lys ... Luca-MeLys(Ac), Lys(Ac), Paf(Ac), Phe4NH2Ac, Or Glu.

[0229] In certain embodiments of peptides of formula Z, X9 is selected from the group consisting of Cys, (D)Cys, alpha-M eCys, (D)Pen, or Pen.

[0230] In certain embodiments of peptides of formula Z, X10 is unsubstituted Phe, or halo, alkyl , haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-amino Phe substituted with ethoxy or 2-acetylaminoethoxy.

[0231] In certain embodiments of peptides of formula Z, X10 is Phe, Phe[4-(2-amino ethoxy)][F(4-2ae)], Phe[4-(2-acetylaminoethoxy)], AEF, AEF(Ac), AEF(BH), AEF(Boc), AEF(Me)2, bM eRPhe, Phe42ae-ethyl, Phe42aeSMSB, Phe4Pip, or Phe(4-CONH2).

[0232] In certain embodiments of peptides of formula Z, X11 is 6amide 2Nal, 6OMe2Na l, bMe2Nal(2S,3R), 2-Nal, aMe(2-Nal), rbMe2N al, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4 -dimethoxy), 1-Nal, unsubstituted Trp, or cyano, halo, alkyl, haloalkoxy and Trp substituted with aryl, hydroxy, or alkoxy.

[0233] In certain embodiments of peptides of formula Z, X11 is 6amide 2Nal, 6OMe2Na l, bMe2Nal(2S,3R), rbMe2Nal, 2-Nal, Phe(2-Me ), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1 -Nal.

[0234] In certain embodiments of the peptide of formula Z, X12 is selected from the group consisting of 4diFAchx, Achx, Ac px, AmeK(Boc), 4-amino-4-carboxy-tetrahydropyran (THP ), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha- MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, Sulfa-MeTyr, Ala, or Cyclohexyl Ala, 1-aminocyclohexyl A la(Achc), Acvc, Lys, or Aib.

[0235] In certain embodiments of the peptide of formula Z, X12 is selected from the group consisting of 4diFAchx, Achx, Ac px, AmeK(Boc), 4-amino-4-carboxy-tetrahydropyran (THP ), alpha-MeLys, or alpha-MeLeu.

[0236] In certain embodiments of peptides of formula Z, X13 is selected from the group consisting of Glu, Gln, Lys(Ac), Or Lys.

[0237] In certain embodiments of peptides of formula Z, X14 is selected from the group consisting of Asn, 2-Nap, Aib, Ar g, Cit, Asp, Phe, Gly, Lys, Leu, Ala, (D)Ala, Beta -Ala, His, Thr, n-Leu, Gln, Ser, (D)Ser, Tic, Tr p, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), D ab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac).

[0238] In certain embodiments of peptides of formula Z, X16 is absent and X15 is His, Ai b, THP, Phe, substituted Phe, substituted (D)Phe, a-MePhe, substituted a-MeP he, Trp, substituted Trp, 1-Nal, aMe(1-Nal), substituted 1-Nal, 2- Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted Asn.

[0239] In certain embodiments of peptides of formula Z, X15 is selected from the group consisting of His, PhetetraF, Ph e3OH, ameF, THP, Phe, substituted Phe, (D)Phe, substituted (D)Phe, a-MePhe, bhPhe, Trp, substituted Trp, 1-Nal, aMe(1-Nal) , substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, N-substituted Asn is (N-Me)Asn, (N-Et)Asn, (Nn-Pr)Asn, (N- iPr)Asn, (N-iBu)Asn, (N-nBu)Asn, (N-tBu)Asn , (N-benzyl)Asn, (N-Ph)Asn, (N-2-aminophenyl)Asn, (N-3-aminophenyl)Asn, (N-4-aminophenyl)Asn, (N-pyr )Asn, (N-3-Pyz)Asn, (N-4-Pyz)Asn, (N-pip)As n, (N-5-indolyl)Asn, (N-propylamido)Asn, or (N-imidazoline 2-yl)Asn.

[0240] In certain embodiments of the peptide of formula Z, X16 is selected from the group consisting of Aib, Phe, 3Pal, substituted P he, substituted (D)Phe, substituted or unsubstituted Tyr, unsubstituted (D)Tyr, a-MeP he, substitution a-MePhe, b-hPhe, 1-Nal, aMe(1-Nal), substitution 1 -Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted Asn and X15 is any amino acid.

[0241] In certain embodiments of peptides of formula Z, X16 is dPhe4-2ae or dPhe4 It is OCF3.

[0242] In certain embodiments, the peptide is: Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[3-Quin]-[α-MeLys]-[L ys(Ac)]-N-[(D)Leu)]-NH2 (SEQ ID NO: 1) [Propionic acid]-[(D)Arg]-[Abu]-QTWQ-[Cys]-P he[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[THP ]-NH2 (SEQ ID NO: 2), [Propionic acid]-[(D)Arg]-[Pen]-QTWQ-[Pen]-P he[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[aM ePhe]-NH2 (SEQ ID NO: 2), [Propionic acid]-[(D)Arg]-[Pen]-QTWQ-[Pen]-[ Phe(4-OMe)]-[2-Nal]-[THP]-EN-[THP]-NH2( SEQ ID NO: 4), [3,3,3-Trifluoropropionic acid]-[(D)Arg]-[Pen]-QT -WQ-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[T HP]-EN-[THP]-NH2 (SEQ ID NO: 5), [Propionic acid]-[(D)Arg]-[Pen]-QTWQ-[Pen]-P he[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(COC F3)]-N-[THP]-NH2 (SEQ ID NO: 6), [Propionic acid]-[(D)Arg]-[Pen]-QTWQ-[Pen]-P he[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(COt Bu)]-N-[THP]-NH2 (SEQ ID NO: 7), [Propionic acid]-[(D)Arg]-[Pen]-QTWQ-[Pen]-P he[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[NM e-bAla]-NH2 (SEQ ID NO: 8), [Pentanoic acid]-[(D)Arg]-[Pen]-QTWQ-[Pen]-Ph e[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[THP] -NH2 (SEQ ID NO: 9), [Propionic acid]-[(D)Arg]-[Pen]-QTWQ-[Pen]-P he[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[THP ]-NH2 (SEQ ID NO: 10), Ac-[(D)Arg]-[Abu]-QT-[W(7-Ph)]-[Lys(Ac )]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aM eLys]-[Lys(Ac)]-N-[α-MePhe]-NH2 (SEQ ID NO: 11), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-ENN-ac (SEQ ID NO: 1 2), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[THP]-NH2( SEQ ID NO: 13), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[N-Me-bAla ]-NH2 (SEQ ID NO: 4), pr-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-QN-[THP]-NH2( SEQ ID NO: 15), Ac-[(D)Arg]-[Cys]-QTWQA-Phe[4-(2-ami Noethoxy)]-[2-Nal]-[THP]-[Orn(COMe)]-N-[THP ]-NH2 (SEQ ID NO: 16), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-ENF-NH2 (SEQ ID NO: 17), [(D)Arg]-[Pen]-QTWQ-[Pen]-[Phe(4-OMe )]-[2-Nal]-[THP]-EN-[THP]-NH2 (SEQ ID NO: 18), pr-[(D)Arg]-[Pen]-Q-[Hyp]-WQ-[Pen]-Phe [4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[THP]- NH2 (SEQ ID NO: 19), pr-[(D)Arg]-[Cys]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[THP]-NH2( SEQ ID NO: 20), pr-[(D)Arg]-[Abu]-QTWQ-[Cys]-[Phe(4- OMe)]-[2-Nal]-[THP]-EN-[THP]-NH (SEQ ID NO: 21 ), [(D)Arg]-[Abu]-QTWQ-[Cys]-[Phe(4-OMe )]-[2-Nal]-[THP]-EN-[THP]-NH2 (SEQ ID NOs: 21 and 22) ,twenty five), pr-[(D)Arg]-[Cys]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[α-MePhe]- NH2 (SEQ ID NO: 23), N3_acid-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4 -(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[THP]-NH 2 (SEQ ID NO: 24), FPrp triazole Me_ acid-[(D)Arg]-[Abu]-QTWQ-[ Cys]-[Phe(4-OMe)]-[2-Nal]-[THP]-EN-[THP ]-NH2 (SEQ ID NO: 25), pr-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(COtBu)]-N -F-NH2 (SEQ ID NO: 26), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[Achc]-[aMeGlu]-NF- NH2 (SEQ ID NO: 27), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[Achc]-[aMeGlu]-NF- [Aib]-NH2 (SEQ ID NO: 28), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[Achc]-[aMeGlu]-N-[a -MePhe]-NH2 (SEQ ID NO: 29), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-QN-[α-MePhe]- NH2 (SEQ ID NO: 30), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-ame W-NH2 (SEQ ID NO: 31), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-1[2 -Nal]-NH2 (SEQ ID NO: 32), pr-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(CO2Allyl) ]-NF-NH2 (SEQ ID NO: 33), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-[Ph e(4-CONH)]-NH (SEQ ID NO: 34), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-[2- Nal]-NH2 (SEQ ID NO: 35), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-[aM e(4-F)Phe]-NH2 (SEQ ID NO: 36), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-[TH P]-NH2 (SEQ ID NO: 37), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[Achc]-[aMeGlu]-N-[T HP]-NH2 (SEQ ID NO: 38), Ac-[(D)Arg]-[Abu]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[Achc]-[aMeGlu]-N-[T HP]-NH2 (SEQ ID NO: 39), Ac-[(D)Arg]-[Cys]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[Achc]-[aMeGlu]-N-[a -MePhe]-NH2 (SEQ ID NO: 40), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-[Phe(3, 4-diOMe)]-[2-Nal]-[THP]-[aMeGlu]-N-[a-Me Phe]-NH2 (SEQ ID NO: 41), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[Achc]-EN-[THP]-NH2 (SEQ ID NO: 42), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-NF-[ Aib]-[α-MeLys]-NH2 (SEQ ID NO: 43), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-[aM eTyr]-NH2 (SEQ ID NO: 44), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[Achc]-[aMeGlu]-NF- [Aib]-[α-MeLys]-NH2 (SEQ ID NO: 45), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-[Ph e(3,5-diF)]-NH2 (SEQ ID NO: 46), [(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-(2-( Boc)aminoethoxy)]-[2-Nal]-[THP]-EN-[THP]-NH 2 (SEQ ID NO: 47), pr-[(D)Arg]-[Abu]-QTWQ-[aMeCys]-Phe[ 4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENF-NH2 (combination Column number 48), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[Aib]-NF-NH2( SEQ ID NO: 49), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[Achc]-N-[a-Me Phe]-NH2 (SEQ ID NO: 50), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(COcPr)]-N -[THP]-NH2 (SEQ ID NO: 51), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(COPr)]-N- [THP]-NH2 (SEQ ID NO: 52), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NF- NH2 (SEQ ID NO: 53), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(COEt)]-N- F-NH2 (SEQ ID NO: 54), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(COcPr)]-N -F-NH2 (SEQ ID NO: 55), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[T HP]-NH2 (SEQ ID NO: 56), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(COEt)]-N- [THP]-NH2 (SEQ ID NO: 57), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(COPr)]-N- F-NH2 (SEQ ID NO: 58), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(COPent)]- NF-NH2 (SEQ ID NO: 59), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(COCF3)]-N -F-NH2 (SEQ ID NO: 60), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(COiPr)]-N -F-NH2 (SEQ ID NO: 61), Ac-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[(D)Lys]-NH2 (SEQ ID NO: 64), Ac-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 65), Ac-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[α-MePhe]-NH2 (SEQ ID NO: 66), Ac-[Abu]-QT-[W(7-Ph)]-[Lys(Ac)]-[Cys]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[α-MePhe]-NH2 (SEQ ID NO: 67), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[(D)Leu]-[aMePhe]-NH2 (SEQ ID NO: 68), Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Ly s(Ac)]-N-[(D)Leu]-[(D)aMePhe]-NH2 (SEQ ID NO: 69 )、 Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Ly s(Ac)]-N-[Aib-Ahx]-NH2 (SEQ ID NO: 70), Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Ly s(Ac)]-N-[Aib]-[bhPhe]-NH2 (SEQ ID NO: 71), Ac-[Pen]-N-[(D)Dap]-[W(7-Me)]-[Lys(Ac)] -[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeL ys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 72), Ac-[Pen]-N-[(D)Lys]-[W(7-Me)]-[Lys(Ac)] -[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeL ys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 73), Ac-[Pen]-N-[(D)Asp]-[W(7-Me)]-[Lys(Ac)] -[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeL ys]-[Lys(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 74), Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[THP]-NH2 (SEQ ID NO: 75), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[α-MePhe]-NH2 (SEQ ID NO: 76), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-EN-[α-MePhe]-NH2 (SEQ ID NO: 77), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-[Ph e(3,4-diOMe)]-NH2 (SEQ ID NO: 78), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-[(D )Phe(3,4-diOMe)]-NH2 (SEQ ID NO: 79), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[aMe(2-Nal )]-NH2 (SEQ ID NO: 80), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-[W( 5-F)]-NH2 (SEQ ID NO: 81), Ac-[Pen]-QTW-[Lys(Ac)]-[Pen]-Phe[4-(2 -aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N -[α-MePhe]-NH2 (SEQ ID NO: 82), pr-[(D)Arg]-[Abu]-QTWQ-[aMeCys]-Phe[ 4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[a-MePh e]-NH2 (SEQ ID NO: 83), Ac-[Pen]-QTW-[Lys(Ac)]-[Pen]-Phe[4-(2 -aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N -[THP]-NH2 (SEQ ID NO: 84), pr-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[α-MePhe]- NH2 (SEQ ID NO: 85), pr-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[aMe(2-Nal)]-[THP]-EN-[a-Me Phe]-NH2 (SEQ ID NO: 86), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2 -aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N -[THP]-NH2 (SEQ ID NO: 87), Ac-[(D)Arg]-[Pen]-NTW-[Lys(Ac)]-[Pen] -Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[ THP]-NH2 (SEQ ID NO: 88), Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2 -aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N -[α-MePhe]-NH2 (SEQ ID NO: 89), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-Q-[Pen] -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[T HP]-NH2 (SEQ ID NO: 90), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-Q-[Pen] -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[a -MePhe]-NH2 (SEQ ID NO: 91), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-EN-[THP]-NH2 (SEQ ID NO: 92), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-Q-[Pen] -Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[ a-MePhe]-NH2 (SEQ ID NO: 93), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acv c]-EN-[α-MePhe]-NH2 (SEQ ID NO: 94), Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2 -aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N -[THP]-NH2 (SEQ ID NO: 95), Ac-[(D)Arg]-[Pen]-NT-[W(b-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-EN-[α-MePhe]-NH2 (SEQ ID NOs: 96, 109), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[α-MePhe]- NH2 (SEQ ID NO: 97), Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2 -aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N -[α-MePhe]-NH2 (SEQ ID NO: 98), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-Q-[Pen] -Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[ THP]-NH2 (SEQ ID NO: 99), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[α-MePhe]-[(D)Tyr]-NH (SEQ ID NO: 100) , Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acv c]-EN-[THP]-NH2 (SEQ ID NO: 101), Ac-[(D)Arg]-[Pen]-NTW-[Lys(Ac)]-[Pen] -Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[ a-MePhe]-NH2 (SEQ ID NO: 102), Ac-[Pen]-NTW-[Lys(COCF3)]-[Pen]-Phe[4 -(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac) ]-N-[THP]-NH2 (SEQ ID NO: 103), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[ 4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac) ]-N-[α-MePhe]-NH2 (SEQ ID NO: 104), Ac-[(D)Arg]-[Pen]-NTW-[Lys(Ac)]-[Pen] -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[T HP]-NH2 (SEQ ID NO: 105), Ac-[(D)Arg]-[Pen]-NTW-[Lys(Ac)]-[Pen] -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[a -MePhe]-NH2 (SEQ ID NO: 106), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[THP]-[(D)Tyr]-NH2 ((SEQ ID NO: 107), Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[ 4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac) ]-N-[THP]-NH2 (SEQ ID NO: 108), Ac-[(D)Arg]-[Pen]-NT-[W(b-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-EN-[α-MePhe]-NH2 (SEQ ID NO: 109), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(N-benzyl)A sn]-NH2 (SEQ ID NO: 110), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-[Lys(Ac)]-N-[α-MePhe]-NH2 (SEQ ID NO: 111), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-Phe[4-NH2]-NH2 (SEQ ID NO: 112), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[(D)Leu]-NH2 (SEQ ID NO: 113), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[α-MePhe]-(D)Phe[4-NH2]-NH2 (SEQ ID NO: No. 114), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[α-MePhe]-(D)Phe[3-NH2]-NH2 (SEQ ID NO: No. 115), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[α-MePhe]-[3Pal]-NH2 (SEQ ID NO: 116), Ac-[Cys]-NT-[W(7-Me)]-[Lys(Ac)]-[aMeCy s]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]- [Lys(Ac)]-N-[THP]-NH2 (SEQ ID NO: 117), Ac-[Cys]-NT-[W(7-Me)]-[Lys(Ac)]-[aMeCy s]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]- [Lys(Ac)]-N-[α-MePhe]-NH2 (SEQ ID NO: 118), Ac-[Cys]-NT-[W(7-Me)]-Q-[aMeCys]-Phe[4 -(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac) ]-N-[α-MePhe]-NH2 (SEQ ID NO: 119), Ac-[Cys]-NT-[W(7-Me)]-Q-[aMeCys]-Phe[4 -(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac) ]-N-[THP]-NH2 (SEQ ID NO: 120), Ac-[Cys]-NTW-[Lys(Ac)]-[aMeCys]-Phe[4 -(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac) ]-N-[THP]-NH2 (SEQ ID NO: 121), Ac-[Cys]-NTW-[Lys(Ac)]-[aMeCys]-Phe[4 -(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac) ]-N-[α-MePhe]-NH2 (SEQ ID NO: 122), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[α-MePhe]- NH2 (SEQ ID NO: 123), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-EN-[α-MePhe]-NH2 (SEQ ID NO: 124), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(N-Ph)Asn ]-NH2 (SEQ ID NO: 125), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(N-(2-amino phenyl))Asn]-NH2 (SEQ ID NO: 126), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(N-Pip)As n]-NH2 (SEQ ID NO: 127), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(N-Pyr)As n]-NH2 (SEQ ID NO: 128), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(N-(4-amino phenyl))Asn]-NH2 (SEQ ID NO: 129), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(N-(3-amino phenyl))Asn]-NH2 (SEQ ID NO: 130), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(N-(4-Pyz ))Asn]-NH2 (SEQ ID NO: 131), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(N-(5-Indo (aryl)Asn]-NH2 (SEQ ID NO: 132), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(N-(3-Pyz ))Asn]-NH2 (SEQ ID NO: 133), pr-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-THP]-EN-[THP]-NH2 (sequence Column number 358), pr-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[(aM e)-4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[THP ]-NH2 (SEQ ID NO: 135), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(N-propylamino) Asn]-NH2 (SEQ ID NO: 136), Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(N-(imidazoline (2-yl)methyl)Asn]-NH2 (SEQ ID NO: 137), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(CO CF)]-N-[α-MePhe]-NH (SEQ ID NO: 138), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(CO tBu)]-N-[α-MePhe]-NH2 (SEQ ID NO: 139), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(CO CF)]-N-[THP]-NH (SEQ ID NO: 140), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(CO tBu)]-N-[THP]-NH2 (SEQ ID NO: 141), PentCO-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Ly s(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]- [THP]-EN-[α-MePhe]-NH2 (SEQ ID NO: 142), Biotin-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys( Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[T HP]-EN-[THP]-NH2 (SEQ ID NO: 143), Biotin-PEG2(2:2)-[(D)Arg](x,2:1,3:2)-Pen( 1:3,3:1)-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-P he[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[THP ]-NH2 (SEQ ID NO: 144), Biotin-PEG3(2:2)-[(D)Arg](x,2:1,3:2)-Pen( 1:3,3:1)-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-P he[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[THP ]-NH2 (SEQ ID NO: 145), Flag tag-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Ly s(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]- [THP]-EN-[THP]-NH2 (SEQ ID NO: 146), Flag-tagged PEG2(2:2)-[(D)Arg](x,2:1,3:2)-Pe n(1:3,3:1)-NT-[W(7-Me)]-[Lys(Ac)]-[Pen] -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[T HP]-NH2 (SEQ ID NO: 147), Flag-tagged PEG3(2:2)-[(D)Arg](x,2:1,3:2)-Pe n(1:3,3:1)-NT-[W(7-Me)]-[Lys(Ac)]-[Pen] -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[T HP]-NH2 (SEQ ID NO: 148), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Cit]-[ Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu] -EN-[α-MePhe]-NH2 (SEQ ID NO: 149), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-[aMeGlu]-N-[aMeTyr]-NH2 (SEQ ID NO: 150), or Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[aMeTyr]-NH2 (SEQ ID NO: 151); Peptide inhibitors are also available via Abu-Cys thioether bonds or Pen-Pen disulfide bonds. It is cyclized via an alkyl bond.

[0243] In certain embodiments, the peptide is Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[ 4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac )]-N-[Aib]-[(D)Tyr]-NH2 (SEQ ID NO: 202), Ac-[Pen]-NT-[W(7-F)]-[Lys(Ac)]-[Pen]-P he[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys (Ac)]-N-[α-MePhe]-NH (SEQ ID NO: 21), Ac-[Pen]-NT-[W(7-Cl)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[α-MePhe]-NH2 (SEQ ID NO: 223), Ac-[Pen]-NT-[W(5-Br)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[α-MePhe]-NH2 (SEQ ID NO: 225), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[(D)Lys]-[(D)Phe(4-OCF3)]-am(sequence No. 227), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[T HP]-N(H)Me (SEQ ID NO: 231), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(D )Leu]-[(D)Tyr]-NH2 (SEQ ID NO: 232), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[( D)Phe(4-NH)]-[(D)Tyr]-NH (SEQ ID NO: 235), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[Phe(tetrafluoro)]-am (SEQ ID NO: 242), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[(D)Lys]-[(D)Phe[4-(2-aminoethoxy)] ]-am (SEQ ID NO: 244), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-acetylaminoethoxy)]-[2-Nal]-[α-MeLys] -[Lys(Ac)]-N-[THP]-NH2 (SEQ ID NO: 253), Ac-[Pen]-NT-[W(7-Me)]-Phe_4NH2_Ac-[Pen ]-Phe[4-(2-aminoethoxy)]_Ac-[2-Nal]-[α-MeLys ]-[Lys(Ac)]-N-[THP]-NH2 (SEQ ID NO: 254), Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- [(R)bMePhe]-[2-Nal]-[a-MeLys]-[Lys(Ac)]- N-[THP]-NH2 (SEQ ID NO: 255), Benzhydroxyiodine acid-[Pen]-NT-[W(7-Me)]-[Lys( Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a -MeLys]-[Lys(Ac)]-N-[a-MePhe]-NH2 (SEQ ID NO: 22 9), Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac )]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aM eLys]-[Lys(Ac)]-N-[a-MePhe]-NH2 (SEQ ID NO: 201) , Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[Aib]-NH2( SEQ ID NO: 203), Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]-[2-Nal]-[THP]-EN-[Aib]-NH2( SEQ ID NO: 204), Nterm_bA(2:3)-[(D)Arg]-[Abu]-QTWQ-[C ys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E(2 :3) -N-[THP]-NH2 (SEQ ID NO: 329), FPrp triazole Me_ acid-[(D)Arg]-[Abu]-QTWQ-[ Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E- N-[THP]-NH2 (SEQ ID NO: 206), Pr-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-EN-[α-MePhe]-NH2 (SEQ ID NO: 208), N3_acid-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys( Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[T HP]-EN-[α-MePhe]-NH2 (SEQ ID NO: 211), MeSO2-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys (Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[ THP]-EN-[α-MePhe]-NH2 (SEQ ID NO: 212), [(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-(2-A ethoxy)]-[2-Nal]-[THP]-EN-[THP]-NH2 (SEQ ID NO: No. 24), Pr-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-( 2-aminoethoxy)]_ethyl)]-[2-Nal]-[THP]-EN-[THP ]-NH2 (SEQ ID NO: 213), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-EN-[(D)Leu]-[(D)Tyr]-NH2 (SEQ ID NO: 215), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-EN-[THP]-[(D)Tyr]-NH2 (SEQ ID NO: 216), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acv c]-EN-[THP]-[(D)Tyr]-NH2 (SEQ ID NO: 217), Dota-[a)]-[(D)Arg]-[Pen]-NT-[W(7-Me)]- [Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Na l]-[THP]-EN-[THP]-NH2 (SEQ ID NO: 218), Dota_PEG2_acid-[(D)Arg]-[Pen]-NT-[W(7-Me) ]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2- Nal]-[THP]-EN-[THP]-NH2 (SEQ ID NO: 219), Dota_PEG3_acid-[(D)Arg]-[Pen]-NT-[W(7-Me) ]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2- Nal]-[THP]-EN-[THP]-NH2 (SEQ ID NO: 220), Ac-[(D)Arg]-[Pen]-NT-[W(7-F)]-[Lys(Ac) ]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP] -EN-[α-MePhe]-NH2 (SEQ ID NO: 222), Ac-[(D)Arg]-[Pen]-NT-[W(7-Cl)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-EN-[α-MePhe]-NH2 (SEQ ID NO: 224), Ac-[(D)Arg]-[Pen]-NT-[W(5-Br)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-EN-[α-MePhe]-NH2 (SEQ ID NO: 226), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-EN-[(D)Lys]-[(D)Phe(4-OCF)]-am (SEQ ID NO: 2 28), Benzhydroxyiodine acid-[(D)Arg]-[Pen]-NT-[W(7-M e)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[ 2-Nal]-[THP]-EN-[α-MePhe]-NH2 (SEQ ID NO: 230), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Ach c]-EN-[THP]-NH2 (SEQ ID NO: 233), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acv c]-EN-[THP]-N(H)Me (SEQ ID NO: 234), Pr-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-( 2-aminoethoxy)]-[(R)(bMe)(2-Nal)]-[THP]-EN- [THP]-NH2 (SEQ ID NO: 236), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-acetylaminoethoxy)]-[2-Nal]- [THP]-EN-[THP]-NH2 (SEQ ID NO: 237), Pr-[(D)Arg]-[Pen]-QT-[Trp_psi]-Q-[Pen] -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[T HP]-NH2 (SEQ ID NO: 238), FPrp triazole Me_ acid-[(D)Arg]-[Pen]-NT-[W(7- Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]- [2-Nal]-[THP]-EN-[α-MePhe]-NH (SEQ ID NO: 240) , Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe_4Pip-[2-Nal]-[THP]-EN-[aM ePhe]-NH2 (SEQ ID NO: 241), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-EN-[Phe(tetrafluoro)]-am (SEQ ID NO: 243), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-EN-[(D)Lys]-[(D)Phe[4-(2-aminoethoxy)]]-a m (SEQ ID NO: 245), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-(SMSB)-aminoethoxy)]-[2-Na l]-[THP]-EN-[α-MePhe]-NH2 (SEQ ID NO: 246), Sulfocyanine 3-[(D)Arg]-[Pen]-NT-[W(7-Me)]- [Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Na l]-[THP]-EN-[α-MePhe]-NH2 (SEQ ID NO: 247), Sulfocyanine 3_dPEG2-[(D)Arg]-[Pen]-NT-[W(7 -Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)] -[2-Nal]-[THP]-EN-[α-MePhe]-NH (SEQ ID NO: 248 ), Sulfocyanine 3_dPEG3-[(D)Arg]-[Pen]-NT-[W(7 -Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)] -[2-Nal]-[THP]-EN-[α-MePhe]-NH (SEQ ID NO: 249 ), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-EN-[Phe(3-OH)]-am (SEQ ID NO: 251), SMSBCO-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Ly s(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]- [THP]-EN-[α-MePhe]-NH2 (SEQ ID NO: 252), Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac )]-[Pen]-[(R)bMePhe]-[2-Nal]-[THP]-EN-[ THP]-NH2 (SEQ ID NO: 256), Ac-[(D)Arg]-[Pen]-NT-[W(5-Me)]-[Lys(Ac )]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP ]-EN-[α-MePhe]-NH2 (SEQ ID NO: 257), FPrp triazole Me_ acid-[Pen]-NT-[W(7-Me)]-[Lys (Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[ a-MeLys]-[Lys(Ac)]-N-[a-MePhe]-NH2 (SEQ ID NO: 2 39), MeSO2-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pe n]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]- [Lys(Ac)]-N-[α-MePhe]-NH2 (SEQ ID NO: 209), N3_acid-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen ]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[ Lys(Ac)]-N-[α-MePhe]-NH2 (SEQ ID NO: 210), Pr-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Ly s(Ac)]-N-[α-MePhe]-NH2 (SEQ ID NO: 207), or SMSBCO-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[P en]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys] -[Lys(Ac)]-N-[α-MePhe]-NH2 (SEQ ID NO: 250).

[0244] In one embodiment, the peptide inhibitor consists of about 25 or fewer amino acids. In one embodiment, the peptide inhibitor consists of about 20 or fewer amino acids. In embodiments, the peptide inhibitor consists of about 18 or fewer amino acids. In an embodiment, the peptide inhibitor consists of about 15 or fewer amino acids. In some embodiments, the peptide inhibitor consists of about 12 or fewer amino acids. In some embodiments, the peptide inhibitor consists of about 10 or fewer amino acids.

[0245] In certain embodiments, the peptide is EtCO-[(D)Arg]-[Pen]-NTWQ-[Pen]-Phe[4 (2-aminoethoxy)]-[Nal]-[THP]-EN-[THP]-NH2 Column number 351), EtCO-[(D)Arg]-[Abu]-QTWQ-Cys-Phe[4(2 -aminoethoxy)]-[Nal]-[THP]-EN-[THP]-NH2 (SEQ ID NO: No. 352), EtCO-[(D)Arg]-[Pen]-NTWQ-[Pen]-Phe[4 (2-aminoethoxy)]-[Nal]-[THP]-EN-[aMePhe]-NH 2 (SEQ ID NO: 353)

[0246] (Peptide inhibitors are linked via a Pen-Pen disulfide bond or Abu-Cys cyclized via a thioether bond) or a pharmaceutically acceptable salt or solvate thereof.

[0247] In additional embodiments, the present invention provides a compound of formula (I)-(XIf) or a sequence shown in Table E1. and a peptide inhibitor comprising a peptide containing any of the variants of X4 to In a specific embodiment, the amino acid sequence of the present invention comprises an isosteric substitution of one or more amino acid residues at X15. Isosteric substitutions are conservative amino acid substitutions, and in certain embodiments, isosteric substitutions are Substitution with an acid analogue.

[0248] In additional embodiments, the present invention provides a compound of formula (I)-(XIf) or a sequence shown in Table E1. and a peptide inhibitor comprising a peptide containing a variant of any of the amino acids One or both of the amino acid residues X4 and X9 contain different amino acid residues (or chemical substances), but X The amino acid residues X4 and X9 are bonded to each other to form, for example, an intramolecular bond or a triazole ring. In a specific embodiment, the bond is a disulfide bond. , thioether bond, lactam bond, triazole ring, selenoether bond, diselenide bond, or an olefinic bond.

[0249] Additional Features of Peptide Inhibitors Any of the peptide inhibitors of the present invention may be further defined, for example, as described below. Each of the additional defining characteristics described herein is determined by the amino acid designated at the particular position. This approach can be applied to any peptide inhibitor, allowing for the presence of additional defining characteristics. In a specific embodiment, these characteristics are realized by the compounds of formula (I) to (XIf). The amino acid sequence may be present in any of the peptides.

[0250] In various embodiments, R 1 is a bond, hydrogen, C1-C6 alkyl, C6-C12 arylate C6-C12 aryl, C1-C6 alkyl, C1-C20 alkanoyl, or PEGylated versions of any of the above as a spacer, e.g., acetyl .R 1 The amino acid sequence can replace the typical amine group located at the amino terminus of a peptide without adding any additional amino acid sequence. It is understood that R may also be present. 1 It is further understood that there may be In certain embodiments, the peptide inhibitor is selected from the group consisting of hydrogen, C1-C6 alkyl, C6-C1 2 aryl, C6-C12 aryl, C1-C6 alkyl, or C1-C20 alkanoyl and an N-terminus selected from the group consisting of, either alone or in combination with any of the foregoing spaces, e.g., acetyl. The components of any of the peptide inhibitors described herein include PEGylated versions thereof. In specific embodiments, R 1 Or the N-terminal moiety is hydrogen. In certain embodiments, R 1 teeth , a bond, for example a covalent bond.

[0251] Any particular embodiment of a peptide inhibitor having any of the various formulas described herein In terms of form, R 1 Or the N-terminal moiety is methyl, acetyl, formyl, benzoyl, triflate Oroacetyl, isovaleryl, isobutyryl, octanyl, and lauric acid, hexadecanol In one embodiment, the hydroxybenzoate is selected from the group consisting of hydroxybenzoates, ... , R 1 Or the N-terminal portion is pGlu. 1 is hydrogen. In specific embodiments, R 1 is an acetyl group, whereby the peptide inhibitor is acylated at the N-terminus to cap the N-terminal amino acid residue, e.g., the N-terminal Pen residue. To protect or protect.

[0252] In certain embodiments of any of the peptide inhibitors described herein, R 1 or N-terminal part In certain embodiments, R 1 or the N-terminal portion is 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, cyclo Pentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, amber 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-phenyl Propionic acid, trimethyl acetate, tertiary butyl acetate, lauryl sulfate, gluconic acid, glutamine Acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, alkyl sulfone The acid is selected from aryl sulfonic acids and aryl sulfonic acids.

[0253] In specific embodiments, R 1 Or the N-terminal part is methanesulfonic acid, ethanesulfonic acid , 1,2-ethanedisulfonic acid, and 2-hydroxyethanesulfonic acid. It is alkylsulfonic acid.

[0254] In specific embodiments, R 1 Or the N-terminal part is benzenesulfonic acid, 4-chlorobenzaldehyde 2-Naphthalenesulfonic acid, 4-toluenesulfonic acid, and camphor The arylsulfonic acid is selected from sulfonic acids.

[0255] Peptide dimers In certain embodiments, the present invention provides a monomeric peptide inhibitor described herein or in the accompanying tables. and dimers of any of the monomeric peptide inhibitors described herein. These dimers fall within the general term "peptide inhibitors" as used herein. Exemplary dimers of the present invention are also shown in the accompanying table, where the dimerized The selected monomer is shown in parentheses, followed by the linker. The units are linked via their C-termini. The term "dimer" refers to a peptide dimer. The peptide of the present invention refers to a compound in which two peptide monomer subunits are linked together. Peptide dimeric inhibitors consist of two identical monomeric subunits that form homodimers, or heterodimers. It may contain two non-identical monomeric subunits that dimerize. The cysteine ​​residues in the monomer subunits and the cysteine ​​residues in the other monomer subunits Two peptide monomer subunits linked through a disulfide bond between the amino acid residues Includes.

[0256] In some embodiments, the peptide inhibitors of the present invention are those in which the free cysteine ​​residue is When present in a dimeric conformation, it may be active in the dimeric conformation. The peptides are synthesized as dimers or, in particular, as free cysteine ​​monomer peptides and as In some embodiments, the dimer forms a homodimer. In other embodiments, the dimer is a heterodimer.

[0257] In certain embodiments, the monomeric subunits of the present invention include those defined herein. Suitable linking moieties, including but not limited to, within each peptide monomer subunit, e.g. by a disulfide bridge between two cysteine ​​residues, or by another suitable linker Some of the monomeric subunits can be dimerized by free amino acids. It has been shown that the C-terminus and N-terminus contain amines. To generate the inhibitor, either the C- or N-terminal free amine is eliminated, thereby The monomeric subunits may be modified to dimerize at the remaining free amines. In some cases, one or more of the monomeric subunits may be terminated with a trifluoropentane. acetyl, octonyl, butyl, pentyl, hexyl, palmityl, trifluoromethyl butylbutyric acid, cyclopentanecarboxylic acid, cyclopropylacetic acid, 4-fluorobenzoic acid, 4 -Fluorophenylacetic acid, 3-phenylpropionic acid, tetrahydro-2H-pyran-4 An acylated organic compound selected from the group consisting of carboxylic acids, succinic acids, and glutaric acids. acylated. In some cases, the monomeric subunits have a free carboxy terminus and a free The amino termini are included, allowing the user to achieve dimerization at the desired terminus. Therefore, those skilled in the art can selectively modify the subunits of the monomers of the present invention. The dimer subunits are selectively modified to yield a single specific amine for the desired dimerization. You will understand that it can be decorated.

[0258] The C-terminal residue of the monomeric subunits disclosed herein is optionally an amide. It is further understood that, in certain embodiments, dimerization at the C-terminus is achieved by the dimerization of the C-terminus, as is known in the art. As is commonly understood in the art, suitable amino acids having side chains with amine functional groups are used. It is understood that dimerization is promoted by the N-terminal residue. As is commonly understood in the art, this may be achieved via a free amine at the terminal residue. This may generally be achieved by using suitable amino acid side chains having It is understood.

[0259] The linker moiety connecting the monomeric subunits may be of any structure compatible with the teachings herein. In at least one embodiment, the linker moiety may comprise a , cysteine, lysine, DIG, PEG4, PEG4-biotin, PEG13, PEG2 5, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, AD A, Boc-IDA, glutaric acid, isophthalic acid, 1,3-phenylenediacetic acid, 1,4- Phenylenediacetic acid, 1,2-phenylenediacetic acid, triazine, Boc-triazine, ID A-biotin, PEG4-biotin, AADA, suitable aliphatic, aromatic, heteroaromatic, and polyethylene glycol-based phosphorus having a molecular weight of about 400 Da to about 40,000 Da. In certain embodiments, PEG is selected from the non-limiting group consisting of HO2C Non-limiting examples of suitable linker moieties include: A typical example is provided in Table 2.

[0260] [Table 5-1]

[0261] [Table 5-2]

[0262] [Table 5-3]

[0263] In some embodiments, the peptide dimeric inhibitor is dimerized via a linker moiety. In some embodiments, the peptide dimeric inhibitors contain one or more nucleotides in each monomer subunit. Dimerization occurs via an intermolecular disulfide bond formed between two cysteine ​​residues. In some embodiments, the peptide dimeric inhibitor comprises a linker moiety and two cis- Dimerization occurs through both the ATP-binding domain and the intermolecular disulfide bond formed between the ATP-binding domain residues. In some embodiments, the intramolecular bond is a thioether, lanthanide, or phenylalanine bond instead of a disulfide bond. The aryl group may be a methyl group, ...

[0264] Those skilled in the art will appreciate that the linker (e.g., C- and N-terminal linker) moieties disclosed herein are suitable. These are non-limiting examples of suitable linkers, and the present invention may include any suitable linker moiety. It will be appreciated that some embodiments of the present invention may be implemented in accordance with the tables herein. or as provided in any of the tables herein. A homodimer composed of two monomeric subunits containing or consisting of the sequences shown. or heterodimeric peptide inhibitors, wherein the C-terminus or The N-terminus (or internal amino acid residue) is linked by any suitable linker moiety to form I The present invention includes peptide inhibitors that provide dimeric peptide inhibitors with L-23R inhibitory activity. In certain embodiments, the linker is attached to the N-terminus or C-terminus of one monomer subunit and to the second The amino acid residues of the other monomer subunits that make up the dimer are linked to internal amino acid residues of the other monomer subunits. In the present specification, the linker is an internal amino acid residue of a monomer subunit and a dimer. In a further embodiment, the linker binds to the N- or C-terminus of both subunits.

[0265] In specific embodiments, one or both of the monomeric subunits has the formula (I)-(XIf): or any one of the peptides shown in Table E1 or described herein. The present invention includes any of the sequences or structures of:

[0266] In certain embodiments, the peptide inhibitor has the structure of Formula XII:

[0267] (R 1 -XR 2 )2-L(XII) or a pharmaceutically acceptable salt or solvate thereof, In the formula, each R 1 is independently absent, a bond (e.g., a covalent bond), or R1 is hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 arylC1 -C6 alkyl, C1-C20 alkanoyl, either alone or in combination with any of the foregoing; containing the PEGylated version as a spacer, Each R 2 are independently absent, a bond (e.g., a covalent bond), or an OH or or NH2, L is a linker moiety; Each X is an independently selected group comprising a sequence of formula (I)-(XIf) described herein. In certain embodiments, one or more of the peptide dimeric inhibitors is a peptide monomer subunit. Both peptide monomer subunits are connected via an intramolecular bond between, for example, X4 and X9. In certain embodiments, one or both peptide monomer subunits are directly cyclized. It is open-chain, i.e., not cyclized.

[0268] In specific embodiments, each R 1 are independently a bond (e.g., a covalent bond), or is hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 alkanoyl, either alone or in space In a specific embodiment, the N-terminus of each subunit is , hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 alkanoyl, or any of the foregoing, Some contain PEGylated versions as spacers.

[0269] Any particular embodiment of a peptide inhibitor having any of the various formulas described herein In terms of form, each R 1 (or N-terminal portion) is methyl, acetyl, formyl, benzoyl, Trifluoroacetyl, isovaleryl, isobutyryl, octanyl, and lauric acid, The hydroxybenzoate is selected from the group consisting of hydroxybenzoates, ...

[0270] In specific embodiments, each R 2 (or C-terminal portion) may be independently linked (e.g., covalently linked) a bond) or selected from OH or NH2.

[0271] In specific embodiments of any of the peptide dimeric inhibitors described herein, Either or both R 1 is hydrogen.

[0272] In specific embodiments of the peptide dimeric inhibitors of the present invention, the linker moiety (L) is The linker may be any of those described in the specification or shown in Tables 1 or 7. In certain embodiments, L is a lysine linker, a diethylene glycol linker, an iminodiacetic acid linker, or a methylamino acid linker. iminodiacetic acid (IDA) linker, β-Ala-iminodiacetic acid (β-Ala-IDA) linker, or is the PEG linker.

[0273] In various embodiments of any of the peptide dimeric inhibitors, the peptide monomer subunits Each of the units is linked to a linker moiety via its N-terminus, C-terminus, or internal amino acid residue. In certain embodiments of any of the peptide dimeric inhibitors, each peptide moiety is The N-termini of the dimer subunits are connected by a linker moiety. In certain embodiments of any of the inhibitors, the C-terminus of each peptide monomer subunit The ends are connected by a linker moiety. In certain embodiments, each peptide monomer subunit comprises a phosphorus bonded to an internal amino acid. They are connected by a car part.

[0274] Peptide inhibitor conjugates and biopolymers In certain embodiments, the peptide inhibitors of the present invention, including both monomers and dimers, are lipophilic. The compound may contain one or more conjugated chemical substituents, such as a hydroxyl group, ... In the specification, they may be referred to as half-life extending moieties. Without wishing to be bound by any particular theory, Although not a peptide inhibitor, the lipophilic substituent binds to albumin in the bloodstream, thereby inhibiting peptide blockade. It is believed that this shields the harmful agent from enzymatic degradation, thereby extending its half-life. The polymer moiety is believed to increase half-life and reduce clearance from the bloodstream.

[0275] In additional embodiments, peptide inhibitors, such as peptide inhibitors of Formulas (I)-(XIf), any of which further comprises a linker moiety attached to an amino acid residue present in the inhibitor; For example, the linker moiety may be a side chain of any amino acid in the peptide inhibitor, an N- The peptide inhibitor may be attached to the terminal amino acid, or the C-terminal amino acid of the peptide inhibitor.

[0276] In additional embodiments, peptide inhibitors, such as peptide inhibitors of Formulas (I)-(XIf), Any of these further comprises a half-life extending moiety attached to an amino acid residue present in the inhibitor. For example, the half-life extending moiety can be attached to the side chain of any amino acid of the peptide inhibitor, or the C-terminal amino acid of a peptide inhibitor.

[0277] In additional embodiments, peptide inhibitors, such as peptide inhibitors of Formulas (I)-(XIf), One of these is a half-chain amino acid linked to a linker moiety that is attached to an amino acid residue present in the inhibitor. Further comprising a half-life extending moiety, for example, the half-life extending moiety can be any amino acid of the peptide inhibitor. a linker moiety attached to the side chain of the peptide inhibitor, the N-terminal amino acid of the peptide inhibitor, or can be bound to the C-terminal amino acid of

[0278] In specific embodiments, the peptide inhibitor has the structure shown below, where n=0-24 or n=14 to 24),

[0279] [ka]

[0280] In certain embodiments, the peptide inhibitors of the invention comprise a half-life extending moiety as shown in Table 8.

[0281] [Table 6-1]

[0282] [Table 6-2]

[0283] In certain embodiments, the half-life extending moiety is directly attached to the peptide inhibitor, although other embodiments may be In some embodiments, the half-life extending moiety may be a linker moiety, e.g., one of those shown in Tables 1, 2, or 4. The peptide inhibitor is attached via either

[0284] [Table 7-1]

[0285] [Table 7-2]

[0286] In specific embodiments, the peptide inhibitors of the invention comprise a linker moiety shown in Table 2 or 4. and any of the following combinations shown in Table 5, and any of the long parts.

[0287] [Table 8]

[0288] [Table 9]

[0289] [Table 10]

[0290] [Table 11]

[0291] In some embodiments, the peptide, e.g., a conjugate moiety such as those shown in Table 6, e.g., a half-length There may be multiple linkers present between the extender moieties.

[0292] [Table 12]

[0293] In certain embodiments, the peptides of the invention include conjugated chemical substituents, i.e., half-life extending moieties. The half-life of a peptide inhibitor is the same as that of a peptide inhibitor that does not contain conjugated chemical substituents. At least 100%, at least 120%, at least 150%, at least 20% of the reduction period 0%, at least 250%, at least 300%, at least 400%, or at least In certain embodiments, the lipophilic substituent and / or polymer moiety is a peptide. enhances the permeability of the inhibitor across the epithelium and / or its retention in the lamina propria. In one embodiment, the permeability and activity of peptide inhibitors of the invention comprising conjugated chemical substituents across epithelia are improved. and / or its retention in the lamina propria are the same except that they do not contain conjugated chemical substituents. 100%, at least 120%, at least 150%, or less than the half-life of the peptide inhibitor at least 200%, at least 250%, at least 300%, at least 400%, or At least 500%.

[0294] In one embodiment, one or more amino acid residues in the peptide inhibitors of the invention (e.g., The side chain of a lipophilic substituent (e.g., a Lys residue) is conjugated (e.g., covalently bonded) to a lipophilic substituent. The substituent may be covalently attached to an atom of the amino acid side chain or alternatively may be attached via one or more spacers. The spacer, when present, may be coupled to the amino acid side chain via a spacer. In a specific embodiment, the peptide inhibitor may be a peptide having a structure as shown in Table 2. The peptides disclosed in 1. to 6. contain any of the conjugate moieties shown.

[0295] In certain embodiments, the lipophilic substituent has 4 to 30 C atoms, e.g., at least 8 or carbon atoms having 12 C atoms, preferably 24 C atoms or less, or 20 C atoms or less The hydrocarbon chain may be linear or branched, saturated or unsaturated. In certain embodiments, the hydrocarbon chain forms part of the bond to the amino acid side chain or spacer. The moiety to be formed, for example, an acyl group, a sulfonyl group, a N atom, an O atom, or a S atom, is substituted. In some embodiments, the hydrocarbon chain is substituted with an acyl group, thus providing a carbonized The hydrogen chain is an alkanoyl group, such as palmitoyl, caproyl, lauroyl, myristyl, It may form part of yl, or stearoyl.

[0296] The lipophilic substituent may be conjugated to any amino acid side chain in the peptide inhibitors of the present invention. In certain embodiments, the amino acid side chains are esters, sulfonyls, or hydroxyl groups with spacers or lipophilic substituents. carboxy, to form an ester, thioester, amide, or sulfonamide; For example, lipophilic substituents include As, ... n, Asp, Glu, Gln, His, Lys, Arg, Ser, Thr, Tyr, Tr In certain embodiments, the parent may be conjugated to p, Cys, or Dbu, Dpr, or Orn. The oily substituent is conjugated to Lys. The amino acids shown as ##STR00001## are, for example, Dbu, Dpr, or Or to which a lipophilic substituent is added. It can be replaced by n.

[0297] In certain embodiments, the peptide inhibitors of the present invention comprise a chemical moiety attached to one or more of the peptides. Conjugation to amino acid side chains can, for example, enhance stability, increase permeability, or may be modified to enhance drug-like properties. For example, the lysine N (epsilon) N (epsilon), the β-carboxyl of aspartic acid, or the γ-carboxyl of glutamic acid The xyl can be appropriately functionalized. Thus, to generate modified peptides, The amino acids within the group may be appropriately modified. Furthermore, in some cases, the side chains may be trifluoromethyl. Pentyl, acetyl, octonyl, butyl, pentyl, hexyl, palmityl, triflate Oromethylbutyric acid, cyclopentanecarboxylic acid, cyclopropylacetic acid, 4-fluorobenzoic acid Acid, 4-fluorophenylacetic acid, 3-phenylpropionic acid, tetrahydro-2H-pyra acyl selected from the group consisting of carboxylic acids, succinic acid, glutaric acid, or bile acids; Those skilled in the art will appreciate that a range of conjugates, e.g., PEG, isog It will be understood that lu, lu, and combinations thereof may be linked. It will be understood that amino acids having a peptide may be isosterically substituted. For example, Lys can be substituted with Dap, Dab, α-MeLys, or Orn. Examples of modified residues are shown in Table 7.

[0298] [Table 13-1]

[0299] [Table 13-2]

[0300] In further embodiments of the present invention, alternatively or additionally, for example, solubility and / or immunogenicity may be improved. to increase half-life and / or bioavailability in the body (e.g., in plasma). To this end, the side chains of one or more amino acid residues in the peptide inhibitors of the present invention are linked to a polymer moiety. Such modifications also improve the clearance ( For example, it is known to reduce renal clearance.

[0301] As used herein, "polyethylene glycol" or "PEG" refers to a compound of the general formula H PEG is a polyether compound of -(O-CH2-CH2)n-OH. polyethylene oxide (PEO) or polyoxyethylene , POE), and as used herein, depending on its molecular weight, EO, PEE, or POG refer to oligomers or polymers of ethylene oxide. Although the names are chemically synonymous, PEG is an oligomer with a molecular weight of less than 20,000 Da. PEO is a polymer with a molecular weight greater than 20,000 Da, and P OE tends to refer to polymers of any molecular weight. PEG and PEO are polymers of any molecular weight. Depending on the nature of the substance, it may be a liquid or a low melting point solid. Throughout this disclosure, the three names will be used interchangeably. PEG is prepared by polymerization of ethylene oxide and has a molecular weight ranging from 300 Da to 10,000 Da. P with different molecular weights is commercially available over a wide range of molecular weights, from 1,000 Da to 1,000 Da. EG and PEO are used in different applications and have different physical properties (e.g., The polymer portion preferably has a viscosity of 1000 to 2000 MPa, but the chemical properties of the polymer portion are nearly identical. are water-soluble (amphiphilic or hydrophilic), non-toxic, and pharmacologically inert. The moiety is polyethylene glycol (PEG), PEG hydroxylase, Mono- or copolymers of PEG, monomethyl-substituted polymers of PEG er of PEG, mPEG), or polyoxyethylene glycerol (polyoxyethylene glycerol rol, POG). For example, Int. J. Hematology 68:1 ( 1998); Bioconjugate Chem. 6:150(1995); and Cr it.Rev.Therap.Drug Carrier Sys.9:249(199 2) In addition, PEG prepared for the purpose of extending half-life, for example, mono- Mono-activated alkoxy terminators such as methoxy-terminated polyethylene glycols (mPEG's) Polyalkylene oxide (mono-activated, alkoxy-terminated polyalkylene oxide, P OA'), and bis-activated polyethylene oxide (glycol), or other PEG Derivatives are also contemplated. Suitable polymers are from about 200 Da to about 40,000 Da or about 20 Weights vary significantly from 0 Da to about 60,000 Da, but typically for purposes of the present invention In certain embodiments, the molecular weight is selected to be 200 to 2,000 or 200 to 500. Depending on the initiator used in the polymerization process, different forms of PEG are used. PEG may also be used, and a common initiator is monofunctional methyl ether PEG, or methoxypoly(ethylene glycol), abbreviated as mPEG.

[0302] Low molecular weight PEG is also available as pure oligomers, referred to as monodisperse, uniform, or discrete. These are used in certain embodiments of the present invention.

[0303] PEGs with different geometries are also available: branched PEGs have a central core group Star-shaped PEGs have 3 to 10 PEG chains emanating from a central core group. PEGs usually have multiple P chains grafted onto the polymer backbone. PEG may also be linear. The larger number indicates the average molecular weight (e.g., PEG with n=9 has a molecular weight of approximately 400 da. It has an average molecular weight of 1000 kJ / kg and is designated as PEG400.

[0304] As used herein, "PEGylation" refers to the attachment of a PEG structure to a peptide inhibitor of the invention. The act of covalent attachment, which is then referred to as a "PEGylated peptide inhibitor." In certain embodiments, the PEGylated side chains comprise PEGs of about 200 to about 40,000 molecules. In some embodiments, the peptide of Formula I, Formula I', or Formula I'' is The spacer of the peptide is PEGylated. In certain embodiments, the PEG of the PEGylated spacer is , PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG1 0, or PEG11. In certain embodiments, the PEG of the PEGylated spacer is PEG 3 or PEG8.

[0305] Other suitable polymer moieties include polylysine, polyaspartic acid, and polyglutamic acid. Examples of such amino acids include polyamino acids such as carboxylic acids (e.g., Gombotz, et al. (1999) 95),Bioconjugate Chem.,vol.6:332-351,Hud ecz, et al. (1992), Bioconjugate Chem., vol. 3, 49-57, and Tsukada, et al. (1984), J. Natl. Ca. See Cancer Inst., vol. 73, :721-729. Polymer moiety In some embodiments, it is 500 to 1000 carbon atoms. 40,000Da, e.g., 500-10,000Da, 1000-5000Da, 10 It has a molecular weight of 2,000 to 20,000 Da, or 20,000 to 40,000 Da.

[0306] In some embodiments, the peptide inhibitors of the invention comprise two or more such polymers. moieties, in which case the total molecular weight of all such moieties will generally be within the range of those provided above. It is within the range.

[0307] In some embodiments, the polymer moiety is attached to the amino, carboxyl, or is coupled (covalently) to the thiol group of a Cys residue. The carboxyl groups of Asp and Glu residues are the carboxyl groups of Lys residues and the epsilon amino group of Lys residues. Sil groups may also be involved.

[0308] Those skilled in the art will be familiar with suitable techniques that can be used to carry out coupling reactions. For example, a PEG moiety having a methoxy group may be used in the preparation of Nektar The via maleimide coupling using commercially available reagents from Rapeutics AL The Cys thiol group can be coupled to the Cys thiol group. For details of suitable chemistries, see See also WO 2008 / 101017 and the references cited above. Imido-functionalized PEG can also be conjugated to the side chain sulfhydryl groups of Cys residues.

[0309] As used herein, oxidation of disulfide bonds may occur in one step, or a two-step process. As used herein, for one-step oxidation, A trityl protecting group was used during assembly to allow deprotection of the amine and subsequent solution oxidation. If a second disulfide bond is required, it can be formed either naturally or by selective oxidation. For selective oxidations requiring orthogonal protecting groups, the protecting groups for cysteine ​​are Acm and trityl are used as groups. Cleavage results in the removal of one protecting pair of cysteine. The second acid of the cysteine-protected Acm group is then added to the cysteine-protected Acm group to allow oxidation of the pair. In the case of native oxidation, trityl protecting groups are used for all cysteines, The native folding of the peptide is permitted. Those skilled in the art will appreciate the techniques used to carry out the oxidation step. The reader will be fully aware of suitable techniques that can be used to

[0310] Some chemical moieties, including poly(ethylene) glycol, can bind to, for example, lysine amino acid residues. epsilon amino groups in the hydroxyl groups, the thiols present in cysteine ​​amino acid residues, or other hydroxyl groups. Reacts with functional groups present in the 20 naturally occurring amino acids, including the amino acid side chains When multiple naturally occurring amino acids react in a peptide inhibitor, these nonspecific As a result of the chemical reaction, one or more poly(ethylene) molecules are attached at different positions within the peptide inhibitor. The final peptide inhibitors were obtained containing many isomers of the peptide conjugated to glycol chains. can be done.

[0311] One advantage of certain embodiments of the present invention is the ability to selectively bind naturally occurring amino acids present in peptide inhibitors. It has an inherent functional group that reacts with activated PEG using chemicals that do not react with the amino acids it is made of. By incorporating one or more unnatural amino acids, one or more chemical moieties can be For example, azide and alkyne groups can be added to the It does not react with all naturally occurring functional groups in proteins. In peptide inhibitors where PEG or other modifications are desired, without undesired nonspecific reactions, In certain embodiments, the nucleotides involved in the reaction may be incorporated into one or more specific sites. Certain chemicals provide a stable covalent bond between the PEG chain and the peptide inhibitor. In addition, such reactions can be carried out under mild aqueous conditions that do not damage most peptides. In certain embodiments, the unnatural amino acid residue is AHA.

[0312] The chemical moieties attached to natural amino acids are limited in number and scope. Chemical moieties that bind to hydroxylic acids offer a significantly broader range of useful chemical moieties that can be attached to target molecules. Essentially, unnatural amino acids, such as aldehydes or keto derivatives, can be used. Non-natural amino acids containing reactive sites or side chains to which chemical moieties, such as derivatized amino acids, can be attached. Any target molecule, including any protein (or portion thereof), containing an acid, can be linked to a chemical moiety. It can function as a substrate for the synthesis of ribozymes.

[0313] Numerous chemical moieties can be attached to a particular molecule through a variety of methods known in the art. Various such methods are described in U.S. Pat. No. 8,568,706. As an illustrative example, the azide moiety may be PEG or other azide moieties described herein. The azide moiety can be useful as a reactive functional group to conjugate chemical moieties such as function and are not present in most naturally occurring compounds (hence, (Azides are unreactive with the native amino acids of the compound.) Azides also have a limited number of reactions. The azide undergoes selective ligation with its partner, significantly reducing its molecular size. It can be introduced into a biological sample without any change. One reaction to this is the copper-mediated Huisgen [3+2] cycloaddition of azides. It can be used for selective PEGylation of peptide inhibitors (Tornoe et al. .,J.Org.Chem.67:3057,2002, Rostovtsev et al. al., Angew. Chem., Int. Ed. 41:596, 2002, and Wan g et al., J. Am. Chem. Soc. 125:3192, 2003, Spe. ers et al., J. Am. Chem. Soc., 2003, 125, 4686) .

[0314] Synthesis of peptide inhibitors The peptide inhibitors of the present invention can be synthesized by a number of techniques known to those skilled in the art. In certain embodiments, the monomeric subunits are synthesized using the techniques described in the accompanying Examples. In certain embodiments, the present invention provides a compound of Formula I, II, or These include, but are not limited to, any of the amino acid sequences set forth in any of the tables herein. and / or comprising, consisting of, or a peptide having an amino acid sequence as described herein. The peptide inhibitors of the present invention (including chemical synthesis of peptides consisting essentially of the same) In another embodiment, the peptide is recombinantly synthesized instead of chemically synthesized. In certain embodiments, the peptide The inhibitor is a dimer, and the method comprises combining both monomeric subunits of the peptide dimeric inhibitor. and then dimerizing the two monomeric subunits to generate a peptide dimeric inhibitor. In various embodiments, dimerization can be performed by any of the various methods described herein. In a specific embodiment, the peptide inhibitor (or a monomeric subunit thereof) The method for producing the peptide inhibitor (or its monomeric subunits) after its synthesis is In specific embodiments, the cyclization further comprises cyclizing the aryl group (e.g., aryloxy) as described herein. In certain embodiments, the present invention provides a compound of formula (I) to ( IX), any of the amino acid sequences set forth in the accompanying Examples or Tables, but including these peptides having, or consisting of, the amino acid sequences set forth herein, but not limited to an intramolecular bond, e.g., between two amino acid residues in a peptide consisting essentially of For example, the peptides of the present invention may be modified by introducing disulfide, amide, or thioether bonds. Methods for producing tide inhibitors (or monomeric subunits thereof) are provided.

[0315] In related embodiments, the present invention provides a compound according to any one of formulas (I)-(IX), or the accompanying embodiments. It includes polynucleotides that encode polypeptides having the sequences set out in the Examples or Tables.

[0316] Additionally, the present invention provides vectors, such as expression vectors, comprising the polynucleotides of the present invention. include.

[0317] Treatment method In certain embodiments, the present invention provides a method for the treatment of IL-23 by contacting IL-23 with a peptide inhibitor of the present invention. and (b) inhibiting the binding of IL-23 to IL-23R on a cell. In embodiments, the cells are mammalian cells. In specific embodiments, the method comprises in vitro Inhibition of binding can be achieved by a variety of conventional experiments known in the art. It can be determined by methods and assays.

[0318] In certain embodiments, the present invention provides a method for the treatment of IL-23 by contacting IL-23 with a peptide inhibitor of the present invention. In certain embodiments, the present invention includes a method of inhibiting IL-23 signaling by a cell, the method comprising: In a specific embodiment, the cell is a mammalian cell. In a specific embodiment, the inhibition of IL-23 signaling is performed intracellularly. This can be determined by measuring changes in phospho-STAT3 levels.

[0319] In some embodiments, the present invention provides a method for treating a disease state or condition associated with IL-21 or IL-23R. Suffering from an indication (e.g., activation of the IL-23 / IL-23R signaling pathway) A method for treating a subject comprising administering to said subject a peptide inhibitor of the present invention. In one embodiment, the method comprises administering to the subject an amount of IL-23 that is inappropriate, unregulated, or elevated. or those suffering from a pathology or indication characterized by IL-23R activity or signaling. 1. A method for treating an elephant, comprising the step of: binding of IL-23 to IL-23R in said subject; administering to an individual a peptide inhibitor of the present invention in an amount sufficient to inhibit (partially or completely) In a specific embodiment, the method comprises: Inhibition of binding of the compound to a specific organ or tissue of interest, e.g., the stomach, small intestine, large intestine / colon, intestinal mucosa, It occurs in the lamina propria, Peyer's patches, mesenteric lymph nodes, or lymphatic vessels.

[0320] In some embodiments, the methods of the present invention involve administering a peptide inhibitor of the present invention to a subject in need thereof. In a specific embodiment, the subject in need thereof is provided with an IL - Have been diagnosed as being at risk for developing a disease or disorder associated with IL-23 / IL-23R In a specific embodiment, the subject is a mammal. .

[0321] In certain embodiments, the disease or disorder is autoimmune inflammation and related diseases and disorders, such as For example, multiple sclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease (IBD), juvenile IBD, adolescent Stage IBD, Crohn's disease, ulcerative colitis, sarcoidosis, systemic lupus erythematosus, orthotopic spondylitis (axial spondyloarthritis), psoriatic arthritis, or psoriasis. The disease or disorder is psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, Palmoplantar pustulosis, psoriasis vulgaris, or erythrodermic psoriasis), atopic dermatitis, ectopic acne, ulcerative Intestinal diseases associated with colitis, Crohn's disease, celiac disease (non-tropical sprue), seronegative arthropathy microscopic colitis, collagen colitis, eosinophilic gastroenteritis / esophagitis, radiation or chemotherapy colitis associated with disorders of innate immunity such as leukocyte adhesion deficiency-1; Granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak- Higashi syndrome, Wiskott-Aldrich syndrome, pouchitis, proctocolectomy and ileoanal anastomosis Postoperative pouchitis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis , primary biliary cirrhosis, viral enteropathy, pericholecystitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease.

[0322] In certain related embodiments, the present invention provides a method for the treatment of IL-23 or IL-23R signaling ( or the binding of IL-23 to IL-23R) A method in a subject, comprising providing to said subject a peptide inhibitor of the present invention. In a specific embodiment, the present invention provides a method for the treatment of IL-23 or IL-23R signaling. The purpose of this study was to selectively inhibit IL-23 signaling (or the binding of IL-23 to IL-23R). 1. A method for administering a peptide of the present invention to the GI tract of a subject in need thereof by oral administration. In a specific embodiment, the method comprises providing an inhibitor to the GI tissue ( The exposure of an administered peptide inhibitor in the small intestine or colon is higher than that in the blood. at least 10 times, at least 20 times, at least 50 times, or at least 100 times more In a specific embodiment, the present invention provides a method for inhibiting IL-23 or IL-23R signaling (or The present invention relates to a method for selectively inhibiting the binding of IL-23 to IL-23R in a subject in need thereof. 1. A method for treating a GI tract disorder comprising providing a peptide inhibitor to said subject, The peptide inhibitor does not block the interaction between IL-6 and IL-6R or inhibits IL- In a further related embodiment, the present invention includes a method for antagonizing 12 signaling pathways. A method for inhibiting GI inflammation and / or neutrophil infiltration into the GI tract, comprising administering a peptide of the present invention In some embodiments, the present invention provides a method for treating a cancer, comprising providing an inhibitor to a subject in need thereof. The disclosed method involves combining a peptide inhibitor of the invention (i.e., a first therapeutic agent) with a second therapeutic agent. In certain embodiments, the second The therapeutic agent may be administered before, at the same time as, 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 embodiments, the second therapeutic agent is a nonsteroidal anti-inflammatory drug, a steroid, or an immunomodulatory agent. In another embodiment, the method includes administering to the subject a third therapeutic agent. In embodiments, the second therapeutic agent is an antibody that binds to IL-23 or IL-23R.

[0323] Pharmaceutical Composition In a specific embodiment, the peptide inhibitor, or a pharmaceutical composition comprising the peptide inhibitor, is administered sequentially. As used herein, a sustained release matrix refers to an enzyme-containing matrix. Materials that are decomposable by elementary or acid-base hydrolysis or by dissolution , a matrix usually made of polymers. When inserted into the body, the matrix The sustained release matrix is ​​preferably a liposome, a polymer, or a combination thereof. Lactide (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide cog Licolide (copolymer 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, phenylalanine, tyrosine, isoleucine, etc. Which amino acids, polynucleotides, polyvinylpropylene, polyvinylpyrrolidone, and The biodegradable matrix is ​​selected from biocompatible materials such as silicone. , polylactide, polyglycolide, or polylactide coglycolide (lactic acid and glycol The matrix is ​​one of the following:

[0324] In certain embodiments, the present invention provides a method for treating a cancer cell line comprising administering to a patient a compound comprising one or more peptide inhibitors of the present invention and and a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient. The carrier, diluent, or excipient may be a non-toxic solid, semi-solid, or liquid filler, diluent, , encapsulating materials, or any type of formulation adjuvant. For example, parabens, chlorobutanol by including various antibacterial and antifungal agents such as phenol, sorbic acid, etc. It is desirable to include isotonic agents such as sugars and sodium chloride. In some cases, this may be desirable.

[0325] In certain embodiments, the compositions are administered orally, parenterally, intracisternally, intravaginally, intraperitoneally, intrarectally, or topically. (by powder, ointment, eye drops, suppository, or transdermal patch), or by inhalation (e.g., intranasal spray) , ocular (including intraocular), or oral. The term refers to intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal, and intraarticular injections and infusions. Thus, in certain embodiments, the composition is administered via these routes of administration. The compound is formulated for delivery by either

[0326] In certain embodiments, pharmaceutical compositions for parenteral injection are prepared as sterile injectable solutions or dispersions immediately prior to use. Pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions for reconstitution into liquids Suitable aqueous and non-aqueous carriers and diluents include solutions, emulsions, or sterile powders. Examples of the solvent or vehicle include water, ethanol, polyols (glycerol, proline, etc.) pyrene glycol, polyethylene glycol, etc.), carboxymethyl cellulose, and Suitable mixtures thereof, β-cyclodextrin, vegetable oils (such as olive oil), and oleic acid Examples of suitable injectable organic esters include ethyl acetate and methyl methacrylate. By using coating materials, by maintaining the required particle size in the case of dispersions, and by using surfactants. The composition can also contain preservatives, humectants, and the like to maintain proper fluidity. The injectable pharmaceutical form may contain adjuvants such as emulsion stabilizers, emulsifiers, and dispersing agents. may contain agents that delay absorption, such as aluminum monostearate and gelatin. can be brought about by

[0327] Injectable depot forms are made of one or more biodegradable polymers, such as polylactides. Poly(ethylene glycol), poly(orthoester), poly(anhydride), and PEG. ii) By forming a microencapsulated matrix of peptide inhibitors in glycol The ratio of peptide to polymer and the specific polymer used Depending on the nature of the pharmacophore, the release rate of the peptide inhibitor can be controlled. Formulations also include peptide inhibitors in liposomes or microemulsions that are compatible with body tissue. It can also be prepared by encapsulating a harmful agent.

[0328] Injectable formulations may be prepared by, for example, filtration through a bacterial-retaining filter or by using In the form of a sterile solid composition which can be dissolved or dispersed immediately beforehand in sterile water or other sterile injectable medium. Sterilization can be achieved by incorporating a sterilant in the solution.

[0329] Topical administration includes administration to the skin or mucous membranes, including the lungs and the surface of the eye. Compositions for topical pulmonary administration, including those, may include solutions and suspensions in aqueous and non-aqueous formulations, It can also be prepared as a dry powder, which may or may not be compressed. In powdered compositions, the active ingredient may be in finely divided form, for example, up to 1 mm in diameter. 00 micrometers in size, including particles having a size of 00 micrometers. Suitable inert carriers include lactose, etc. Examples of sugars include:

[0330] Alternatively, the composition may be pressurized and contain a compressed gas such as nitrogen or a liquefied gas propellant. The liquefied propellant medium, and indeed the entire composition, must be such that the active ingredient is contained therein to any substantial extent. The pressurized composition may also be a liquid or solid non-ionic surfactant. The composition may contain a surface active agent such as a solid anionic surfactant. It is preferred to use solid anionic surfactants in the form of their sodium salts.

[0331] A further form of topical administration is to the eye. The harmful agent is applied to the cornea and internal regions of the eye, such as the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris, Contact with the ocular surface for a period of time sufficient to penetrate the iris / ciliary body, lens, choroid / retina, and sclera The ophthalmic solution may be delivered in a pharmaceutically acceptable ophthalmic vehicle so as to be maintained in a pharmaceutically acceptable form. Acceptable ophthalmic vehicles can be, for example, ointments, vegetable oils, or encapsulating materials. Alternatively, the peptide inhibitors of the present invention may be injected directly into the vitreous and aqueous humor.

[0332] Compositions for rectal or vaginal administration preferably contain the peptide inhibitors of the invention in a suitable Suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or suppositories Wax (which is solid at room temperature but becomes liquid at body temperature and therefore melts in the rectum or vaginal cavity) and suppositories which may be prepared by mixing a pharmaceutical preparation with a liquid medicine such as acetaminophen (which melts to release the active compound).

[0333] The peptide inhibitors of the present invention may also be administered in liposomes or other lipid-based carriers. As is known in the art, liposomes generally consist of phospholipids or other lipids. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and suitable substitute capable of forming liposomes may be used. The composition in liposome form may contain the peptide of the present invention. In addition to the inhibitor, stabilizers, preservatives, excipients, etc. may be included. In certain embodiments, lipids is a mixture of both natural and synthetic phosphatidylcholines (lecithins) and serine-containing phospholipids. Methods to form liposomes are known in the art.

[0334] Pharmaceutical compositions used in the present invention suitable for parenteral administration generally contain sodium chloride, glycerol, Phosphorus, glucose, mannitol, sorbitol, etc. are used to combine with the recipient's blood. It may comprise sterile aqueous solutions and / or suspensions of peptide inhibitors made isotonic.

[0335] In some aspects, the present invention provides pharmaceutical compositions for oral delivery. and peptide inhibitors can be administered using any of the methods, techniques, and / or delivery vehicles described herein. Furthermore, those skilled in the art will appreciate that the peptide inhibitors of the present invention may be formulated for oral administration according to the methods described above. , which are not disclosed herein but are well known in the art and are useful for oral delivery of peptides. It will be understood that the present invention may be modified or integrated into a system or delivery vehicle suitable for use in cormorant.

[0336] In certain embodiments, formulations for oral administration may contain a steroid compound to artificially increase the permeability of the intestinal wall. adjuvants for the purpose (e.g., resorcinol and / or polyoxyethylene oleyl ether) non-ionic surfactants such as methylcellulose and n-hexadecyl polyethylene ether), and enzymes. Enzyme inhibitors to inhibit enzymatic degradation (e.g., pancreatic trypsin inhibitor, diisopropyl fluoride) may contain diisopropylfluorophosphate (DFF), or trasylol In certain embodiments, the peptide inhibitor in a solid dosage form for oral administration is prepared from sucrose, lactose, or the like. , cellulose, mannitol, trehalose, raffinose, maltitol, dextrose starch, agar, alginate, chitin, chitosan, pectin, tragacanth gum, Gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic poly These may be mixed with at least one additive, such as a glyceride or a glyceride. The dosage form may also contain other types of excipients, such as inert diluents, magnesium stearate, etc. Any lubricants, preservatives such as parabens, sorbic acid, ascorbic acid, alpha-tocopherol , antioxidants such as cysteine, disintegrants, binders, thickeners, buffers, pH adjusters, sweeteners, Flavoring or fragrance agents may be included.

[0337] In a specific embodiment, oral dosage forms suitable for use with the peptide inhibitors of the present invention Alternatively, the unit dose may comprise a mixture of the peptide inhibitor and non-drug ingredients or excipients, as well as the ingredients or packaging. Oral compositions may contain other non-recyclable materials that may be considered either packaging or non-recyclable materials. In some embodiments, the dosage form may include at least one of a solid, a solid, and a semi-solid dosage form. and an oral dosage form comprising an effective amount of a peptide inhibitor, such as a pill, tablet, capsule, gel, or paper. Dosage forms are provided that include at least one of a drink, a beverage, a syrup, an ointment, and a suppository. In some cases, achieving delayed release of the peptide inhibitor in the small intestine and / or colon of a subject. An oral dosage form is provided that is designed and configured to

[0338] In one embodiment, an oral pharmaceutical composition comprising a peptide inhibitor of the present invention is administered to the peptide in the small intestine. It contains an enteric coating designed to delay release of the inhibitor. In some embodiments, the peptide inhibitors of the present invention and aprotinin, etc., are combined in a delayed-release pharmaceutical formulation. Pharmaceutical compositions containing such protease inhibitors are provided. The composition includes an enteric coating that is soluble in gastric juices at a pH of about 5.0 or greater. In one embodiment, hydroxypropyl methylcellulose phthalate, phthalic acid Derivatives of cellulose, including cellulose acetate and cellulose trimellitate, and cellulose acetate and other carbohydrate polymers having a dissociable carboxylic acid group, such as cellulose and similar derivatives of other carbohydrate polymers. In accordance with the present invention, a pharmaceutical composition is provided that includes an enteric coating comprising a polymer that

[0339] In one embodiment, the pharmaceutical composition comprising the peptide inhibitor of the present invention is in an enteric coating. The enteric coating provides a controlled release of the drug into the lower digestive system of the subject. designed to protect and release pharmaceutical compositions at high pressures and to avoid systemic side effects. In addition to enteric coatings, the peptide inhibitors of the present invention may be administered in any compatible oral drug delivery system. It may be encapsulated, coated, bound, or otherwise associated with a delivery system or component. In some embodiments, the peptide inhibitors of the present invention are incorporated into polymeric hydrogels, nanoparticles, microparticles, or other media. The lipid carrier system may be provided in a lipid carrier system including at least one of spheres, micelles, and other lipid systems.

[0340] To overcome the problem of peptide degradation in the small intestine, some embodiments of the present invention: The peptide inhibitors of the present invention are contained, whereby the hydrogel polymer is or a hydrogel polymer carrier system that protects peptide inhibitors from proteolytic degradation in the colon. The peptide inhibitors of the present invention further increase the dissolution rate and enhance intestinal absorption of the peptide. It may be formulated to be suitable for use with a carrier system designed to enhance method using liposomes, micelles, and nanoparticles to increase GI tract penetration of peptides. Including child use.

[0341] To provide pharmaceuticals for oral delivery, various biological response systems can be mediated by one or more of the present invention. In some embodiments, the peptide inhibitors of the present invention may be combined with The agent is a mucosal layer having a hydrogel and hydrogen bonding groups to provide a therapeutic agent for oral administration. Adhesive polymers (e.g., PEG, poly(methacrylic) acid, P MAA], cellulose, Eudragit®, chitosan, and alginate). Other embodiments are directed to the use of peptide inhibitors disclosed herein in combination with biological response systems such as A method for optimizing or extending drug residence time in a peptide inhibitor comprising: The surface has mucoadhesive properties via hydrogen bonding, binding with mucins and / or hydrophobic interactions. These modified peptide molecules are also useful in the methods of the present invention. In accordance with the desired characteristics of the targeted mucoadhesive system, the targeted mucoadhesive system may exhibit increased drug residence time within the subject. can specifically bind to receptors on the surface of enterocytes and M cells, thereby inhibiting the This further increases the uptake of particles containing

[0342] Another embodiment is a method for oral delivery of a peptide inhibitor of the present invention, comprising administering the peptide Tide inhibitors inhibit the ability of peptides to cross the intestinal mucosa by increasing paracellular or transcellular permeation. The method also includes administering the therapeutic agent to a subject in combination with a permeation enhancer that promotes delivery of the therapeutic agent. Various penetration enhancers and methods for delivery are reviewed in Brayden, DJ, Mrsny, R .J., 2011. Oral peptide delivery: prioritiz ing the leading technologies.Ther.Delivery ry 2(12),1567-1573.

[0343] In certain embodiments, the pharmaceutical compositions and formulations of the invention comprise a peptide inhibitor of the invention and one or more The permeation enhancer may include one or more permeation enhancers. Examples of permeation enhancers include, for example, bile salts, fats, etc. Acids, surfactants (anionic, cationic, and non-anionic), chelating agents, Zonul ar OT, ester, cyclodextrin, dextran sulfate, azone, crown ace Examples of suitable esters include EDTA, sucrose esters, and phosphotidylcholine. Absorption enhancers are typically not carriers per se, but are used to transport peptides and proteins across the intestinal mucosa. It is widely used with other carriers to improve oral bioavailability by delivering Such substances may form non-specific interactions with the intended peptide inhibitor. They can be added as excipients or incorporated into the formulation to achieve this.

[0344] Enhances tight junction permeability and is generally recognized as safe Food ingredients and / or other naturally occurring substances that have been determined to be "As Safe (GRAS)" include: , such as aspartic acid glycerides, acylcarnitines, bile salts, and medium-chain fatty acids. Sodium salts of medium chain fatty acids (MCFAS) also act as permeation enhancers. The most extensively studied MCFAS is a salt of capric acid. The most common fatty acid in milk fat is sodium caprate, which contains 2-3% of the fatty acids in the milk fat fraction. Until now, sodium caprate has been used in suppository formulations (Do It is primarily used as an excipient in the drug cephalosporin (ktacillin™). The permeation characteristics of sodium caprylate (8 carbons), an MCFAS, are similar to those of sodium caprate. It has been shown to be lower in vitro compared to sodium caprylate and peptides. Oil suspensions are formulated by compounding drugs with other excipients in oil to enhance permeability. suspension, OS) was prepared (Tuvia, S. et al., Pharmaceu tical Research,Vol.31,No.8,pp.2010-2021( 2014).

[0345] For example, in one embodiment, a permeation enhancer is combined with a peptide inhibitor, and the permeation enhancer These include some of the following: medium-chain fatty acids, long-chain fatty acids, bile salts, amphiphilic surfactants, and chelating agents. In certain embodiments, the medium-chain fatty acid salt increases the paracellular permeability of the intestinal epithelium. In one embodiment, N-[hydroxybenzoyl] The peptide inhibitors of the present invention may be administered using a penetration enhancer comprising sodium [amino]caprylate. By forming weak non-covalent bonds, the permeation enhancer favors membrane transport and is also effective in the blood circulation. In another embodiment, the peptide inhibitors of the present invention are conjugates, thereby increasing the cellular penetration of the peptide into various cell types. In at least one embodiment, a peptide inhibitor of the present invention and a cyclodextrin non-covalently bonded to a permeation enhancer selected from the group consisting of a dendrimer, a dendrimer, and a permeation enhancer selected from the group consisting of a dendrimer, ... and a dendrimer. The penetration enhancer reduces peptide aggregation and improves the stability and activity of the peptide inhibitor molecule. Increases solubility.

[0346] In certain embodiments, the pharmaceutical composition or formulation comprises a peptide inhibitor of the invention and a transient transmembrane peptide. Transient permeability enhancers (TPEs) are included. Permeation enhancers and TPEs are , can be used to increase the oral bioavailability or peptide inhibitors. One example of a TPE that may be used is a dispersant containing a powder containing sodium caprylate and a therapeutic agent. It is an oily suspension formulation (Tuvia, S. et al., Pharmaceutical Research,Vol.31,No.8,pp.2010-2021(2014) .

[0347] In certain embodiments, pharmaceutical compositions and formulations comprise a peptide inhibitor of the invention and one or more may contain two or more absorption enhancers, enzyme inhibitors, or mucoadhesive polymers.

[0348] In specific embodiments, the peptide inhibitors of the present invention are formulated in various forms, e.g., emulsions, liposomes, The drug is formulated in a formulation vehicle such as a gel, microsphere, or nanoparticle.

[0349] Another embodiment of the present invention is treating a subject with a peptide inhibitor of the present invention that has an increased half-life. In one aspect, the present invention provides a method for treating rheumatoid arthritis by administering a therapeutically effective amount once daily (qd). ) or twice daily (bid) administration, in vitro or in vivo (e.g. monocyclic peptides having a half-life of at least several hours to a day when administered to a human subject In another embodiment, the peptide inhibitor is administered in a therapeutically effective amount once a week (qw In another embodiment, the peptide has a half-life of at least 3 days, sufficient for administration. The tido-inhibitors are sufficient to provide a therapeutically effective dose administered once every two weeks (biw) or once a month. In another embodiment, the peptide inhibitor is underivatized or are derivatized or modified to have a longer half-life compared to unmodified peptide inhibitors. In another embodiment, the peptide inhibitor comprises one or two agonists to increase serum half-life. It contains one or more chemical modifications.

[0350] When used in at least one of the treatment or delivery systems described herein, The peptide inhibitors may be used in pure form, or, if such form exists, in a pharmaceutically acceptable form. It may be used in the form of a salt.

[0351] The total daily dosage of the peptide inhibitors and compositions of the present invention should be determined within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject can be determined by the treating physician. The type of treatment will depend on a variety of factors, including: a) the disorder being treated and the severity of the disorder; b) the type of treatment being used; c) the activity of the particular compound being used; and c) the specific composition used, the patient's age, weight, and general health. d) time of administration, route of administration, and excretion of the specific peptide inhibitor used e) duration of treatment; f) in combination with or concurrently with the specific peptide inhibitor used The drugs used, as well as similar factors well known in the medical field.

[0352] In a specific embodiment, the present invention is administered to a human or other mammalian host in a single or divided dose. The total daily dose of the peptide inhibitor of the invention is, for example, 0.0001 to 300 mg / kg per day. (body weight) or in an amount of 1 to 300 mg / kg (body weight) per day.

[0353] Non-invasive detection of intestinal inflammation The peptide inhibitors of the present invention can be used to detect, evaluate, and assess intestinal inflammation using microPET imaging. and diagnostics, and the peptide inhibitors can be used to detect chelates as part of non-invasive diagnostic procedures. In one embodiment, the peptide inhibitor is labeled with a bifunctional group or a detectable label. In another embodiment, the peptide inhibitor is radiolabeled. In one embodiment, the labeled peptide inhibitor is administered to the subject orally or rectally. Following uptake of the peptide inhibitor, a labeled peptide inhibitor is included in the drinking water. Using microPET imaging, inflammation can be visualized throughout a subject's intestinal and digestive tract. It can be made into [Example]

[0354] Synthesis of substituted tryptophans Synthesis of 7-methyltryptophan 7-Methyltryptophan was purchased from a commercial source. The compounds can be synthesized according to one of the methods.

[0355] Synthesis of 7-ethyltryptophan 7-Ethyltryptophan was synthesized according to the method shown in Scheme 1.

[0356] [ka]

[0357] Synthesis of 7-isopropyltryptophan 7-Isopropyltryptophan was synthesized according to the method shown in Scheme 2.

[0358] [ka]

[0359] Synthesis of additional 7-substituted tryptophans Additional 7-substituted tryptophans were synthesized or synthesized according to the method shown in Scheme 3. It is possible.

[0360] [ka] R is cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy.

[0361] Example 1: Synthesis of peptide monomers On Protein Technology's Symphony multichannel synthesizer The peptide monomers of the present invention were synthesized using Merrifield solid phase synthesis techniques. HBTU(O-benzotriazole-N,N,N',N'-tetramethyl-uronium- Hexafluorophosphate), Diisopropylethylamine e, DIEA) coupling conditions were used to assemble the peptide. The coupling is PyAOP (7-azabenzotriazol-1-yloxy) tripyrrolidone. Lysinophosphonium hexafluorophosphate) and DIEA conditions were used. For peptides with amides, Rink Amide MBHA resin (100-200 mol) was used. For peptides with C-terminal acids, pre-loaded The Wang resin with N-α-Fmoc-protected amino acid that had been previously prepared was used. The reagent (premixed HBTU and DIEA) was prepared at a concentration of 100 mmol. Similarly, an amino acid solution was prepared at a concentration of 100 mmol. Identify and screen for superiority based on chemical optimization and / or phage display. Those with improved binding and / or inhibitory properties were identified.

[0362] assembly Peptides were assembled using standard Symphony protocols. The train was assembled as follows: Resin (250 mg, 0.14 mmol) in each reaction vial ) was washed twice with 4 ml of DMF, followed by 2.5 ml of 20% 4-methylpiperidine ( The resin was then filtered and washed twice with DMF (4 ml). The resin was washed and treated again with N-methyl piperidine for another 30 minutes. followed by 2.5 mL of amino acids and 2.5 mL of HBTU-DIEA. After 45 minutes of frequent stirring, the resin was filtered and washed three times with DMF (4 ml each). For a typical peptide of the present invention, double coupling was performed. After the reaction was complete, the resin was washed with DMF (4 ml each) before proceeding to the next amino acid coupling. Washed three times.

[0363] Ring-closing metathesis to form olefins The resin (100 μmol) was washed with 2 mL of DCM (3 × 1 min) and then with 2 mL of DCM. After washing with CE (3 x 1 min), add 2 mL of a 6 mM solution of Grubbs first generation catalyst in DCE. The solution was treated with 200 mL of HCl (4.94 mg ml; 20 mol % with respect to resin substitution). The resin was refluxed under reflux overnight (12 hours) and then drained. The resin was washed with DMF (4 ml each); DCM (4 ml each); After washing three times with HCl, the cells were dried and cut into pieces.

[0364] Disconnect After peptide assembly is complete, reagent K (82.5% trifluoroacetic acid, 5% water, 5 % thioanisole, 5% phenol, 2.5% 1,2-ethanedithiol) The peptide was cleaved from the resin by treatment with a reagent. The peptide could be successfully cleaved from all remaining side chain protecting groups.

[0365] The cleaved peptide was precipitated in cold diethyl ether, followed by two washes with ethyl ether. The filtrate was discarded, a second aliquot of cold ether was added, and the procedure was repeated. The peptide was dissolved in a solution of acetonitrile:water (7:3 with 1% TFA) and filtered. The fragments were then analyzed by electrospray ionization mass spectrometry before purification. ion mass spectrometry, ESI-MS) (Micromass / Waters ZQ) was used to verify the quality of the linear peptide.

[0366] Oxidation-mediated disulfide bond formation Peptides containing free thiols (e.g., diPen) can be synthesized using the common Fmoc-SPP method. Assembled on Rink Amide-MBHA resin according to the S procedure. Cleavage Reagent 9 0% trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5% trifluoroacetic acid The peptide was cleaved from the resin by treatment with isopropylsilane. The peptide was precipitated in cold diethyl ether and subsequently washed twice with ethyl ether. The liquid was discarded, a second aliquot of cold ether was added, and the procedure was repeated. The desired acid was obtained by dissolving in a solution of acetonitrile:water (7:3 with 1% TFA) and filtering. The crude unmodified peptide was obtained.

[0367] X4 and X9 are Cys, Pen, hCys, (D)Pen, (D)Cys, or (D) The crude cleaved peptides containing either hCys were dissolved in 20 mL of water:acetonitrile. Saturated iodine in acetic acid was then added dropwise with stirring until a yellow color persisted. The solution was stirred for 15 minutes and the reaction was monitored by analytical HPLC and LCMS. Once the reaction was complete, solid ascorbic acid was added until the solution was clear. After dilution with water, the mixture was analyzed by reversed-phase HPLC (Luna C18 support, 10 μm, 100 A, transfer Phase A: water containing 0.1% TFA, mobile phase B: acetonitrile containing 0.1% TFA Acetonitrile (ACN) gradient was run starting at 5% B over 60 min at a flow rate of 15 mL / min. The solvent mixture was purified by loading onto a 50% ethanol solution (50% ethanol, then changing to 50% B). The fractions containing the pure product were freeze-dried in a lyophilizer.

[0368] Thioether bond formation Peptides containing free thiols (e.g., Cys) and hSer(OTBDMS) on Rink Amide-MBHA resin following a general Fmoc-SPPS procedure. Chlorination was carried out using PPh3 (10 equiv.) and Cl3CCN (10 equiv.) in DCM. The peptide was cleaved by treating the resin with 90% cleavage reagent for 2 hours. Trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5% trifluoroacetic acid The peptide was cleaved from the resin by treatment with isopropylsilane. The precipitate was then washed twice with ethyl ether. The filtrate was discarded and the residue was placed in a cool evaporator. A second aliquot of ether was added and the procedure repeated. The crude peptide was dissolved in acetonitrile: The desired uncyclized product was dissolved in a solution of water (7:3 with 1% TFA) and filtered to give the desired uncyclized product. The crude peptide was obtained.

[0369] A free thiol (e.g., Cys, Pen, hCys, (D)Pen, (D)Cys, or (D)hCys, and alkyl The crude peptide with the halogenated form (hSer(Cl)) was dissolved in 0.1 M TRIS buffer pH The mixture was dissolved in 8.5% ethanol. Cyclization was carried out overnight at room temperature. Then, after first diluting it 2-fold with water, the mixture was inverted. Phase HPLC equipment (Luna C18 support, 10u, 100A, mobile phase A: 0.1%TF A: Water containing 0.1% TFA, Mobile phase B: Acetonitrile (ACN) containing 0.1% TFA, Gradient Load the solution into a 5% B column (starting at 5% B and changing to 50% B over 60 min at a flow rate of 15 mL / min). The solvent mixture was purified by centrifugation. The fractions containing the pure product were then frozen. It was freeze-dried in a dryer.

[0370] purification Gemini C18 column (4.6 mm × 250 mm) (Phenomenex) , analytical reversed-phase high performance liquid chromatography (H PLC) was performed using a Gemini 10 μm C18 column (22 mm × 250 mm) ( Phenomenex) or Juptires 10 μm, 300 A °C 18 column (21 Semi-preparative reverse-phase HPLC was performed on a 1.2 mm x 250 mm (Phenomenex). A linear gradient of B in buffer A (mobile phase) was run at a flow rate of 1 mL / min (analytical) and 15 mL / min (preparative). Mobile phase A: Water containing 0.15% TFA, Mobile phase B: Acetonitrile containing 0.1% TFA Separation was achieved using 1 mL / min (analytical) and 15 mL / min (analytical). A linear gradient of B in buffer A (mobile phase A: water containing 0.15% TFA, mobile phase B: water containing 0.15% TFA) was run at a flow rate of 1000 kJ / min. Separation is achieved using mobile phase B: acetonitrile (ACN) containing 0.1% TFA did.

[0371] Example 1A: Representative Synthesis of Additional Peptide Monomers Peptide synthesis Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[Nal]-[αmeK]-[Lys(A c)]-N-[Aib]-[Ahx]-NH2 ( * Disulfide bond in Pen-Pen format) (SEQ ID NO: 70) (Peptide #70)

[0372] Prepare for the synthesis of peptide #70 using FMOC solid phase peptide synthesis techniques.

[0373] Rink Amid was synthesized using standard FMOC-protected synthesis conditions reported in the literature. e. Assemble peptide #70 on MBHA resin. The assembled peptide is cleaved with strong acid. The disulfide bond is then cleaved and subsequently isolated from the resin and protecting groups by precipitation. Oxidation to form the hydroxybenzoate is followed by purification by RPHPLC and counterion exchange. The pure fractions are lyophilized to give the final product, peptide #70.

[0374] Swelling resin: 10 g of Rink Amide MBHA solid phase resin (0.66 mmol / g Load) equipped with a filter frit, ground glass joint, and vacuum side arm Transfer the resin to a 250 mL peptide container. Wash the resin three times with DMF.

[0375] Step 1: Coupling of FMOC-aminohexanoic acid (Ahx) 20% 4-methyl-piperidine in DMF, 2 bed volumes of resin, was added to the swollen resin and drained. Shake for 3-5 minutes before stirring, add a second 2-bed volume of 4-methylpiperidine solution, and The resin-bound FMOC group is deprotected by shaking the resin for 20 to 30 minutes. After deprotection, wash the resin three times with DMF while shaking. The acid (3 equivalents, 7.1 g) was dissolved in 100 ml of water with Oxyma (4.5 equivalents, 4.22 g). Dissolve in DMF. Incubate for 15 minutes with shaking in DIC ( The acid is preactivated by adding 3.9 equivalents (4 ml). After 1 minute of coupling, an additional aliquot of DIC (2.6 equivalents, 2.65 ml) was added. The progress of the coupling reaction is monitored by a colorimetric Kaiser test. Once determined to be complete, allow to stand with shaking before starting the next deprotection / coupling cycle. The resin is then washed three times with DMF.

[0376] Step 2: Coupling of FMOC-aminoisobutyric acid (Aib) 20% 4-methyl-piperidine in DMF, 2 bed volumes of resin, was added to the swollen resin and drained. Shake for 3-5 minutes before stirring, add a second 2-bed volume of 4-methylpiperidine solution, and Deprotection of the resin-bound FMOC group is achieved by shaking for 20-30 minutes. After deprotection of the resin, wash the resin with DMF three times while shaking. Isobutyric acid (3 equivalents, 6.5 g) was mixed with Oxyma (4.5 equivalents, 4.22 g) in 100 ml Dissolve in DMF. Dissolve in DIC with shaking for 15 min before adding to the Ahx-bound resin. The acid is preactivated by adding (3.9 equivalents, 4 ml). After 5 min of coupling, an additional aliquot of DIC (2.6 equiv., 2.65 ml) was added. The progress of the coupling reaction is monitored by a colorimetric Kaiser test. Once determined to be complete, shake before starting the next deprotection / coupling cycle. The resin is then washed three times with DMF.

[0377] Step 3: Coupling of FMOC-Asn(Trt)-OH: Resin-bound 3Pal FMOC is removed from the N-terminus of FMOC-Asn(Trt)-O and washed as described above. H (2 eq., 8 g) in 100 ml of DMF with Oxyma (3 eq., 2.81 g) Allow to dissolve. Preactivate the acid for approximately 15 minutes before adding it to the Aib-Ahx-amide resin. Add DIC (2.6 equivalents, 2.65 ml) to dissolve the An aliquot of (1.4 equivalents, 1.43 ml) was added to the reaction. Once the reaction is determined to be complete, the resin is cooled before starting the next deprotection / coupling cycle. Wash three times with DMF.

[0378] Step 4: Coupling of FMOC-Lys(Ac)-OH: Coupling of the resin-bound peptide FMOC is removed from the N-terminus and the resin is washed as before. OH (2 equiv., 5.4 g) was added to 100 ml of D Dissolve in MF. Add to Asn(Trt)-Aib-Ahx-amide resin. Approximately 15 minutes. Before the addition, DIC (2.6 equivalents, 2.65 ml) is added to preactivate the acid. After 15 minutes, an additional aliquot of DIC (1.4 equivalents, 1.43 ml) is added to the reaction. Once the reaction is complete as determined by the Kaiser test, the next deprotection / coupling cycle Before starting the run, the resin is again washed three times with DMF.

[0379] Step 5: Coupling of FMOC-αMe-lysine(Boc)-OH: FMOC to resin The peptide bound to FMOC-αMe is removed from the N-terminus and the resin is washed as described above. Lysine (3 eq, 9.7 g) was dissolved in 100 ml of Oxyma (4.5 eq, 4.22 g). Dissolve Lys(Ac)-Asn(Trt)-Aib-Ahx-Amin in 1 ml of DMF. Approximately 15 minutes before adding the acid to the resin, DIC (3.9 equiv., 4 ml) was added to preactivate the acid. After about 15 minutes, an additional aliquot of DIC (2.6 equivalents, 2.65 ml) is added. Once the reaction is complete as determined by the Kaiser test, the next step is deprotection / Before starting the coupling cycle, the resin is washed three times with DMF.

[0380] Step 6: Coupling of FMOC-3-(2-naphthyl)-L-alanine (Nal): FMOC is removed from the N-terminus of the resin-bound peptide and the resin is washed as before. MOC-3-(2-naphthyl)-L-alanine (3 equivalents, 8.7 g) was added to Oxyma (4 Dissolve αMeLys(Boc) in 100 ml of DMF. )-Lys(Ac)-Asn(Trt)-Aib-Ahx-amide resin. Before the 15 min, add DIC (3.9 eq, 4 ml) to preactivate the acid. After 1 minute, an additional aliquot of DIC (2.6 equivalents, 2.65 ml) is added. Once the reaction is determined to be complete by experiment, the next deprotection / coupling cycle begins. Before this, the resin was washed again with DMF three times.

[0381] Step 7: FMOC-4-[2-(Boc-amino-ethoxy)]-L-phenylalanine Coupling of FMOC-AEF: FMOC-AEF is coupled from the N-terminus of the resin-bound peptide. The resin is washed as described above. [Ci)]-L-phenylalanine (3 eq., 10.8 g) was added to Oxyma (4.5 eq., 4 Dissolve Nal-αMeLys(Boc)- in 100 ml of DMF. Approximately 15 minutes before adding to the Lys(Ac)-Asn(Trt)-Aib-Ahx-amide resin Add DIC (3.9 eq, 4 ml) to preactivate the acid. After about 15 min. An additional aliquot of DIC (2.6 equivalents, 2.65 ml) is added to the reaction. Once the reaction is determined to be complete by testing, the next deprotection / coupling cycle begins. Before this, the resin is washed three times with DMF.

[0382] Step 8: Coupling of FMOC-Pen(Trt)-OH: Resin-bound peptide FMOC is removed from the N-terminus of FMOC-Pen(Trt) and the resin is washed as described above. )-OH (3 equiv., 12.14 g) with Oxyma (4.5 equiv., 4.22 g) in 1 Dissolve AEF-Nal-αMeLys(Boc)-Lys(A c) Preheat the acid about 15 minutes before adding it to the -Asn(Trt)-Aib-Ahx-amide resin. Add DIC (3.9 equivalents, 4 ml) to activate the reaction mixture. After about 15 minutes, An additional aliquot (2.6 equivalents, 2.65 ml) is added to the reaction. Once the reaction is determined to be complete, the next deprotection / coupling cycle should be initiated. The resin is again washed three times with DMF.

[0383] Step 9: Coupling of FMOC-Lys(Ac)-OH: Coupling of the resin-bound peptide FMOC is removed from the N-terminus and the resin is washed as before. OH (2 equiv., 5.4 g) was added to 100 ml of D Dissolve in MF. Pen(Trt)-AEF-Nal-αMeLys(Boc)-Ly Approximately 15 minutes before adding the s(Ac)-Asn(Trt)-Aib-Ahx-amide resin Add DIC (2.6 eq, 2.65 ml) to preactivate the acid. Approximately 15 min Afterwards, an additional aliquot of DIC (1.4 equivalents, 1.43 ml) is added to the reaction. Once the reaction is determined to be complete by the -test, the next deprotection / coupling cycle is initiated. Before starting, the resin is again washed three times with DMF.

[0384] Step 10: Coupling of FMOC-7-Me-Trp-OH: Resin-bound peptide FMOC is removed from the N-terminus of the amide and the resin is washed as described above. rp-OH (2 eq., 5.81 g) was mixed with Oxyma (3 eq., 2.81 g) in a 100 Dissolve Lys(Ac)-Pen(Trt)-AEF-Nal-αM in 1 ml of DMF. eLys(Boc)-Lys(Ac)-Asn(Trt)-Aib-Ahx-amide resin Approximately 15 minutes before adding the acid, DIC (2.6 equiv., 2.65 m After approximately 15 minutes, an additional aliquot of DIC (1.4 eq, 1.43 ml) is added. Once the reaction is complete as determined by the Kaiser test, the next step is deprotection / Before starting the coupling cycle, the resin is again washed three times with DMF.

[0385] Step 11: Coupling of FMOC-Thr(tBu)-OH: Resin-bound peptide FMOC is removed from the N-terminus of the peptide and the resin is washed as described above. u) -OH (4 eq., 10.5 g) was dissolved in 100 ml of water with Oxyma (6 eq., 5.62 g). Dissolve in ml of DMF. -Nal-αMeLys(Boc)-Lys(Ac)-Asn(Trt)-Aib-Ah Approximately 15 minutes before adding to the x-amide resin, DIC (5.2 equivalents) was added to preactivate the acid. After about 15 minutes, an additional aliquot of DIC (2.6 eq., 2 Add 0.65 ml of HCl to the reaction. Once the reaction is complete as determined by the Kaiser test, The resin is again washed three times with DMF before the next deprotection / coupling cycle begins.

[0386] Step 12: Coupling of FMOC-Asn(Trt)-OH: Coupling of the resin-bound peptide FMOC is removed from the N-terminus of the peptide and the resin is washed as described above. t) -OH (4 eq, 15.8 g) was dissolved in 100 ml of water with Oxyma (6 eq, 5.62 g). Dissolve in ml of DMF. Thr(tBu)-7MeTrp-Lys(Ac)-Pen (Trt)-AEF-Nal-αMeLys(Boc)-Lys(Ac)-Asn(Tr t)-Aib-Ahx-Amide resin to preactivate the acid approximately 15 minutes before adding it. Add DIC (5.2 eq, 5.3 ml) to the solution. After about 15 minutes, add an additional aliquot of DIC. Add 2.65 ml of ethanol (2.6 equivalents) to the reaction. The reaction is complete by Kaiser test. Once it is determined that the resin has been DM-treated, the resin should be re-treated before the next deprotection / coupling cycle begins. Wash three times with F.

[0387] Step 13: Coupling of FMOC-Pen(Trt)-OH: FMOC is attached to the resin Remove from the N-terminus of the peptide and wash the resin as described above. -OH (2 equiv., 8.1 g) was added to 100 ml of water with Oxyma (3 equiv., 2.81 g). Dissolve Asn(Trt)-Thr(tBu)-7MeTrp-Lys(A c)-Pen(Trt)-AEF-Nal-αMeLys(Boc)-Lys(Ac)- The acid was preactivated approximately 15 minutes before adding it to the Asn(Trt)-Aib-Ahx-amide resin. Add DIC (2.6 equivalents, 2.65 ml) to neutralize the An additional aliquot (2.6 equivalents, 2.65 ml) is added to the reaction. Once the reaction is determined to be complete, the final deprotection and acetate capping of the assembled peptide is performed. Before washing, the resin is again washed three times with DMF.

[0388] Step 14: Acetyl capping: Removal of FMOC from the N-terminus of the resin-bound peptide Remove the residue and wash the resin as before. Add 150 ml of Capping Reagent A (THF / Acetic Anhydride) / pyridine, 80:10:10) to construct Pen(Trt)-Asn(Trt)- Thr(tBu)-7MeTrp-Lys(Ac)-Pen(Trt)-AEF-Nal -αMeLys(Boc)-Lys(Ac)-Asn(Trt)-Aib-Ahx-Ami The resin is washed three times with DMF, followed by five times with DCM. It was divided into ~50 ml centrifuge tubes and placed under vacuum for 1.5 hours before being cleaved with TFA.

[0389] Step 15: TFA cleavage and ether precipitation: 200 ml of TFA cleavage cocktail (90 / 5 Prepare 40 ml of cleavage solution (2.5 / 2.5 TFA / water / Tips / DODT). The ester was added to each of the five tubes containing the protected resin-bound peptide and incubated for 2 hours. Filter the spent resin and place the filtrate in an 18-50 ml centrifuge tube for precipitation. Cold diethyl ether was added to each, forming a white precipitate. The ether is decanted and discarded, and the precipitate is centrifuged twice more. The resulting white precipitate cake was dried overnight in a hood to give the crude reduced peptide. do.

[0390] Step 16: Disulfide oxidation: The crude peptide is oxidized and purified in four 1 L batches. Dissolve 2.5 g of crude peptide in 1 L of 20% ACN / water. Add a saturated solution of iodine in ethanol to 1 L of iodine until the yellow / brown color of I2 remains and does not disappear. Add dropwise to the peptide solution. Before quenching the excess I2 with a little ascorbic acid The pale yellow solution is allowed to stand for 5 minutes.

[0391] Step 17: RP-HPLC purification: RP-HPLC purification is performed immediately after each I2 oxidation. Column (Phenomenex, Luna, C18(2), 100A, 250 x 50m) m) in 20% MPB in MPA (MPA = 0.1% TFA / water, MPB = 0.1 in ACN) Equilibrate with 1% TFA at 70 ml / min. Add 1 L of quenched oxidized peptide to Load onto the equilibrated column at 70 mL / min. After the solvent front elutes, load at 70 mL / min. A gradient of 25-45% MPB was run over 60 minutes. The desired material was isolated in fractions. Each fraction is analyzed by analytical RPHPLC. The pure fractions from all four purifications are combined and frozen. Freeze and dry to give the purified TFA salt ready for counterion exchange.

[0392] Step 18: Counterion exchange to acetic acid: The same preparative RP-HPLC column was run at 70 ml / min. 5% MPB in MPA (MPA = 0.3% AcOH in water, MPB = 0.3% AcO in ACN H, MPC = 0.5M NH4OAc in water) and equilibrate with purified peptide T. Dissolve FA salts in 50 / 50 ACN / water and dilute to 15% ACN. Add 70 ml of the solution. The captured peptides were loaded onto the equilibrated column at 1000 kJ / min, and the solvent front eluted. The column is washed with 5% MPB in MPA for 5 minutes. The captured peptides are then transferred to the column at 70 ml / min. The counter ion is exchanged for acetate by washing with 5% MPB in MPC for 40 minutes at 25°C. The chip was washed with 5% MPB in MPA at 70 ml / min for 10 min to remove all NH4O from the system. Finally, the peptides were purified with a gradient of 5–70% MPB in MPA over 60 min. The column is eluted with HCl and the fractions are collected.

[0393] Step 19: Final lyophilization and analysis: The collected fractions were analyzed by analytical RP-HPLC. All fractions with a purity of >95% are combined. RPH is obtained by lyophilization of the combined fractions. Peptide #70 was obtained as a white powder with a purity of >95% as determined by PLC. Peptide identity is confirmed by LC / MS.

[0394] Example 2: Peptide binding of interleukin-23 to the interleukin-23 receptor Do inhibition Peptide optimization was performed to identify IL-1s that are active at low concentrations (e.g., IC50<10 nM). Peptide inhibitors of β-23 signaling were identified. Peptides were tested as described below. inhibits the binding of IL-23 to human IL-23R and inhibits the IL-23 / IL-23R mechanism. Peptides that inhibited the activity were identified.

[0395] Assays were performed to determine peptide activity as described below, and the results of these assays The results are provided in Tables E1-E3. Human ELISA was performed using the IL23-IL23R competition described below. The rat ELISA is a rat IL-23R competitive binding assay described below. The LISA assay shows that pStat3HTRF inhibits IL-23 expression in DB cells, as described below. R pSTAT3 cell assay. The peptides shown in Table E1 were used to evaluate the activity of these peptides. The cyclization occurs via a disulfide bridge formed between the two Pen residues in Table E1. The peptides shown are cyclized via a thioether bond between the indicated amino acid residues. Table E1 is an exemplary structure showing a thioether cyclization, indicated in the table by the term "cyclo." The cyclic region is enclosed in parentheses immediately following the term "cyclo." For tides, residues Abu are present in the indicated positions, but other embodiments, e.g., non-cyclized In relation to the topology, Abu may be referred to as hSer(Cl) or homoSer residue. .

[0396] IL23-IL23R competitive binding ELISA Immulon® 4HBX plates were pre-treated with 50 ng / well of IL23R_hu The wells were coated with FC and incubated overnight at 4°C. The wells were washed four times with PBST. Block with PBS containing 3% non-fat milk for 1 hour at room temperature, then wash four times with PBST. The test sample was diluted in assay buffer (PBS containing 1% non-fat milk) to a final concentration of 2 nM. Serial dilutions of test peptide and IL-23 were added to each well and incubated at room temperature for 2 hours. After washing the wells, 50 ng / well of goat anti-p4 diluted in assay buffer was added. Immunoprecipitation with polyclonal antibody (R&D Systems #AF309) for 1 hour at room temperature. Bound IL-23 was detected by incubating the wells again with PBST. The plate was then washed four times with 1:5000 diluted secondary antibody HRP conjugated to the plate in assay buffer. Anti-goat IgG (Jackson ImmunoResearch Laboratories) ies #705-035-147) was added and incubated at room temperature for 30 minutes. Afterwards, the plates were washed as above. Visualized with HRP Membrane Substrate and quenched with 2M sulfuric acid. The data were read on a spectrophotometer at 450 nm. The IC50 values ​​for the agonists are shown in Tables E1 to E3.

[0397] Rat IL-23R competitive binding ELISA Assay plates were coated with 300 ng / well of rat IL-23R_huFC. The wells were washed, blocked, and washed again. Serial dilutions of test peptide and IL-23 were added to each well at a final concentration of 7 nM and incubated at room temperature. After washing the wells, the bound IL-23 was removed by goat anti-p40 Detection was performed with a polyclonal antibody followed by HRP-conjugated donkey anti-goat IgG. TMB One Component HRP Membrane Substrate The results were visualized with TE and quenched with 2M sulfuric acid. The IC50 values ​​for the peptides are shown in Tables E1 to E3.

[0398] DB cell IL23R pSTAT3 cell assay IL-23 plays a central role in supporting and maintaining Th17 differentiation in vivo. This process is primarily mediated by signal transducer and activator of transcription 3 (STAT3). STAT3 phosphorylation (to obtain pSTAT3) mediates RORC and pro-inflammatory responses. This is thought to lead to upregulation of IL-17. In IL-23R-expressing DB cells stimulated with IL-23 in the presence of a test compound, The levels of pSTAT3 in the culture medium were examined. DB cells (ATCC #30-2001) were cultured in RPMI-1640 medium. #CRL-2289) were seeded at 5 x 10E5 cells / well in 96-well tissue culture plates. A final concentration of 0.5 nM of test peptide and serial dilutions of IL-23 were added to each well. and incubated at 37°C in a 5% CO2 humidified incubator for 30 minutes. . Cisbio HTRF pST according to the manufacturer's two-plate assay protocol. Changes in phospho-STAT3 levels in cell lysates using the AT3 cell assay kit The IC50 values ​​determined from these data are shown in Table E1. If "0" is listed, the data was undetermined.

[0399] PBMC pSTAT3 assay Cryopreserved peripheral blood mononuclear cells from healthy donors , PBMCs) and cultured in ImmunoCult-XF T supplemented with CTL anti-agglutination wash solution. The cells were washed twice with cell expansion medium (XF T cell expansion medium, XF-TCEM). The cells were counted and treated with penicillin / streptomycin and 100 ng / mL IL-1β ( 2 × 10 per mL of XF-TCEM supplemented with 100 mM NaCl (BioLegend, 579404). 5 The cells were resuspended and incubated at 37°C in 5% CO2 with anti-CD3 (eBioscience, 16- 0037-85 or BDPharmingen, 555329) On day 4 of culture, PBMCs were collected and diluted with 0.1% BSA (RP). Wash twice with RPMI-1640 supplemented with RPMI-1640 (MI-BSA) and incubate at 37°C in 5% CO The cells were incubated in RPMI-BSA in an upright tissue culture flask at RT for 4 hours. After starvation, a total of 6 x 10 cells were cultured in 30 µL of RPMI-BSA. 4 Cells were treated with either peptide or DMSO. The cells were transferred to each well of a 384-well plate that had been previously spotted. The cells were incubated for 30 minutes before adding IL-23 at a final concentration of 5 ng / mL. Cells were stimulated with cytokines in O2 at 37°C for 30 min, transferred to ice for 10 min, and lysed. Phospho-STAT Panel Kit (Meso Scale Discovery) Cell lysates were stored at -80°C until phosphorylated STAT3 was measured using a 500-kJ / mL PBS (K15202D). Stored at ℃.

[0400] [Table 14-1]

[0401] [Table 14-2]

[0402] [Table 14-3]

[0403] [Table 14-4]

[0404] [Table 14-5]

[0405] [Table 14-6]

[0406] [Table 14-7]

[0407] [Table 14-8]

[0408] [Table 14-9]

[0409] [Table 14-10]

[0410] [Table 14-11]

[0411] [Table 14-12]

[0412] [Table 14-13] 0-N / A * Pen / Cys and Pen / Cys form a disulfide bond or and Pen / Cys form a thioether bond.

[0413] Example 3 NK cell-based assay Purified from human peripheral blood of healthy donors by negative selection (Miltenyi Bio tech, catalog number 130-092-657) natural killer (NK) cells, In the presence of 5 ng / mL IL-2 (RnD, Cat. No. 202-IL-010 / CF) In complete medium (10% FBS, L-glutamine, and penicillin-streptomycin), After 7 days, the cells were centrifuged and 1E6 cells / The cells were resuspended in complete medium at 100 mL. 50 ~EC 75 Recombinant IL-23 and IL-10 ng / mL IL-18 (RnD, Cat. No. B003-5) with various concentrations of peptides and added to NK cells seeded at 1E5 cells per well. Then, using Quantikine ELISA (RnD, Cat. No. DIF50) IFNγ in the supernatant was quantified. The IC 50 The values ​​are listed in Table E2. If not shown, data was undetermined. If not shown (N / A), data The data was yet to be determined.

[0414] [Table 15]

[0415] The above U.S. patents, U.S. patents, and patent applications referenced herein and / or listed in the application data sheets are incorporated herein by reference. All patent publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications are hereby incorporated by reference in their entirety. The bodies are incorporated herein by reference.

[0416] From the foregoing, it will be appreciated that, although specific embodiments of the present invention have been described herein for purposes of illustration, the present invention It will be understood that 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. .

Claims

1. A monocyclic peptide inhibitor of the interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor comprises an amino acid sequence of formula (IIIb) or (IIId): Pen-Gln-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-X16 (IIIb), or Abu-Gln-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-X16 (IIId) During the ceremony, X6 is independently any amino acid; X7 is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, Trp-psi, haloalkyl, hydroxy, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; X8 is Gln, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Paf(Ac), PheNHAc, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp; X10 is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; X11 is 6Amido2Nal, 6OMe2Nal, bMe2Nal(2S,3R), 2-Nal, aMe(2-Nal), rbMe2Nal, 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; X12 is 4diFAchx, Achx, Acpx, AmeK(Boc), 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexylAla, 1-aminocyclohexylAla (Achc), Acvc, Lys, or Aib; X13 and X14 are independently any amino acid; i) X16 is absent and X15 is His, Aib, THP, Phe, substituted Phe, substituted (D)Phe, a-MePhe, substituted a-MePhe, Trp, substituted Trp, 1-Nal, aMe(1-Nal), substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted Asn; or ii) X16 is paf, Aib, Phe, 3Pal, substituted Phe, substituted (D)Phe, substituted or unsubstituted Tyr, unsubstituted (D)Tyr, a-MePhe, substituted a-MePhe, b-hPhe, 1-Nal, aMe(1-Nal), substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted Asn; and X15 is any amino acid; A peptide inhibitor or a pharmaceutically acceptable salt or solvate thereof, wherein said peptide inhibitor is cyclized via a Pen-Pen disulfide bond or an Abu-Pen thioether bond.

2. The peptide inhibitor or a pharmaceutically acceptable salt or solvate thereof described in claim 1, wherein X8 is Gln, alpha-Me-Lys, alpha-MeLys(Ac), Lys(Ac), Paf(Ac), Phe4NH2Ac, or Glu.

3. The peptide inhibitor or its pharmaceutically acceptable salt or solvate described in claim 1, wherein X8 is Gln.

4. The peptide inhibitor or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], AEF, AEF(Ac), AEF(BH), AEF(Boc), AEF(Me)2, bMeRPhe, Phe42ae-ethyl, Phe42aeSMSB, Phe4Pip, or Phe(4-CONH2).

5. The peptide inhibitor or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein X10 is Phe[4-(2-aminoethoxy)] or Phe[4-(2-acetylaminoethoxy)].

6. The peptide inhibitor of claim 1, wherein the peptide inhibitor has formula (VIb) or (VId): Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15-X16 (VIb) (SEQ ID NO: 333), or Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15-X16 (VId) (SEQ ID NO: 335) 2. The peptide inhibitor of claim 1, comprising the amino acid sequence:

7. X15 is His, Phe_tetraF, Phe3OH, aMeF, THP, Phe, substituted Phe, (D)Phe, substituted (D)Phe, a-MePhe, Trp, substituted Trp, 1-Nal, aMe(1-Nal), substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, (N-Me)Asn, (N-Et)Asn, (N-n-Pr)Asn, (N-iPr)Asn, (N-iBu)Asn, (N-nBu)Asn, (N-tBu)Asn, (N-benzyl) 2. The peptide inhibitor of claim 1, wherein X16 is selected from the group consisting of (N-pyr)Asn, (N-Ph)Asn, (N-2-aminophenyl)Asn, (N-3-aminophenyl)Asn, (N-4-aminophenyl)Asn, (N-pyr)Asn, (N-3-Pyz)Asn, (N-4-Pyz)Asn, (N-pip)Asn, (N-5-indolyl)Asn, (N-propylamido)Asn, and (N-imidazo-2-yl)Asn, and X16 is absent.

8. The peptide inhibitor of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X12 is 4diFAchx, Achx, Acpx, AmeK(Boc), 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, Ala, cyclohexyl Ala, Lys, Acvc, or Aib.

9. The peptide inhibitor or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, or alpha-MeLeu.

10. The peptide inhibitor or a pharmaceutically acceptable salt or solvate thereof according to claim 9, wherein X12 is alpha-MeLys.

11. The peptide inhibitor or a pharmaceutically acceptable salt or solvate thereof according to claim 9, wherein X12 is alpha-MeLeu.

12. The peptide inhibitor or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein X13 is Glu, Gln, Lys(Ac), or Lys.

13. The peptide inhibitor or a pharmaceutically acceptable salt or solvate thereof described in claim 1, wherein X14 is Asn.

14. The peptide inhibitor of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X11 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, phenyl, or alkoxy.

15. The peptide inhibitor of claim 1, wherein X11 is 6-amide 2Nal, 6OMe2Nal, bMe2Nal(2S,3R), rbMe2Nal, 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal, or a pharmaceutically acceptable salt or solvate thereof.

16. The peptide inhibitor or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein X11 is 2-Nal or 1-Nal.

17. The peptide inhibitor of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X7 is unsubstituted Trp, Trp-psi, Trp5Br, Trp7Cl, Trp7F, Trp5Me, or Trp7Me.

18. A peptide inhibitor or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein X15 is THP and X16 is absent.

19. The peptide inhibitor or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein X15 is Phe or a-MePhe.

20. X15 is His, Phe_tetraF, Phe3OH, aMeF, THP, Phe, substituted Phe, (D)Phe, substituted (D)Phe, a-MePhe, Trp, substituted Trp, 1-Nal, aMe(1-Nal), substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, (N-Me)Asn, (N-Et)Asn, (N-n-Pr)Asn, (N-iPr)Asn, (N-iBu)Asn, (N-nBu)Asn, (N-tBu)Asn, or (N-benzyl).

2. The peptide inhibitor of claim 1, wherein X16 is selected from the group consisting of (N-pyr)Asn, (N-Ph)Asn, (N-2-aminophenyl)Asn, (N-3-aminophenyl)Asn, (N-4-aminophenyl)Asn, (N-pyr)Asn, (N-3-Pyz)Asn, (N-4-Pyz)Asn, (N-pip)Asn, (N-5-indolyl)Asn, (N-propylamido)Asn, and (N-imidazo-2-yl)Asn, and X16 is absent.

21. The peptide inhibitor of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X15 is N(NMe), N(NEt), or N(NiPr), and X16 is absent.

22. The peptide inhibitor or a pharmaceutically acceptable salt or solvate thereof of claim 1, wherein X15 is AiB, Leu, Lys, His, Val, Thr, (D)Leu, (D)Lys, (D)His, (D)Val, or (D)Thr, and X16 is substituted or unsubstituted Phe or substituted or unsubstituted (D)Phe.

23. The peptide inhibitor of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X15 is Asn, Phe, aMePhe, substituted Phe, or THP, and X16 is paf, Aib, 3Pal, substituted or unsubstituted Phe, or substituted or unsubstituted (D)Phe.

24. A pharmaceutical composition comprising a peptide inhibitor described in any one of claims 1 to 23 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

25. A pharmaceutical composition for treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is selected from the group consisting of inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagen-related colitis, eosinophilic gastroenteritis, colitis associated with radiation or chemotherapy, colitis associated with disorders of innate immunity such as leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Barr syndrome, and inflammatory bowel disease (IGD). A pharmaceutical composition for treating Padrak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, pouchitis occurring after 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, comprising the peptide inhibitor according to any one of claims 1 to 23 or a pharmaceutically acceptable salt or solvate thereof.

26. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition is provided to the subject by oral, parenteral, intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, spray, sublingual, buccal, parenteral, rectal, ocular, inhalation, topical, vaginal, or local administration routes.

27. ​​The pharmaceutical composition of claim 25, wherein the disease or disorder is inflammatory bowel disease (IBD), ulcerative colitis, or Crohn's disease, and the pharmaceutical composition is provided to the subject orally.

28. The pharmaceutical composition of claim 26, wherein the disease or disorder is psoriasis and the pharmaceutical composition is provided to the subject orally, topically, parenterally, intravenously, subcutaneously, intraperitoneally, or intravenously.