Peptidomimetic inhibitors of interleukin‑17 and uses thereof

Abstract

The present disclosure relates to cyclic peptidomimetic IL- 17 inhibitors, to pharmaceutical compositions comprising them and to their use for treatment of immunological and inflammatory diseases and disorders.

Description

[0001] PEPTIDOMIMETIC INHIBITORS OF INTERLEUKIN- 17 AND USES THEREOF TECHNICAL FIELD

[0002] The present disclosure is in the fields of peptide biochemistry and immunology and generally relates to anti-inflammatory compounds, and in particular to IL- 17 inhibitors.

[0003] BACKGROUND

[0004] The interleukin- 17 (IL- 17) family of cytokines play a crucial role in the immune system and are involved in various inflammatory responses. The IL- 17 family consists of six members, namely IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F. IL-17 proteins are primarily produced by a group of immune cells called T-helper 17 (Thl7) cells, but they can also be secreted by other cell types, including T-cells, natural killer (NK) cells, and certain innate immune cells.

[0005] IL-17A and IL-17F are prominent members of the IL-17 cytokine family. They are homodimeric polypeptides, each encoded by a separate gene, but sharing significant structural and functional similarity. An IL-17AF heterodimer can also be formed. The biological activity of IL- 17 is exerted by binding to a receptor complex known as the IL- 17 receptor (IL-17R), which is expressed on various cell types throughout the body. The binding of IL-17 to its receptor triggers a signaling cascade that leads to the activation of several pathways involved in inflammation, including the production of pro-inflammatory cytokines, chemokines, and other mediators that recruit and activate immune cells at the site of inflammation, thus aiding in the clearance of pathogens. In the case of IL-17A and IL-17F, the signaling cascade is initiated through the assembly of a ternary complex with the IL-17RA and IL-17RC receptors.

[0006] While IL- 17 is crucial for protective immune responses against certain pathogens, dysregulated or excessive IL-17 production has been implicated in various autoimmune and inflammatory conditions, such as rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. Therefore, there has been significant interest in developing therapeutics that can inhibit the binding of IL- 17 to its receptor and dampen the pathogenic inflammatory response associated with IL-17.One approach to inhibiting IL-17 signaling is through the use of monoclonal antibodies (mAbs) that specifically target the IL-17 pathway. For example, the mAbs approved for the treatment of psoriasis and psoriatic arthritis include secukinumab and ixekizumab that target IL-17A, bimekizumab that targets both IL-17A and IL-17F isoforms, and brodalumab that targets IL-17R.

[0007] However, the disadvantages of the mAbs, including non-oral administration, poor tissue penetration, lacking blood-brain barrier penetration, and relatively long half-life, limit the applications thereof. Thus, research is performed to discover potent small molecules, including short peptides, which effectively target the IL-17 / IL-17R interaction to modulate immune responses. Small-molecule modulators are highly suitable for oral administration, as well as allowing for topical therapy. Furthermore, the small-molecule compounds allow a flexible treatment regimen and may be safer for use due to having faster withdrawal rate of the drug in the case of adverse events.

[0008] Liu et al., (Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide, 2016, Sci Rep., 6:26071), disclose a high affinity IL-17A peptide antagonist (HAP) of 15 amino acid residues, identified through phage-display library screening followed by optimization by amino acid substitutions. HAP binds specifically to IL-17A and inhibits the interaction of the cytokine with its receptor, IL-17RA, thereby blocking the production of multiple inflammatory cytokines. HAP binds the IL-17A dimer, and the N-terminal portions of HAP form a P-strand that inserts between two IL-17A monomers while the C-terminal section forms an a helix that directly blocks IL-17RA from binding to the same region of IL- 17 A.

[0009] Zhang and Dbmling (Small molecule modulators of IL-17A / IL-17RA: a patent review (2013-2021), 2022, Expert Opinion on Therapeutic Patents, 32:11, 1161-1173), review the patent landscape for small-molecule modulators for the treatment of IL-17A-related diseases. Some of the small molecules are at different stages of clinical trials. For example, UCB Biopharma SRL reported spirocyclic and imidazole derivatives as novel modulators of IL- 17 in several patents. Hitgen Inc. disclosed a series of imidazole derivatives for the treatment of IL-17A-related conditions in other patents. One of the patents covers small molecules antagonizing IL-17 that are built on a central bis amide motif scaffold or on a bioisostere scaffold, which seemingly share a binding mode to the interface of the IL-17A dimer involving four hydrogen bonds of the bis amide to the backbone of Leu97A and Leu97B.WO 2025 / 079064 discloses cyclic peptidomimetic IL-17 inhibitors, pharmaceutical compositions comprising them and their use for treatment of immunological and inflammatory diseases and disorders.

[0010] There is an unmet need to develop novel inhibitors with improved efficacy, bioavailability and safety profiles for managing IL- 17 associated autoimmune and inflammatory diseases.

[0011] SUMMARY OF THE INVENTION

[0012] The present invention provides novel peptidomimetics, which are effective inhibitors of the interaction between interleukin 17 (IL- 17) and IL- 17 receptor (IL-17R). In an effort to find a small peptide-based molecule which is potentially effective in treatment of IL- 17 associated diseases, a myriad of peptidomimetics were designed in-silico and scanned using a dedicated algorithm. From the scanned structures, a selected cluster of peptidomimetics were synthesized and tested for inhibiting the interaction between IL- 17 protein members, IL- 17 A, IL-17F and IL-17AF and IL-17R.

[0013] The present invention is based in part on the unexpected finding that a set of cyclic penta-peptidomimetics comprising 5 amino acid residues (hereinafter “amino acids”), wherein at least one is an artificial amino acid, were found to be effective in inhibiting the interaction of IL-17 with IL-17R. It was further found that the inhibition persisted in vivo. This provides positive prospects for utilizing peptidomimetics according to the invention as effective treatment for patients suffering from IL-17 associated diseases, such as autoimmune and inflammatory diseases, for treatment of skin diseases and disorders and for use in cosmetic applications.

[0014] Thus, according to one aspect of the present invention, there is provided a peptidomimetic that inhibits the interaction between IL-17 and IL-17R, the peptidomimetic comprising 5 amino acids (position 1 is the N-terminal one before cyclization and position 5 is the C-terminal one before cyclization), wherein an at least one is an artificial amino acid, and wherein the amino acids are sequentially connected by amide bonds and connected by a head-to-tail cyclization between positions 1 and 5, to form a cyclic penta-peptidomimetic.

[0015] According to some embodiments, at least 3 of the amino acids of the peptidomimetic are artificial. According to some embodiments, the at least one artificial amino acid comprises at least one aromatic moiety. According to some embodiments, the at least one artificial aminoacid comprises an aromatic side-chain. According to some embodiments, the at least one artificial amino acid comprising at least one aromatic moiety is located in at least one position (from the N-terminus of the pentapeptide before cyclization) selected from the group consisting of position 2, position 4, position 5, or any combination thereof. According to some embodiments, the at least one artificial amino acid comprising the at least one aromatic moiety is located at position 4, position 5, or both.

[0016] According to some embodiments, at least one of the 5 amino acids is an alanine (Ala) derivative. According to some embodiments, the alanine derivative is selected from Pal(3), 1-Nal, D-Pal(4), Cha, 3 -(4-Quinolyl)-L- Alanine, and Dip. According to some embodiments, at least one of the 5 amino acids is a phenylalanine (Phe) derivative. According to some embodiments, the phenylalanine derivative is selected from L-Phe(2-OCF3), Phe(2-NO2), Phe(2-CF3), hPhe(2-3-diF), and Phe(F5). According to some embodiments, at least one of the 5 amino acids is a tyrosine (Tyr) derivative. According to some embodiments, the tyrosine derivative is Tyr(3-5-di-Iodo(PEG3Me)). According to some specific embodiments, the peptidomimetic comprises an alanine derivative and a phenylalanine derivative. According to some specific embodiments, the peptidomimetic comprises an alanine derivative and a tyrosine derivative. According to some specific embodiments, the peptidomimetic comprises an alanine derivative, a phenylalanine derivative, and a tyrosine derivative.

[0017] According to some embodiments, at least one of the 5 amino acids is a D-amino acid. According to some embodiments, the at least one D-amino acid is located at position 1, position 3, or both.

[0018] According to some embodiments, at least one of the 5 amino acids is an aromatic amino acid that is halogenated or haloalkylated. According to some embodiments, the aromatic amino acid is halogenated or haloalkylated with one or more halogens selected from F, Cl, Br, and I. According to some embodiments, the one or more halogens are selected from F, Br, and I. According to some embodiments, the haloalkane is a halomethyl moiety or a halomethoxy moiety. According to further embodiments, the haloalkane is a trifluoromethyl moiety or a trifluoromethoxy moiety. According to some embodiments, the at least one halogenated or haloalkylated amino acid is located at position 2, position 4, position 5, or any combination thereof.According to one aspect, the present invention provides a cyclic penta-peptidomimetic that inhibits the interaction between an interleukin 17 (IL-17) and an IL-17 receptor (IL-17R), wherein:

[0019] the amino acid at position 1, counted from the N-terminus of the pentapeptide before cyclization, is selected from the group consisting of: D-Gly(cPr), D- Ala(cPr), D-Ala, D-Pal(4), and D-Gln;

[0020] the amino acid at position 2 is selected from the group consisting of: Pal(3), Ala(cPr), Ala(cBu), Cha, 2-Amino-3-(pyrazin-2-yl)propanoic-acid, and aThr; the amino acid at position 3 is selected from the group consisting of D- Abu(tetrazol-5-yl) and D-Cys(5-Methyl-2H-tetrazole);

[0021] the amino acid at position 4 is selected from the group consisting of L-Phe(2- OCF3), Dip, Phe(2-NO2), Tyr(3-5-di-Iodo(PEG3Me)), and Phe(F5); and the amino acid at position 5 is selected from the group consisting of: Phe(2-CF3), L-Phe(2-OCF3), 1-Nal, hPhe(2-3-diF), Gly(indan-2-yl), 3-(4-Quinolyl))-L- alanine, and Orn(Cbz(2-Cl)).

[0022] According to some embodiments, the amino acid at position 3 is D-Abu(tetrazol-5-yl). According to some embodiments, the amino acid at position 1 is selected from the group consisting of: D-Gly(cPr), D-Ala(cPr), D-Ala, D-Pal(4), and D-Gln;

[0023] the amino acid at position 2 is selected from the group consisting of: Pal(3), Ala(cPr), Ala(cBu), Cha, 2-Amino-3-(pyrazin-2-yl)propanoic-acid, and aThr; the amino acid at position 3 is D-Abu(tetrazol-5-yl);

[0024] the amino acid at position 4 is selected from the group consisting of L-Phe(2- OCF3), Dip, Phe(2-NO2), and Phe(F5); and

[0025] the amino acid at position 5 is selected from the group consisting of: Phe(2-CF3), L-Phe(2-OCF3), 1-Nal, hPhe(2-3-diF), and Orn(Cbz(2-Cl)).

[0026] According to some embodiments, the amino acid at position 1 is selected from the group consisting of: D-Gly(cPr), and D-Ala(cPr);

[0027] the amino acid at position 2 is selected from the group consisting of: Pal(3) and Ala(cPr);the amino acid at position 3 is D-Abu(tetrazol-5-yl);

[0028] the amino acid at position 4 is selected from the group consisting of L-Phe(2- OCF3) and Dip; and

[0029] the amino acid at position 5 is Phe(2-CF3).

[0030] According to some embodiments, the cyclic peptidomimetic is selected from the group consisting of: Compound Nos. 291, 292, 293, 294, 296, 298, 310, 319, 322, 323, 205, 217, 194, 216, 226, and 236, as presented in Tables 2 and 3 and in Figure 1.

[0031] According to some embodiments, the cyclic peptidomimetic is selected from the group consisting of Compound Nos. 291, 292, 293, 294, 296, 298, 319, 322, 205, 216, and 226.

[0032] According to some embodiments, the cyclic penta-peptidomimetic is a compound selected from Compound Nos. 189 to 328 as presented in Tables 1 and 2.

[0033] According to some embodiments, the IL- 17 inhibitory activity of the cyclic penta-peptidomimetic, as determined by AlphaLISA, is p(ICso) of 6.9 or above. According to some embodiments, the IL- 17 inhibitory activity of the cyclic penta-peptidomimetic, as determined by AlphaLISA, is between 6.9 and 8, including each value within the specified range.

[0034] According to some embodiments, the IL- 17 inhibitory activity of the cyclic penta-peptidomimetic, as determined by inhibition of interleukin 8 (IL-8) secretion from cells, is p(ICso) of 5.5 or above. According to some embodiments, the IL- 17 inhibitory activity of the cyclic penta-peptidomimetic, as determined by inhibition of IL-8 secretion from cells, is between 5.5 and 7, including each value within the specified range.

[0035] According to some embodiments, the cyclic penta-peptidomimetic inhibits the interaction between an IL-17A homodimer and an IL-17R.

[0036] According to some embodiments, the cyclic penta-peptidomimetic inhibits the interaction between an IL-17F homodimer and an IL-17R.

[0037] According to some embodiments, the cyclic penta-peptidomimetic inhibits the interaction between an IL-17AF heterodimer and an IL-17R.

[0038] According to some embodiments, the cyclic penta-peptidomimetic inhibits the interaction between an IL-17R and IL-17A homodimer, IL-17F homodimer and / or IL-17AF heterodimer.According to an aspect of the present invention, there is provided a pharmaceutical composition, comprising at least one cyclic penta-peptidomimetic as disclosed herein above, and at least one excipient, salt, or carrier.

[0039] According to some embodiments, the pharmaceutical composition comprises a cyclic penta-peptidomimetic selected from the group consisting of Compound Nos. 291, 292, 293, 294, 296, 298, 310, 319, 322, 323, 205, 217, 194, 216, 226, and 236. According to some embodiments, the pharmaceutical composition comprises a cyclic penta-peptidomimetic selected from the group consisting of Compound Nos. 291, 292, 293, 294, 296, 298, 319, 322, 205, 216, and 226. According to some embodiments, the pharmaceutical composition comprises a cyclic penta-peptidomimetic selected from Compound Nos. 189 to 328 as presented in Tables 1 and 2.

[0040] According to some embodiments, the pharmaceutical composition comprises at least two different cyclic penta-peptidomimetics.

[0041] According to some embodiments, the pharmaceutical composition is for the treatment of an IL-17 associated disease, condition, or disorder, e.g., a disease, condition or disorder in which excessive IL- 17 mediated signaling plays a role.

[0042] According to some embodiments, the IL- 17 associated disease, condition, or disorder, is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), age-associated skin condition, and allograft rejection.

[0043] According to some embodiments, the psoriasis is plaque psoriasis.

[0044] Any stage and severity of plaque psoriasis may be treated with the compositions of the present invention, including mild, moderate, and severe stages. According to some embodiments, the disease is moderate to severe plaque psoriasis. According to some embodiments, the disease is moderate plaque psoriasis. According to other embodiments, the disease is severe plaque psoriasis.

[0045] According to some embodiments, the pharmaceutical composition is formulated for local, parenteral or enteral administration. According to some embodiments, the pharmaceutical composition is formulated for topical administration, intravenous administration, or oral administration. According to some embodiments, the pharmaceutical composition is formulatedfor administration by injection, infusion, inhalation or as a nasal spray. According to yet other embodiments, the pharmaceutical composition is formulated for intradermal or subcutaneous administration. According to particular embodiments, the pharmaceutical composition is formulated for administration locally to the skin, the dermis, or to a wound. According to other embodiments, the composition is formulated for administration by electroporation, using methods and devices known in the art.

[0046] According to other embodiments, a cosmetic composition is provided, comprising at least one cyclic penta-peptidomimetic as disclosed herein above, and at least one cosmetic acceptable excipient, salt, or carrier.

[0047] According to some embodiments, the cosmetic composition comprises a cyclic penta-peptidomimetic selected from the group consisting of Compound Nos. 291, 292, 293, 294, 296, 298, 310, 319, 322, 323, 205, 217, 194, 216, 226, and 236. According to some embodiments, the cosmetic composition comprises a cyclic penta-peptidomimetic selected from the group consisting of Compound Nos. 291, 292, 293, 294, 296, 298, 319, 322, 205, 216, and 226. According to some embodiments, the cosmetic composition comprises acyclic penta-peptidomimetic selected from Compound Nos. 189 to 328 as presented in Tables 1 and 2.

[0048] According to some embodiments, the cosmetic composition is formulated for local administration. According to some embodiments, the local administration is topical administration.

[0049] According to some embodiments, the cosmetic composition is formulated as lotion, cream, ointment, paste, gel, hydrogel and the like, or as powder.

[0050] According to other embodiments, the cosmetic composition is formulated as a solution, mist, or spray.

[0051] According to some embodiments, the cosmetic composition is for use in the prevention, treatment, alleviation of a cosmetic condition, disorder or disease.

[0052] According to some embodiments, the cosmetic condition comprises a skin disorder or an appearance of the skin.

[0053] According to some embodiments, the cosmetic indication is selected from: acne (particularly mild to moderate, and including post-acne marks), excess oil production (including seborrhoea), enlarged pores, hyperpigmentation (including post-inflammatory hyperpigmentation), melasma, dark spots, sunspots and age spots, age signs and wrinkles(including fine lines and deep wrinkles), loss of skin elasticity, sagging and dull skin, sensitive and reactive skin (e.g.„ rosacea, or eczema), skin redness and irritation, rosacea-prone skin, eczema and atopic dermatitis marks, barrier dysfunction, dry and dehydrated skin, flaky, rough skin, tightness and discomfort skin, xerosis (severe dry skin), eye dark circles and puffy eyes, under-eye pigmentation, puffiness and swelling, fine lines and crepey skin.

[0054] According to an aspect of the present invention, there is provided a method for treating a patient suffering from an IL- 17 associated disease, condition, or disorder, comprising the step of administering to a patient in need thereof an effective amount of at least one cyclic penta-peptidomimetic as disclosed herein above, or a pharmaceutically acceptable salt thereof.

[0055] According to some embodiments, the method comprises administering a cyclic penta-peptidomimetic selected from the group consisting of Compound Nos. 291, 292, 293, 294, 296, 298, 310, 319, 322, 323, 205, 217, 194, 216, 226, and 236. According to some embodiments, the method comprises administering a cyclic penta-peptidomimetic selected from the group consisting of Compound Nos. 291, 292, 293, 294, 296, 298, 319, 322, 205, 216, and 226. According to some embodiments, the method comprises administering a cyclic penta-peptidomimetic selected from Compound Nos. 189 to 328 as presented in Tables 1 and 2.

[0056] According to some embodiments, the step of administering to the patient in need thereof an effective amount of the at least one cyclic penta-peptidomimetic, is performed following receiving an affirmative result in a preliminary step, the preliminary step comprising determining whether the patient has an elevated level of at least one IL-17-induced chemokine, cytokine or effector. According to some embodiments, the at least one IL-17-induced chemokine, cytokine or effector is selected from the group consisting of IL-8, Gro-alpha, IL-1A, TNF-alpha, IL-6, IL-22, S100a7a, CK-16, and IL-lbeta.

[0057] According to some embodiments, administering a cyclic penta-peptidomimetic according to the present invention is part of a treatment regimen comprising administering at least one additional therapeutic agent. According to some embodiments, the additional therapeutic agent is an anti-inflammatory agent or an immunosuppressant.

[0058] According to some embodiments, the IL- 17 associated disease, condition, or disorder, is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopicdermatitis, asthma, inflammatory bowel disease, COPD, age-associated skin condition, and allograft rejection.

[0059] According to other embodiments, a cosmetic composition is provided, for use in the prevention, treatment, alleviation of a cosmetic condition, disorder or disease.

[0060] According to some embodiments, the cosmetic condition comprises a skin disorder or an appearance of the skin.

[0061] According to some embodiments, the cosmetic indication is selected from, but not limited to: acne (particularly mild to moderate, and including post-acne marks), excess oil production (including seborrhoea), enlarged pores, hyperpigmentation (including post-inflammatory hyperpigmentation), melasma, dark spots, sunspots and age spots, age signs and wrinkles (including fine lines and deep wrinkles), loss of skin elasticity, sagging and dull skin, sensitive and reactive skin (e.g.„ rosacea, or eczema), skin redness and irritation, rosacea-prone skin, eczema and atopic dermatitis marks, barrier dysfunction, dry and dehydrated skin, flaky, rough skin, tightness and discomfort skin, xerosis (severe dry skin), eye dark circles and puffy eyes, under-eye pigmentation, puffiness and swelling, fine lines and crepey skin.

[0062] According to some embodiments, the cosmetic composition is administered by local administration. According to some embodiments, the local administration is topical administration.

[0063] According to some embodiments, the cosmetic composition is administered as a lotion, a cream, an ointment, a paste, a gel, a hydrogel, and the like, or as a powder.

[0064] According to other embodiments, the cosmetic composition is administered as a solution, a mist, or a spray.

[0065] According to some embodiments, the present invention provides a dosage form suitable for administration wherein the administration route is selected from injection, infusion, inhalation, ingestion, or as a nasal spray and wherein the dosage form comprises at least one container which contains the pharmaceutical composition according as disclosed herein.

[0066] The present invention also provides, according to yet another aspect, a kit comprising at least one container containing the pharmaceutical composition as disclosed herein and instructions for using the kit.

[0067] It is to be understood that any combination of each of the aspects and the embodiments disclosed herein is explicitly encompassed within the disclosure of the present invention.Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

[0068] BRIEF DESCRIPTION OF THE FIGURES

[0069] The novel features described herein are set forth with particularity in the appended claims. A better understanding of the characteristics and advantages of the features described herein will be obtained by reference to the following detailed description that sets forth illustrative examples, in which the principles of the features described herein are utilized, and the accompanying drawings of which:

[0070] Figure 1 depicts atomic structures of some of the peptidomimetics of the invention. The structures of Compound (Comp.) Nos. 194, 205, 216, 217, 221, 226, 236, and 290-328 are provided.

[0071] Figures 2A-2D are exemplary bar charts showing results of AlphaLISA assays performed with four different peptidomimetics of the present invention (Comp. Nos. 205, 291, 298, and 322, with each bar chart representing a separate peptidomimetic labeled Figures 2A-2D, respectively), testing their IL-17A-IL-17R inhibitory activity. The signal is indicative of IL-17A-IL-17R binding. The IL-17A-IL-17R binding signal without any peptidomimetics was set as the baseline level (i.e., 100%).

[0072] Figures 3A-3D are exemplary bar charts showing results of indirect competitive ELISA assays performed with four different peptidomimetics of the present invention (Comp. Nos.

[0073] 205, 291, 298, and 322, with each bar chart representing a separate peptidomimetic labeled Figures 3A-3D, respectively), testing their IL-17A-IL-17R inhibitory activity. The signal, measured as absorbance at 655 nm (OD655), is indicative of IL-17A-IL-17R binding.

[0074] Figures 4A-4D are graphs representing the inhibitory effect of four different peptidomimetics (Comp. Nos. 205, 291, 298, and 322, with each bar chart representing a separate peptidomimetic labeled Figures 4A-4D, respectively) of the present invention on the IL-17-IL-17R interaction in live cells. Specifically, Figures 4A-4D show the IL-8 levels (as an IL- 17 activation / inhibition indicator) in the cell culture medium as a function of theconcentration of the peptidomimetics.

[0075] Figure 5 is a graph of Gro- Alpha cytokine levels, which indicate IL-17A inhibition. Gro- Alpha is a downstream effector chemokine of IL- 17, and as such is used to measure IL- 17 inhibition in vivo. Mice (n=5 per group) were intravenously administered a cyclic pentapeptidomimetic of the present invention or ixekizumab (anti IL-17A antibody), immediately followed by subcutaneous injection of IL-17A. Testing groups were as follows: vehicle alone with no subsequent injection of IL-17A (Vehicle); vehicle (IL- 17 A+ Vehicle); ixekizumab (IL-17A+Ixekizumab); Compound No. 125 (125+IL17A); Compound No. 194 (194+IL17A); Compound No. 205 (205+IL17A); Compound No. 217 (217+IL17A); and Compound No. 231 (231+IL17A). Ih post IL-17A injection, mice were bled and serum was tested for Gro-Alpha levels. Average Gro-Alpha cytokine concentration (pg / ml) is presented. *p < 0.05, **p < 0.01, ns= not significant.

[0076] DETAILED DESCRIPTION OF THE INVENTION

[0077] All terms used herein are as commonly used in the art, unless defined otherwise herein. In case of contradiction between the common definition and the definition of the present application, the definition herein is decisive.

[0078] The present invention provides cyclic penta-peptidomimetics comprising artificial amino acids that exhibit unexpected efficacy in inhibiting the interaction between IL- 17 and IL-17R. A large library of cyclic penta-peptidomimetics were designed and scanned for potential activity in-silico. The most promising subset were synthesized and tested, using a variety of techniques, for their activity in inhibiting the interactions of IL- 17 A, IL-17F and IL-17AF with IL-17R. As is demonstrated herein, the cyclic penta-peptidomimetics of the present invention are shown to be excellent inhibitors of IL- 17 activity, both in vitro as well as in vivo. In addition, the cyclic penta-peptidomimetics are shown to be potentially useful as orally available drugs. Thus, the cyclic penta-peptidomimetics of the present invention show tremendous promise as effective treatments for patients suffering from IL- 17 associated diseases, such as autoimmune and inflammatory diseases, for treatment of skin diseases and disorders. As such, use in cosmetic applications is also contemplated.

[0079] As used herein, the term “IL- 17”, unless expressly stated otherwise, refers to an IL-17A homodimer (“IL-17A"), an IL-17F homodimer (“IL-17F"), and / or an IL-17AF heterodimer (“IL-17AF"). IL-17Ais a member of the IL-17 family, and is a homodimeric glycoprotein witha molecular mass of 35 kDa. Each subunit of the IL-17A homodimer, named "chain A" and "chain B", is composed of a pair of anti-parallel P-sheets. In the IL-17AF heterodimer, the IL-17A subunit is referred to as "chain A" while the IL-17F subunit is referred to as "chain F". As used herein, the term “IL-17R” refers to the heterodimer of IL-17 receptor A (“IL- 17RA") and IL-17 receptor C (“IL-17RC”), unless expressly stated otherwise. Thus, the term "IL-17-IL-17R interaction” refers to an interaction of at least one of IL- 17 A, IL-17F, and IL-17AF with IL-17R. This interaction is considered to be responsible for the biological activity of the cytokine.

[0080] Amino Acids (AAs)

[0081] As used herein, the term "amino acid" ("AA") refers to any compound which contains both an amino (-NH2) and a carboxylic acid (-C(O)OH) functional group. The term “amino acid” also encompasses amino acid residues, which are amino acids in which at least one of the amino and carboxylic functional groups is linked to a neighboring compound by an amide bond.

[0082] The term "artificial amino acid" refers to an amino acid which is not a mammalian DNA-encoded amino acid, i.e., not one of the known 20 amino acids which are encoded by nucleic acid sequences as dictated by the genetic code and that are utilized by a ribosome in protein synthesis. As used herein, the term "artificial amino acid" also includes naturally-occurring non-proteinogenic amino acids (e.g., norvaline, ornithine, homocysteine, etc.) as well as well as amino acids that are in some species coded for by codons that are usually interpreted as stop codons and that are utilized by the ribosome (i.e., selenocysteine and pyrrolysine). Artificial amino acids include D-chirality configurations (i.e., enantiomers or D-amino acids) of DNA-encoded amino acids. The terms “unnatural amino acid”, “non-proteinogenic amino acid”, "modified amino acid" and "non-DNA-encoded amino acid" may be used interchangeably with the term "artificial amino acid". Isomers and structural homologs (e.g., homoserine, homotyrosine) of any of the amino acids are also included herein.

[0083] As used herein, the term "modified amino acid" refers to one of the 20 DNA-encoded amino acids or their D-enantiomer, which includes at least one substituent, as defined herein. Similarly, the term "amino acid derivative", e.g., "phenylalanine derivative", and the like, refers to a particular amino acid, which includes at least one substituent as described herein.

[0084] According to some embodiments, the artificial amino acids of the present invention comprise modified DNA-encoded AAs, D-chirality configurations of DNA-encoded amino acids, structural homologs of DNA-encoded AAs and / or modifications of the D-chiralityconfigurations. According to some embodiments, the DNA-encoded AAs, in modified form, from which the peptidomimetics according to the present invention are comprised, are selected from glycine, alanine, phenylalanine, tyrosine, serine, leucine, aspartate, glutamine, tryptophan, and cysteine. According to some embodiments, the D-chirality configurations of DNA-encoded amino acids, from which the peptidomimetics of the present invention are comprised, are selected from D-Alanine, D-Serine, D-Glutamine, and D-Glutamic acid. According to some embodiments, the peptidomimetics according to the present invention comprises at least one amino acid selected from D-Norleucine, D-Glutamine, D-Alanine, D-Phenylalanine, D-Aspartate, and D-Cysteine.

[0085] According to some embodiments, the modification of the AA or D-chirality configuration thereof, includes substitution of at least one hydrogen moiety / atom and / or at least one carbon moiety / atom with a moiety selected from the group consisting of hydroxy, methyl, dimethyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, carboxyl, cyano, nitro, halogen, guanidino, pyrrole, pyridyl, thienyl, tetrazole, thiazolyl, furyl, cyclo-propyl, cyclo-butyl, cyclohexyl, naphthyl, indanyl moieties, a PEG chain, a derivative thereof or a combination thereof. According to some embodiments, the modification is made to the side chain of the amino acid. According to some embodiments, the modification comprises cyclization of a side chain. For example, position 1 of Compound No. 287 is D-Gln(Pyr), in which the -NH2 of the glutamine side chain is cyclized to form a pyrrole group. According to some particular embodiments, the modification includes substitution of at least one hydrogen moiety / atom and / or at least one carbon moiety / atom with a moiety comprising at least one cyclic group. According to some embodiments, the moiety comprising at least one cyclic group is selected from cyclo-propyl, tetrazole, pyridyl, pyrrole, thienyl, thiazolyl, furyl, cyclo-butyl, cyclohexyl, naphthyl, a PEG chain, and indanyl. According to some embodiments, the modification of the DNA-encoded AA or D-chirality configuration thereof, includes substitution of at least one hydrogen moiety / atom and / or at least one carbon moiety / atom with a moiety selected from the group consisting of cyclo-propyl, cyclo-butyl, tetrazole, hydroxy, methyl, dimethyl, a PEG chain, indanyl, and pyridyl.

[0086] As used herein, the term "substituent" refers to a first atom or functional group that has replaced a second atom or functional group of an amino acid, wherein the second atom or functional group may be a hydrogen atom or any other molecule, compound or moiety. Suitable substituents include, without limitation, halo, hydroxy, mercapto, oxo, nitro, halogen, haloalkyl, alkyl, alkaryl, aryl, pyridyl, cyclo-propyl, cyclo-butyl, cyclohexyl, aralkyl, alkoxy, thioalkoxy,aryloxy, amino, cyano, guanidino, alkoxycarbonyl, amido, carboxy, methyl, methoxy, alkanesulfonyl, alkylcarbonyl, thienyl, thiazolyl, furyl, naphthyl, and indanyl functional groups, or a combination thereof.

[0087] As used herein, the term “cyclic group” refers to a carbon-containing ring made up of at least one of a 3 -membered cyclic group, a 4-membered cyclic group, a 5 -membered cyclic group, and a 6-membered cyclic group. Aromatic, non-aromatic, and heterocyclic rings are included within the scope of the invention. Higher membered cyclic groups are also encompassed in the term “cyclic group”. The term “cyclic conformation” may be used interchangeably with the term “cyclic group”.

[0088] According to some embodiments, at least one position of the peptidomimetic is occupied by an AA comprising at least one PEG substituent. According to some embodiments, at least one AA of position 2, position 4 and / or position 5 of the peptidomimetic is occupied by an AA comprising at least one PEG substituent. According to some embodiments, the AA comprising at least one PEG substituent is selected from Tyr(3-5-di-Iodo(PEG3Me)), Phe(3-OH(PEG3Me)), Tyr(PEG3Me), and Tyr(PEG7Me). Each possibility represents a separate embodiment. According to some embodiments, the at least one AA of position 2 comprising at least one PEG substituent is Phe(3-OH(PEG3Me)). According to some embodiments, the at least one AA of position 4 comprising at least one PEG substituent is selected from Tyr(3-5-di-Iodo(PEG3Me)), Tyr(PEG3Me), and Tyr(PEG7Me). Each possibility represents a separate embodiment. According to some embodiments, the at least one AA of position 5 comprising at least one PEG substituent is Tyr(PEG3Me).

[0089] According to some particular embodiments, the artificial amino acids are selected from the group consisting of: D-Alanine (D-Ala), D-Cyclopropylalanine (D-Ala(cPr)), D-Allothreonine (D-aThr), Allothreonine (aThr), R-2-aminohepatonic acid (D-Nle(Me)), D-Cyclopropylglycine (D-Gly(cPr)), D-4-pyridyl-alanine (D-Pal(4)), D-Glutamine (D-Gln), D-2-alpha- Aminobutyric-acid (D-Abu), L-2-pyridyl-alanine (Pal(2)), D-Leucine (3S-OH) (D-Leu(3S-OH)), D-N,N-pyrrolidinylglutamine (D-Gln(Pyr)), D-N,N-di-methylglutamine (D-Gln(NMe2)), D-N,N-di-methylasparagine (D-Asn(NMe2)), L-3-pyridyl-alanine (Pal(3)), Beta-Cyclobutyl-L-Alanine (Ala(cBu)), Cyclohexylalanine (Cha), 6-hydroxynorleucine (L-Nle(6-OH)), 6-m ethoxy -L-norleucine (L-Nle(6-OMe)), 2-Amino-3-(pyrazin-2-yl)propanoic-acid, 3-(5-pyrimidinyl)-L-alanine, 2-amino-3-(3,3-difluorocyclobutyl)propanoic acid (3-3-diF-Ala(cBu)), 2-amino-3-(5-fluoropyridin-3-yl)propanoic-acid, 4-Pyridazinealanine, Phe(3-CONH2), 3-(2-Tetrazolyl)-L-alanine, Phosphotyrosine (PhosphoTyr), (5)-2-amino-3-(4-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)propanoic acid (Tyr(PEG3Me)), ( )-3-(4-((2,5,8,ll,14,17,20-heptaoxadocosan-22-yl)oxy)phenyl)-2-aminopropanoic acid (Tyr(PEG7Me)),

[0090] (5r)-2-amino-3-(3,5-diiodo-4-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)propanoic acid (Tyr(3 -5 -di-Iodo(PEG3Me)), 3 -tri fl uorom ethoxy -L-homophenylalaine (homoPhe(3 -OCF 3)), 2 -trifluorom ethoxy -L-homophenylalaine (homoPhe(2-OCF3)), 4-trifluorom ethoxy -homophenylalaine (homoPhe(4-OCF3)), 2,3-dihydroxy-L-phenylalanine (Phe(2-3-di-OH)), 3,5-dibromo-L-4-pyridyl-alanine (L-4-pyridyl-alanine(3-5-di-Br)),

[0091] (5)-3-(3-((2,5,8, 1 l-tetraoxatridecan-13-yl)oxy)phenyl)-2-aminopropanoic acid (Phe(3-OH(PEG3Me)), 3 -methoxy -phenylalanine (Phe(3-OMe)), 3 -ethoxy -L-phenylalanine (Phe(3-OEt)), 2-methoxy-phenylalanine (Phe(2-OMe)), Leucine (3S-OH) (Leu(3S-OH)), D-2-alpha-Aminobutyric-acid(tetrazol-5-yl) (D-Abu(tetrazol-5-yl)), D-cysteine(5-Methyl-2H-tetrazole) (D-Cys(5-Methyl-2H-tetrazole)), 3,5-Di-Iodo-tyrosine (Tyr(3-5-di-Iodo)), (1-naphthyl)-alanine (1-Nal), 3-3-diphenyl-L-alanine (Dip), 2-(trifluoromethoxy)-phenylalanine (L-Phe(2-OCF3)), 2-nitro-phenylalanine (Phe(2-NO2)), 5-Bromo-2-fluoro-phenylalanine, pentafluorophenylalanine (Phe(F5)), 7- Azatry ptophan (L-(7-azaTrp)), 2-trifluoromethyl-phenylalanine (Phe(2-CF3)), 3 -(4-Quinolyl)-L- Alanine, L-2-indanylglycine (Gly(indan-2-yl)), 5-methoxy-L-norvaline (Nva(OMe)), 5-phenyl-L-norvaline (Nva(Ph)), Homoserine (Hse), 2-Amino-3-(7-methoxy-4-coumaryl)propionic acid (beta-(7-methoxy-coumarin-4-yl)-Ala), 4-pyridyl-alanine (Pal(4), homophenylalanine (hPhe), 3,5-Di-Bromophenylalanine (Phe(3-5-di-Br)), Cyclopropylalanine (Ala(cPr)), Homotyrosine (hTyr), 2,3-difluoro-L-homophenylalanine (hPhe(2-3-diF)), 2-hydroxyphenylalanine (Phe(2-OH)), 2-carbamoylphenylalanine (Phe(2-CONH2)), (S)-2-amino)-3-(6-trifluoromethyl-pyri din-3 -yl)propanoic acid (4-CF3-Pal(3)), (S)-2-amino)-3-(2-trifluoromethyl-pyridin-3-yl)propanoic acid (2-CF3-Pal(3)), 2-amino-4-[2-(trifluoromethyl)-4-pyridinyl]butanoic acid (3-CF3-hPal(4)), ornithine-2-chlorobenzyloxycarbonyl (Orn(Cbz(2-Cl)), Cys-[Meta-Xylene-mercaptoacetic-acid], (2S)-2-Amino-3-(3,3-difluorocyclobutyl)propanoic acid (3-3-diF-Ala(cBu)), O-Phenylhomoserine (Hse(Ph)), 2,6-difluoro-L-3-pyridyl-alanine (2-6-diF-Pal(3)) (2S)-2-amino-3-(2-m ethoxypyri din-3 -yl)propanoic acid (2-OCH3-Pal(3)), and beta-hydroxyphenylalanine (Phe(bR-OH)).

[0092] Some of the amino acids used in this invention are those which are available commercially or are available by routine synthetic methods. Certain amino acids may require special methods for preparation and / or for incorporation into the peptidomimetic, and either sequential, divergent or convergent synthetic approaches are useful in this invention. Naturalcoded amino acids and their derivatives are represented by three-letter codes according to IUPAC conventions. When there is no indication, the L isomer was used. The D isomers are indicated by “D” or "(D)" before the residue abbreviation or by using the lower case of the amino acid code.

[0093] Peptidomimetics

[0094] As used herein, the term "peptidomimetic" according to the present invention refers to a chain of AAs that contains at least one artificial amino acid. According to some embodiments, the peptidomimetic comprises a chain of AAs linked by peptide bonds, in which at least 20% of the AAs in the chain (e.g., at least one AA of the pentapeptide) are artificial amino acids.

[0095] According to some specific embodiments, the peptidomimetic consists of 5 AAs, referred to herein also as “pentapeptide”, “cyclic pentapeptide”, or "cyclic penta-peptidomimetic". According to some embodiments, the pentapeptide comprises 1, 2, 3, 4 or 5 artificial amino acids. Each possibility represents a separate embodiment. The term "cyclic penta-peptidomimetic" may be referred to "macrocycle" or "compound" throughout the specification as disclosed herein.

[0096] According to some embodiments, the peptidomimetic comprises 30% artificial amino acids, 40%, 50%, 60%, 70%, 80%, 90% artificial amino acids. Each possibility represents a separate embodiment of the invention.

[0097] The position numbers of the amino acids, i.e., position 1, position 2, etc., as used herein, are significant to establish the sequential order of the amino acids in the peptidomimetic. In a linear peptidomimetic, numbering is typically started from the reside at the N-terminus, referred to herein as "position 1 ", “first amino acid”, and the like and the position number of each amino acid in the peptide chain is determined according to the number of amino acids from the start of the chain. For the sake of illustration, the first amino acid is at position 1, the following amino acid which shares a peptide bond (i.e., amide bond) with the first amino acid is at position 2, and so on. As used herein, the terms “end of peptide”, “last / end amino acid”, and the like, refer to the amino acid which is located at the C-terminus end of the amino acid chain. The position of the last amino acid depends on the number of amino acids in the peptide / peptidomimetic. As an illustrative example, when the peptidomimetic consists of 5 AA, the last amino acid is defined as being at position 5. However, when the peptide contains a head-to-tail cyclization, the terms of "beginning" and "end" of the peptide (i.e., N-terminus and C-terminus) become irrelevant, as the peptide forms a continuous cycle. In such situations, and as in the presentinvention, the AA in the last position, for example position 5, is between the AA at position 4 and the AA at position 1.

[0098] As used herein, the term “peptide bond” refer to an amide bond between the carboxyl moiety of an amino acid and the amino moiety of the next amino acid, within a peptide or peptidomimetic amino acid chain.

[0099] For further clarification, and as explained above, a peptidomimetic consisting of 5 AAs includes 4 peptide bonds, i.e., a peptide bond between the AA at position 1 and the AA at position 2, a peptide bond between the AA at position 2 and the AA at position 3, etc. In the embodiments of the peptidomimetic having head-to-tail (C-terminus to N-terminus) cyclization, the peptide has an additional peptide bond between the AA at the 5th position (C-terminus) and the AA at position 1 (N-terminus), i.e., overall, 5 peptide bonds.

[0100] The peptidomimetics of the present invention may be produced by any synthetic method known in the art. Synthetic methods include exclusive solid phase synthesis, partial solid phase synthesis, fragment condensation, or classical solution synthesis. According to some embodiments, the cyclic peptidomimetics are synthesized by solid phase peptide synthesis. In some embodiments, peptidomimetics are purified by preparative high-performance liquid chromatography, or by other methods known in the art.

[0101] Conjugates of the peptidomimetics of the present invention, and an additional molecule, are also included within its scope, provided that the conjugate has similar or even improved properties compared to the parenteral compound. According to some embodiments, the conjugate comprises a cyclic penta-peptidomimetic described above and a carrier molecule. A conjugate according to the present invention comprises any cyclic penta-peptidomimetic according to the present invention, conjugated to a carrier molecule, protein or another moiety which improves the cyclic penta-peptidomimetic’s solubility, stability or permeability.

[0102] According to some embodiments, the conjugate comprises at least one non-proteinaceous moiety.

[0103] The carrier or other moiety may be connected, according to some embodiments, to a side chain of any amino acid of positions 1-5 of the cyclic penta-peptidomimetic, directly or through a spacer or linker. Each possibility represents a separate embodiment.

[0104] According to some embodiments, the conjugate comprises one or more permeabilityenhancing moieties. Any moiety known in the art to facilitate actively or passively or enhance permeability of the compound into cells or through biological membranes may be used.According to some embodiments, the conjugate comprises one or more stabilizing moieties.

[0105] “Permeability” refers to the ability of an agent or substance to penetrate, pervade, or diffuse through a barrier, membrane, or a skin layer. A “cell permeability” or a “cell-penetration” moiety refers to any molecule known in the art which is able to facilitate or enhance penetration of molecules through membranes. Non-limitative examples of a permeability-enhancing moiety include: hydrophobic moieties such as fatty acids, steroids and bulky aromatic or aliphatic compounds; moieties which may have cell-membrane receptors or carriers, such as steroids, vitamins and sugars, natural and non-natural amino acids and transporter peptides. According to some embodiments, the hydrophobic moiety is a lipid moiety or an amino acid moiety. Permeability of a cyclic pentapeptidomimetic of the present invention or a conjugate thereof may be determined by any method known in the art.

[0106] According to some embodiments, the peptidomimetic or a conjugate comprising the peptidomimetic, consists of up to 20 AAs. According to some further embodiments, the peptidomimetic or conjugate consists of up to 15 AAs, up to 12 AAs, up to 10 AAs, up to 9 AAs, up to 8 AAs, up to 7 AAs, up to 6 AAs, or up to 5 AAs. Each possibility represents a separate embodiment of the invention. According to some embodiments, the peptidomimetic or conjugate consists of between 5 and 10 AAs, including each value therebetween. According to some embodiments, the peptidomimetic or conjugate consists of between 3 and 12 AAs, between 3-10 AAs, between 3-7 AAs, between 3-5 AAs, between 4 and 10 AAs, between 4 and 8 AAs, between 4 and 6 AAs, between 5 and 12 AAs, between 5 and 8 AAs, or between 5 and 7 AAs. Each possibility represents a separate embodiment of the invention.

[0107] Water soluble, synthetic polymers, particularly polyalkylene glycols (PEGs), are widely used to conjugate therapeutically active molecules. These therapeutic conjugates have been shown to alter pharmacokinetics favorably by prolonging circulation time and decreasing clearance rates, decreasing systemic toxicity, and in several cases, displaying increased clinical efficacy. The process of covalently conjugating polyethylene glycol, PEG, to therapeutically active molecules is commonly known as "PEGylation". Where appropriate, the abbreviation PEG is used in combination with a numeric suffix, which indicates the number of repeating ethylene glycol units.

[0108] According to some embodiments, the cyclic penta-peptidomimetic of the present invention is PEGylated. According to some embodiments, a PEG chain is connected, directlyor through a spacer or linker, to any of positions 1-5 of the cyclic penta-peptidomimetic. Each possibility represents a separate embodiment. In some embodiments, the length of the PEG chain is between 8-20 units, including each value within the specified range. In some embodiments, the length of the PEG chain is between 8-16 units, including each value within the specified range. In some embodiments, the length of the PEG chain is between 10-14 units, including each value within the specified range.

[0109] According to some embodiments, the peptidomimetic includes at least one non-amide bond. According to some embodiments, the peptidomimetic includes at least one additional AA, which is bonded to one of the AAs of the peptidomimetic via a non-peptide bond. Further embodiments of the at least one additional AA are set out herein in the context at position 5 of the peptidomimetic.

[0110] According to some embodiments, the peptidomimetic comprises 1 artificial AA. According to some embodiments, the peptidomimetic comprises 2 artificial AAs. According to some embodiments, the peptidomimetic comprises 3 artificial AAs. According to some embodiments, the peptidomimetic comprises 4 artificial AAs. According to some embodiments, the peptidomimetic comprises 5 artificial AAs. According to some embodiments, the peptidomimetic consists of 5 AAs, of which 2 AAs are artificial. According to some further embodiments, the peptidomimetic consists of 5 AAs, of which 3 AAs, 4 AAs, or 5AAs are artificial. Each possibility represents a separate embodiment of the invention. According to some particular embodiments, the peptidomimetic consists of only artificial AAs.

[0111] According to some embodiments, the peptidomimetics comprise at least one AA having at least one cyclic group. According to some embodiments, the peptidomimetics comprise at least 2, at least 3, or at least 4 AAs having at least one cyclic group. According to some embodiments, at least one of the cyclic groups is aromatic. According to some embodiments, at least one of the cyclic groups is heterocyclic. According to some embodiments, at least one of the cyclic groups is a 3 to 6-membered cyclic group. According to some embodiments, the peptidomimetic consists of 5 AAs, of which one AA has a cyclic group. According to some further embodiments, the peptidomimetic consists of 5 AAs, of which 2, 3, or 4 AAs have a cyclic group. Each possibility represents a separate embodiment of the invention.

[0112] According to some embodiments, the at least one AA comprising at least one aromatic group is at position 2, position 4 and / or position 5 of the peptidomimetic. According to further embodiments, the at least one AA comprising at least one aromatic moiety is at position 2,position 4 and / or position 5 of the peptidomimetic. According to some specific embodiments, the at least one AA comprising at least one aromatic moiety is at position 5 of the peptidomimetic.

[0113] According to some embodiments, at least one of the AAs in the peptidomimetic is alanine, in L or D chirality, or a derivative thereof. According to some embodiments, the alanine derivative comprises at least one cyclic group in its side-chain. As used herein, the terms “alanine with at least a cyclic substituent” and “alanine with at least a cyclic moiety” refer to amino acids comprising alanine bonded at least to one or more cyclic groups, including the amino acid phenylalanine and modifications or derivatives thereof.

[0114] According to some embodiments, at least one of the AAs in the peptidomimetic is a phenylalanine derivative. According to some embodiments, the at least one phenylalanine derivative is in at least one at position 2, position 4, and / or position 5 of the peptidomimetic.

[0115] According to some embodiments, at least one of the AA residues is glycine derivative. According to some embodiments, the at least one glycine or derivative thereof is in at least one at position 1 and position 5 of the peptidomimetic. It is to be understood that the derivatization of glycine may impart chirality to the derivative. According to some embodiments, the glycine derivative is of L-chirality. According to some embodiments, the glycine derivative is of D-chirality.

[0116] According to some embodiments, at least one of position 1, position 2, position 4, and position 5 of the peptidomimetic is occupied by an AA comprising at least one cyclic group. According to some embodiments, at least one at position 2, position 4, and position 5 of the peptidomimetic is occupied by an AA comprising at least one aromatic moiety. According to some particular embodiments, at least one at position 4 and position 5 of the peptidomimetic is occupied by an AA comprising at least one aromatic moiety. According to some embodiments, position 4 of the peptidomimetic is occupied by an AA comprising at least one aromatic moiety.

[0117] According to further particular embodiments, position 5 of the peptidomimetic is occupied by an AA comprising at least one aromatic moiety.

[0118] According to some embodiments, the peptidomimetic or conjugate has a conformation selected from a linear conformation, linear confirmation comprising a cyclic chain or a cyclic conformation. According to some particular embodiments, the peptidomimetic has a cyclic conformation. As used herein, the term “cyclic peptidomimetic” refers to a peptidomimetic having a chemical structure including a ring or cycle formed by at least 3 covalently bondedamino acids. The cyclic peptidomimetic comprises at least one cycle-forming linkage which forms a bond, referred to herein as a “cyclization bond”, between a first amino acid and another amino acid within the same chain. According to some embodiments, the cyclization bond is formed between the first amino acid and the fifth amino acid.

[0119] According to some embodiments, the cyclization bond if formed between the free carboxyl moiety of the last AA of the peptidomimetic and a free amino moiety of the first compound of the peptidomimetic. According to some particular embodiments, the cyclization bond if formed between the free carboxyl moiety of the last AA of the peptidomimetic and the free amino moiety of the first AA of the peptidomimetic. According to some embodiments, the cyclization bond is formed between the AA at position 1 of the peptidomimetic and the AA at position 5 of the peptidomimetic (herein 5 to 1 or 1 to 5 cyclization). It is to be understood, that according to some exemplary embodiments when the peptidomimetic consists of 5 AA (i.e., pentapeptide), the 5 to 1 cyclization is between position 1 and the last position of the peptidomimetic, i.e., head-to-tail cyclization (optionally referred to also as “C to N cyclization” or "N to C cyclization"). Figure 1 provides the atomic structures of some of the exemplary compounds of the invention.

[0120] Without being bound by any mechanism or theory of action, it is contemplated that the cyclic conformation of the peptidomimetics is advantageous for conferring enzymatic, pH and / or thermo-stability, intestinal permeability, and oral bioavailability while retaining, or even improving, the biological activity. Furthermore, cyclization leads to conformationally constrained conformations that are preferred for binding and activity. In particular, cyclic peptides eliminate terminal charges and are more spatially confined, thus reducing the enzyme mediated degradation propensity and lowering the loss of conformational entropy upon binding.

[0121] Peptidomimetic synthesis

[0122] In solid phase peptide synthesis, the peptide is synthesized from the C-terminus to the N-terminus, namely, the last amino acid residue is attached first to the solid phase, and the other residues are built on the N-terminus of this residue through its N-terminus, and relies on the orthogonal protection of reactive groups but this may vary in other synthesis methods. According to some embodiments, the peptidomimetic is synthesized according to the order of the AA from position 5 to position 1, i.e., from the C-terminus to the N-terminus of the peptide.

[0123] Solid phase peptide synthesis procedures are well known in the art and further described in "Solid-Phase Synthesis: A Practical Guide", Ed. Steven A. Kates and Fernando Albericio,CRC Press; 1st Edition (2000). A skilled artesian may synthesize any of the cyclic penta -peptidomimetics of the present invention using any method known in art. For example, the cyclic penta-peptidomimetics may be synthesized using an automated peptide synthesizer using standard chemistry such as, for example, t-Boc or Fmoc chemistry. The methods include exclusive solid phase synthesis, partial solid phase synthesis, fragment condensation, and classical solution synthesis.

[0124] Coupling of the amino acids in solid phase peptide chemistry can be achieved by means of a coupling agent such as, but not limited, to dicyclohexy carbodiimide (DCC), bis(2-oxo-3-'-oxazolidinyl) phosphinic chloride (BOP-CI), benzotriazolyl-N-oxytrisdimethyl-aminophosphonium hexafluoro phosphate (BOP), 1 -oxo- 1 -chlorophospholane (Cpt-Cl), hydroxybenzotriazole (HOBT), or mixtures thereof.

[0125] The use of additional coupling reagents including, but not limited to: PyBOP (Benzotri azole- 1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), PyBrOP (Bromo-tris-pyrrolidino-phosphonium hexafluoro-phosphate), HBTU (2-(lH-Benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluoro-phosphate), TBTU (2-(lH-Benzotriazole-l-yl)-1, 1,3,3-tetramethyluronium tetrafluoroborate), may be also utilized for synthesizing the peptide compounds of the present invention.

[0126] Additional coupling chemistries may be used, such as pre-formed urethane-protected N-carboxy anhydrides (UNCAs), pre-formed acyl halides, and most preferably, acyl chlorides.

[0127] Such coupling may take place at room temperature or elevated temperatures, in solvents such as toluene, DCM (dichloromethane), DMF (dimethylformamide), DMA (dimethylacetamide), NMP (N-methyl pyrrolidinone), dioxane, tetrahydrofuran, diglyme and 1,3 di chloropropane, or mixtures of the above.

[0128] Synthesized cyclic penta-peptidomimetics of the present invention can be purified by preparative high-performance liquid chromatography.

[0129] The term "solid phase" as used herein is intended to mean an insoluble polymeric matrix whereupon a molecule, e.g., a cyclic penta-peptidomimetic, can be synthesized or coupled with or without a linker or spacer in-between. Solid support resins are typically used in peptide synthesis. These polymers are generally employed in the form of beads. Polymer resins preferred for peptide synthesis are polystyrenes, polyacrylamides and the like, specifically copolymers of styrene and divinylbenzene. Prior to the coupling with the first amino acid, the solid support resin contains surface functionality or can be derivatized to contain surfacefunctionality which can interact with an amine group of an amino acid (or peptide) so as to attach the amino acid (or peptide) to the support directly or indirectly through the amine group of the peptide. The term “solid phase resin” as used herein is not limited to the parent commercial derivatized resins, in their form prior the first coupling of amino acid or peptide. Rather, after the first coupling of amino acid and during the peptide synthesis, while the resin is coupled to a growing peptide, the resin is still considered a solid phase resin.

[0130] Position 1 of the Peptidomimetic

[0131] According to some embodiments position 1 is occupied by an AA having D-chirality. According to some embodiments, position 1 is occupied by an AA selected from the group consisting of D-Gln, D-Gly(cPr), D-Ala(cPr), D-aThr, D-Ala, D-Leu(3S-OH), D-Pal(4), D-Abu, D-Nle(Me), D-Gln(Pyr), D-Gln(NMe2), and D-Asn(NMe2). Each possibility represents a separate embodiment of the invention.

[0132] According to some embodiments, position 1 is occupied by an AA selected from the group consisting of D-Ala, D-Gly(cPr), D-Gln, D-Pal(4), D-aThr, D-Ala(cPr), D-Nle(Me), D-Leu(3S-OH). According to some embodiments, position 1 is occupied by an AA selected from the group consisting of D-Gly(cPr), D-Ala(cPr), D-Ala, D-Pal(4), and D-Gln. Each possibility represents a separate embodiment of the invention.

[0133] According to some embodiments, position 1 of the peptidomimetic is occupied by an AA having a hydrophobic aliphatic moiety. According to some embodiments, the AA having a hydrophobic aliphatic moiety is selected from D-Ala, D-Abu, D-Gly(cPr), D-Ala(cPr), and D-Nle(Me). Each possibility represents a separate embodiment of the invention.

[0134] According to some embodiments, position 1 of the peptidomimetic is occupied by an AA having an aromatic moiety. According to some embodiments, the AA having an aromatic moiety is selected from D-Pal(4), beta-(2-furyl)-D-Ala, and D-hPhe. Each possibility represents a separate embodiment of the invention.

[0135] According to some embodiments, position 1 of the peptidomimetic is occupied by an AA having a hydrophilic moiety. According to some embodiments, the AA having a hydrophilic moiety is selected from D-aThr, D-Ser, D-Gln, D-Gln(Pyr), D-Gln(NMe2), D-Asn(NMe2) and D-Leu(3S-OH). Each possibility represents a separate embodiment of the invention.

[0136] According to some embodiments, position 1 of the peptidomimetic is occupied by an AA which having a cyclic substituent. According to some embodiments, alanine or thederivative thereof having at least a cyclic substituent is selected from D-Pal(4), D-Gly(cPr), D-Ala(cPr), and D-Gln(Pyr).

[0137] According to some embodiments, the peptidomimetic includes the AA D-Gly(cPr) at position 1. According to some embodiments, the peptidomimetic includes the AA D-Ala(cPr) at position 1.According to some embodiments, the peptidomimetic includes the AA D-Ala at position 1. According to some additional embodiments, the peptidomimetic includes the AAD-Pal(4) at position 1. According to some additional embodiments, the peptidomimetic includes the AA D-Gln at position 1.

[0138] Position 2 of the Peptidomimetic

[0139] According to some embodiments, position 2 is occupied by an amino acid selected from the group consisting of: Pal(3), aThr, Ala(cPr), Phe(3-OMe), Phe(3-OH(PEG3Me)), Ala(cBu), L-Nle(6-OH), L-Nle(6-0me), Nva(OMe), 3 -ethoxy -L-phenylalanine, Leu(3S-OH), Cha, 2-Amino-3-(pyrazin-2-yl)propanoic-acid, 3-(5-pyrimidinyl)-L-alanine, Hse, 3-3-diF-Ala(cBu), 2-amino-3-(5-fluoropyridin-3-yl)propanoic-acid, 4-Pyridazinealanine, PheQ-CONTL), and 3-(2-Tetrazolyl)-L-alanine. Each possibility represents a separate embodiment of the invention. According to some embodiments, the amino acid at position 2 of the peptidomimetic is selected from the group consisting of 2-Amino-3-(pyrazin-2-yl)propanoic-acid, 3-(2-Tetrazolyl)-L-alanine, 3-(5-pyrimidinyl)-L-alanine, 3-3-diF-Ala(cBu), 3 -ethoxy -L-phenylalanine, Ala(cBu), Ala(cPr), Cha, Hse, Leu(3S-OH), Pal(3), Phe(3-CONH2), Phe(3-OH(PEG3Me)), Phe(3-OMe), and aThr. Each possibility represents a separate embodiment of the invention. According to some embodiments, the amino acid at position 2 of the peptidomimetic is selected from the group consisting of Pal(3), Ala(cPr), Ala(cBu), Cha, 2-Amino-3-(pyrazin-2-yl)propanoic-acid, and aThr. Each possibility represents a separate embodiment of the invention. According to some embodiments, the amino acid at position 2 of the peptidomimetic is aThr or Pal(3). Each possibility represents a separate embodiment.

[0140] According to some embodiments, position 2 of the peptidomimetic is occupied by Pal(3). According to some embodiments, position 2 of the peptidomimetic is occupied by Ala(cPr). According to some embodiments, position 2 of the peptidomimetic is occupied by Ala(cBu). According to some embodiments, position 2 of the peptidomimetic is occupied by Cha. According to some embodiments, position 2 of the peptidomimetic is occupied by 2-Amino-3-(pyrazin-2-yl)propanoic-acid. According to some embodiments, position 2 of the peptidomimetic is occupied by aThr.According to some embodiments, position 2 of the peptidomimetic is occupied by an AA comprising at least one group selected from an aromatic moiety, an aliphatic moiety, and a cyclo-aliphatic moiety.

[0141] According to some embodiments, position 2 of the peptidomimetic is occupied by an AA comprising an aromatic moiety. According to some embodiments, the AA comprising an aromatic moiety is selected from Pal(3), Phe(3-OMe), Phe(3-OH(PEG3Me)), 3-ethoxy-L-phenylalanine, 2-Amino-3-(pyrazin-2-yl)propanoic-acid, 3-(5-pyrimidinyl)-L-alanine, 2-amino-3-(5-fluoropyridin-3-yl)propanoic-acid, 4-Pyridazinealanine, Phe(3-CONH2), and 3-(2-Tetrazolyl)-L-alanine. Each possibility represents a separate embodiment.

[0142] According to some embodiments, position 2 of the peptidomimetic is occupied by an AA comprising a cyclo-aliphatic moiety. According to some embodiments, the AA comprising a cyclo-aliphatic moiety is selected from Ala(cPr), Ala(cBu), 3-3-diF-Ala(cBu), and Cha. Each possibility represents a separate embodiment.

[0143] According to some embodiments, position 2 of the peptidomimetic is occupied by an AA comprising an aliphatic side-chain. According to some embodiments, the AA comprising an aliphatic side-chain is selected from aThr, Nle(6-0me), Nva(OMe), Leu(3S-OH), Hse, and Nle(6-OH). Each possibility represents a separate embodiment.

[0144] According to some embodiments, the peptidomimetic includes at position 2 an artificial AA which is an alanine with at least a cyclic group, selected from the group consisting Cha, Pal(3), Ala(cBu), Ala(cPr), 3-3-diF-Ala(cBu), Phe(3-OMe), 3 -ethoxy -L-phenylalanine 4-Pyridazinealanine, Phe -CONFE), 3-(2-Tetrazolyl)-L-alanine, 2-Amino-3-(pyrazin-2-yl)propanoic-acid, and 3-(5-pyrimidinyl)-L-alanine. Each possibility represents a separate embodiment.

[0145] According to some embodiments, the peptidomimetic includes at position 2 an artificial AA which is a derivative of phenylalanine selected from the group consisting of Phe(3-OMe), Phe(3-OH(PEG3Me)), 3 -ethoxy -L-phenylalanine, and PheQ-CONFE). Each possibility represents a separate embodiment. According to some embodiments, the peptidomimetic includes at position 2 an AA which comprises a heterocycle. According to some embodiments, the peptidomimetic includes at position 2 an AA which comprises a heterocycle selected from the group consisting of Pal(3), 2-Amino-3-(pyrazin-2-yl)propanoic-acid, 3-(5-pyrimidinyl)-L-alanine, 2-amino-3-(5-fluoropyridin-3-yl)propanoic-acid, 4-Pyridazinealanine, and 3-(2-Tetrazolyl)-L-alanine. Each possibility represents a separate embodiment.Without being bound by theory or mechanism of action, it is contemplated that occupying position 2 of the peptidomimetic with an AA that is space-filling, such as Pal(3) is particularly advantageous, as this AA is modelled to effectively fill the hydrophobic IL-17 pocket space, while receiving a hydrogen bond.

[0146] Position 3 of the Peptidomimetic

[0147] According to some embodiments, position 3 is occupied by an AA selected from D-Abu(tetrazol-5-yl) and D-Cys(5-Methyl-2H-tetrazole)). Each possibility represents a separate embodiment of the invention. According to some embodiments, position 3 is occupied by an AA having D-chirality. According to some embodiments, position 3 is occupied by an AA having an anionic residue and / or a cluster of negative atomic partial charges at pH 7.4.

[0148] According to the principles of the present invention, one of the criteria used by the algorithm employed for identifying peptidomimetics having improved bioavailability is minimizing complete charges on the peptidomimetics, while dispersing the charge over several atoms as partial charges. As is well-established in the art, peptidomimetics and other peptides that include charged moieties have reduced absorbance by the intestines, thereby limiting their use as oral drugs. Tetrazoles are neutral in the pH of the gastrointestinal tract, thereby improving absorbance by the intestines, as is exemplified by orally available small molecule drugs that contain tetrazoles, such as losartan and candesartan. According to some embodiments, the anionic moiety at pH 7.4 is replaced with a neutral one which contains atoms of a negative partial charge. According to some embodiments, the amino acid at position 3 has a tetrazole, providing a cluster of negative atomic partial charges. According to some embodiments, the negative atomic partial charges are defined by the AMBER Force Field. Negative partial charges are caused by the uneven distribution of electrons in chemical bonds, with bonds between a strong electronegative atom and less electronegative atoms causing a negative partial charge on the more electronegative atom. According to some embodiments, the amino acid at position 3 of the peptidomimetic is selected from D-Abu(tetrazol-5-yl) and D-Cys(5-Methyl-2H-tetrazole). According to other embodiments, the amino acid at position 3 of the peptidomimetic is D-Abu(tetrazol-5-yl). According to other embodiments, the amino acid at position 3 of the peptidomimetic is D-Cys(5-Methyl-2H-tetrazole).

[0149] According to some embodiments, position 3 is occupied by an AA having D-chirality and an anionic residue and / or a cluster of negative atomic partial charges at pH 7.4. Accordingto some embodiments, the AA has D-chirality and an anionic residue and / or a cluster of negative atomic partial charges at pH 7.4.

[0150] Without being bound by theory or mechanism of action, it is contemplated that the effectivity of the residues occupying position 3 is at least partially due to an electrostatic interaction thereof with the lysine at position 114 in chain A of the IL- 17 protein.

[0151] Position 4 of the Peptidomimetic

[0152] According to some embodiments, position 4 of the peptidomimetic is occupied by an amino acid selected from the group consisting of Phe(2-OMe), Nva(Ph), Tyr(3-5-di-Iodo), L-Phe(2-OCF3), Phe(2-OH), homoTyr, Dip, Abu(4-pyridyl), Cys-[Meta-Xylene-mercaptoacetic-acid], Phe(2-NO2), 5-bromo-2-fluoro-phenylalanine, PhosphoTyr, Tyr(PEG3Me), Tyr(PEG7Me), Tyr(3-5-di-Iodo(PEG3Me)), Phe(bR-OH), Phe(3-5-di-Br), homoPhe(3-OCF3), homoPhe(2-OCF3), homoPhe(4-OCF3), Phe(2-3-di-OH), Phe(F5), L-4-pyridyl-alanine(3-5-di-Br), Hse(Ph), 2-6-diF-Pal(3), 2-OCH3-Pal(3). Each possibility represents a separate embodiment of the invention. According to some embodiments, position 4 of the peptidomimetic is occupied by an amino acid selected from the group consisting of 2-6-diF-Pal(3), Cys-[Meta-Xylene-mercaptoacetic-acid], Dip, Hse(Ph), L-4-pyridyl-alanine(3-5-di-Br), L-Phe(2-OCF3), Nva(Ph), Phe(2-NO2), Phe(2-OMe), Phe(3-5-di-Br), Phe(F5), Phe(bR-OH), Tyr(3-5-di-Iodo), Tyr(3-5-di-Iodo(PEG3Me)), homoPhe(2-OCF3), homoPhe(3-OCF3), and homoPhe(4-OCF3). Each possibility represents a separate embodiment of the invention. According to some embodiments, the amino acid at position 4 of the peptidomimetic is selected from L-Phe(2-OCF3), Dip, Phe(2-NO2), Tyr(3-5-di-Iodo(PEG3Me)), and Phe(F5). Each possibility represents a separate embodiment of the invention.

[0153] According to some embodiments, position 4 of the peptidomimetic is occupied by an AA having L-chirality. According to some embodiments, position 4 of the peptidomimetic is occupied by an AA comprising at least one aromatic moiety. According to some embodiments, position 4 of the peptidomimetic is occupied by an AA comprising a single aromatic moiety. According to some embodiments, the AA having a single aromatic moiety is selected from Phe(2-OMe), Nva(Ph), Tyr(3-5-di-Iodo), L-Phe(2-OCF3), Phe(2-OH), homoTyr, Abu(4-pyridyl), Cys-[Meta-Xylene-mercaptoacetic-acid], Phe(2-NO2), 5-bromo-2-fluoro-phenylalanine, PhosphoTyr, Tyr(PEG3Me), Tyr(PEG7Me), Tyr(3-5-di-Iodo(PEG3Me)), Phe(bR-OH), Phe(3-5-di-Br), homoPhe(3-OCF3), homoPhe(2-OCF3), homoPhe(4-OCF3),Phe(2-3-di-OH), Phe(F5), 2-6-diF-Pal(3), 2-OCH3-Pal(3), L-4-pyridyl-alanine(3-5-di-Br), and Hse(Ph). Each possibility represents a separate embodiment of the invention.

[0154] According to some embodiments, position 4 of the peptidomimetic is occupied by an AA having more than one aromatic moiety. According to some embodiments, the AA having more than one aromatic moiety is Dip.

[0155] According to some embodiments, position 4 of the peptidomimetic is occupied by an AA having a modified 6-membered aromatic moiety. According to some embodiments, the AA having a modified aromatic moiety is selected from Phe(2-OMe), Tyr(3-5-di-Iodo), L-Phe(2-OCF3), Phe(2-OH), Cys-[Meta-Xylene-mercaptoacetic-acid], Phe(2-NO2), 5-bromo-2-fluoro-phenylalanine, PhosphoTyr, Tyr(PEG3Me), Tyr(PEG7Me), Tyr(3-5-di-Iodo(PEG3Me)), Phe(3-5-di-Br), homoPhe(3-OCF3), homoPhe(2-OCF3), homoPhe(4-OCF3), Phe(2-3-di-OH), Phe(F5), 2-6-diF-Pal(3), and 2-OCH3-Pal(3). Each possibility represents a separate embodiment. According to some particular embodiments, the AA having a modified 6-membered aromatic moiety is selected from L-Phe(2-OCF3), Phe(2-NO2), Tyr(3-5-di-Iodo(PEG3Me)), and Phe(F5). Each possibility represents a separate embodiment.

[0156] According to some further embodiments, position 4 of the peptidomimetic is occupied by an AA comprising an aromatic ring with a halogenated modification. According to some embodiments, the AA comprising an aromatic ring with a halogenated modification is selected from Tyr(3-5-di-Iodo), L-Phe(2-OCF3), 5-bromo-2-fluoro-phenylalanine, Tyr(3-5-di-Iodo(PEG3Me)), Phe(3-5-di-Br), homoPhe(3-OCF3), homoPhe(2-OCF3), homoPhe(4-OCF3), Phe(F5), L-4-pyridyl-alanine(3-5-di-Br), and 2-6-diF-Pal(3).

[0157] According to some embodiments, the AA at position 4 of the peptidomimetic comprises a PEG modification. According to some embodiments, the peptidomimetic includes at position 4 an AA which is a tyrosine derivative. According to some embodiments, the tyrosine derivative is selected from Tyr(3-5-di-Iodo), homoTyr, PhosphoTyr, Tyr(PEG3Me), Tyr(PEG7Me), and Tyr(3-5-di-Iodo(PEG3Me)). Each possibility represents a separate embodiment of the invention. According to some embodiments, the tyrosine derivative comprises a PEG molecule. According to some embodiments, the tyrosine derivative comprises a PEG molecule is selected from Tyr(PEG3Me), Tyr(PEG7Me), and Tyr(3-5-di-Iodo(PEG3Me)). According to some embodiments, the tyrosine derivative at position 4 is Tyr(3-5-di-Iodo) or a derivative thereof comprising a PEG molecule. According to some embodiments, the AA at position 4 of thepeptidomimetic is Tyr(3,5-di-Iodo) or a PEG substituted residue, including but not limited to Tyr(3-5-di-Iodo(PEG3Me)).

[0158] According to some embodiments, the peptidomimetic includes at position 4 an artificial AA which is an alanine derivative with at least a cyclic substituent. According to some embodiments, the alanine derivative with at least a cyclic substituent is selected from the group consisting of Phe(2-OMe), L-Phe(2-OCF3), Phe(2-OH), Phe(2-NO2), 5-bromo-2-fluoro-phenylalanine, Phe(bR-OH), Dip, Phe(3-5-di-Br), homoPheQ-OCFs), homoPhe(2-OCF3), homoPhe(4-OCF3), Phe(2-3-di-OH), Phe(F5), L-4-pyridyl-alanine(3-5-di-Br), 2-6-diF-Pal(3), and 2-OCH3-Pal(3). Each possibility represents a separate embodiment.. According to some particular embodiments, the alanine derivative is selected from L-Phe(2-OCF3), Dip, Phe(2-NO2), and Phe(F5). Each possibility represents a separate embodiment of the invention.

[0159] According to some embodiments, the peptidomimetic includes at position 4 an artificial AA which is a phenylalanine derivative. According to some embodiments, the peptidomimetic includes at position 4 an artificial AA which is a phenylalanine derivative selected from the group consisting of Phe(2-OMe), L-Phe(2-OCF3), Phe(2-OH), Phe(2-NO2), 5-bromo-2-fluoro-phenylalanine, Phe(bR-OH), Phe(3-5-di-Br), homoPhe(3-OCF3), homoPhe(2-OCF3), homoPhe(4-OCF3), Phe(2-3-di-OH), and Phe(F5). According to some embodiments, the phenylalanine derivative is selected from L-Phe(2-OCF3), Phe(2-NO2), and Phe(F5). Each possibility represents a separate embodiment of the invention.

[0160] Without being bound by theory or mechanism of action, it is contemplated that an advantageous function of the AA which occupies position 4 in the inhibition of IL-17A is space filling. Specifically, volumetric modifications of the aromatic rings of the AA generally show high p(ICso) contributions, as measured at least by ELISA or AlphaLISA.

[0161] Position 5 of the Peptidomimetic

[0162] According to some embodiments, position 5 of the peptidomimetic is occupied by an amino acid selected from the group consisting of Phe(2-CF3), L-(7-azaTrp), Gly(indan-2-yl), L-Phe(2-OCF3), Pal(2), Pal(4), beta-(7-methoxy-coumarin-4-yl)-Ala, 1-Nal, hPhe, 3-(4-Quinolyl)-L-Alanine, hPhe(2-3-diF), Phe(2-CONH2), 4-CF3-Pal(3), Om(Cbz(2-Cl)), 2-CF3-Pal(4), Tyr(PEG3Me), 3-CF3-hPal(4), and Dip. Each possibility represents a separate embodiment of the invention. According to some embodiments, position 5 of the peptidomimetic is occupied by an amino acid selected from the group consisting of 1-Nal, 2-CF3-Pal(4), 3-(4-Quinolyl)-L-alanine, Dip, Gly(indan-2-yl), L-(7-azaTrp), Gly(indan-2-yl), L-Phe(2-OCF3), Orn(Cbz(2-Cl)), Phe(2-CF3), Tyr(PEG3Me), hPhe, and hPhe(2-3-diF). Each possibility represents a separate embodiment. According to some embodiments, position 5 of the peptidomimetic is occupied by an amino acid selected from Phe(2-CF3), L-Phe(2-OCF3), 1-Nal, hPhe(2-3-diF), Gly(indan-2-yl), 3-(4-Quinolyl))-L-alanine, and Om(Cbz(2-Cl)). Each possibility represents a separate embodiment of the invention. According to some embodiments, the amino acid at position 5 of the peptidomimetic is selected from Gly(indan-2-yl) and Phe(2-CF3). Each possibility represents a separate embodiment of the invention.

[0163] According to some embodiments, position 5 of the peptidomimetic is occupied by Phe(2-CF3). According to some embodiments, position 5 of the peptidomimetic is occupied by L-Phe(2-OCF3). According to some embodiments, position 5 of the peptidomimetic is occupied by 1-Nal. According to some embodiments, position 5 of the peptidomimetic is occupied by hPhe(2-3-diF). According to some embodiments, position 5 of the peptidomimetic is occupied by Gly(indan-2-yl). According to some embodiments, position 5 of the peptidomimetic is occupied by 3-(4-Quinolyl))-L-alanine. According to some embodiments, position 5 of the peptidomimetic is occupied by Om(Cbz(2-Cl)).

[0164] According to some embodiments, position 5 of the peptidomimetic is occupied by an AA comprising an aromatic moiety. According to some embodiments, position 5 of the peptidomimetic is occupied by an AA comprising an aromatic moiety with a halogenated modification. According to some embodiments, position 5 of the peptidomimetic is occupied by an AA comprising an aromatic moiety with a halogenated modification selected from Phe(2-CF3), L-Phe(2-OCF3), hPhe(2-3-diF), 4-CF3-Pal(3), Om(Cbz(2-Cl)), 2-CF3-Pal(4), and 3-CF3-hPal(4). Each possibility represents a separate embodiment.

[0165] According to some embodiments, the peptidomimetic includes at position 5 an artificial AA which is a phenylalanine derivative. According to some embodiments, the peptidomimetic includes at position 5 an artificial AA which is a phenylalanine derivative selected from the group consisting of Phe(2-CF3), L-Phe(2-OCF3), hPhe, hPhe(2-3-diF), and Phe(2-CONH2). Each possibility represents a separate embodiment.

[0166] According to some embodiments, the peptidomimetic includes at position 5 an artificial AA which comprises a heterocycle. According to some embodiments, the peptidomimetic includes at position 5 an artificial AA which comprises a heterocycle selected from the group consisting of L-(7-azaTrp), Gly(indan-2-yl), 3-(4-Quinolyl)-L-Alanine, Pal(2), Pal(4), beta-(7-methoxy-coumarin-4-yl)-Ala, and 3-CF3-hPal(4). Each possibility represents a separate embodiment.

[0167] According to some embodiments, the AA at position 5 of the peptidomimetic comprises a PEG modification. According to some embodiments, the AA at position 5 of the peptidomimetic comprising a PEG modification is Tyr(PEG3Me).

[0168] Exemplary compounds

[0169] According to some embodiments, the present invention provides a head-to-tail cyclic penta-peptidomimetic that inhibits the interaction between an interleukin 17 (IL- 17) and an IL-17 receptor (IL-17R), wherein:

[0170] the amino acid at position 1 is selected from the group consisting of D-Gln, D- Gly(cPr), D-Ala(cPr), D-aThr, D-Ala, D-Leu(3S-OH), D-Pal(4), D-Abu, D-Nle(Me), D-Gln(Pyr), D-Gln(NMe2), and D-Asn(NMe2);

[0171] the amino acid at position 2 is selected from the group consisting of Pal(3), aThr, Ala(cPr), Phe(3-OMe), Phe(3-OH(PEG3Me)), Ala(cBu), L-Nle(6-OH), L-Nle(6- Ome), Nva(OMe), 3 -ethoxy -L-phenylalanine, Leu(3S-OH), Cha, 2-Amino-3- (pyrazin-2-yl)propanoic-acid, 3-(5-pyrimidinyl)-L-alanine, Hse, 3-3-diF-Ala(cBu), 2- amino-3-(5-fluoropyridin-3-yl)propanoic-acid, 4-Pyridazinealanine, Phe(3-CONH2), and 3-(2-Tetrazolyl)-L-alanine;

[0172] the amino acid at position 3 is selected from the group consisting of D-Abu(tetrazol- 5-yl) and D-Cys(5-Methyl-2H-tetrazole);

[0173] the amino acid at position 4 is selected from the group consisting of Phe(2-OMe), Nva(Ph), Tyr(3-5-di-Iodo), L-Phe(2-OCF3), Phe(2-OH), homoTyr, Dip, Abu(4- pyridyl), Cys-[Meta-Xylene-mercaptoacetic-acid], Phe(2-NO2), 5-bromo-2-fluoro- phenylalanine, PhosphoTyr, Tyr(PEG3Me), Tyr(PEG7Me), Tyr(3-5-di- Iodo(PEG3Me)), Phe(bR-OH), Phe(3-5-di-Br), homoPhe(3-OCF3), homoPhe(2- OCF3), homoPhe(4-OCF3), Phe(2-3-di-OH), Phe(F5), L-4-pyridyl-alanine(3-5-di-Br), Hse(Ph), 2-6-diF-Pal(3), and 2-OCH3-Pal(3); and

[0174] the amino acid at position 5 is selected from the group consisting of Phe(2-CF3), L-(7- azaTrp), Gly(indan-2-yl), L-Phe(2-OCF3), Pal(2), Pal(4), beta-(7-methoxy-coumarin- 4-yl)-Ala, 1-Nal, hPhe, 3 -(4-Quinolyl)-L- Alanine, hPhe(2-3-diF), Phe(2-CONH2), 4- CF3-Pal(3), Om(Cbz(2-Cl)), 2-CF3-Pal(4), Tyr(PEG3Me), 3-CF3-hPal(4), and Dip.According to some embodiments, the at least one cyclic penta-peptidomimetic is selected from the group consisting of Compound Nos. 189 to 328, or a pharmaceutically acceptable salt thereof. Compounds Nos. 189 to 328 are as listed in Tables 1 and 2.

[0175] Table 1: Selected cyclic penta-peptidomimetics of the present invention.

[0176] Comp. Internal Cyclic Peptidomimetic

[0177] No. No.

[0178] 189 A_17_325 nc[DGln-Pal(3)-DAbu(tetrazol-5-yl)-Phe(2-OMe)-Phe(2-CF3)] 190 A_17_338 nc[(D-Cyclopropylglycine)(3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(Norvaline-phenyl)(2-(trifluoromethyl)-phenylalanine)]

[0179] 191 A_17_340 nc[(D-Glutamine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-l-5- yl))(Norvaline-phenyl)(L-(7-azaTrp) )]

[0180] 192 A_17_354 nc [DaThr-aThr-DAbu(tetrazol-5 -yl)-Tyr(3 -5 -di-Iodo)-Gly(indan-2- yl)]

[0181] 193 A_17_355 nc[DaThr-aThr-DAbu(tetrazol-5-yl)-Phe(2-OMe)-Phe(2-CF3)]

[0182] 194 A_17_370 nc[(D-alanine)(3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-phenylalanine)(2-(trifluoromethoxy)- phenylalanine)!

[0183] 195 A_17_395 nc[(D-Alanine)(3 -pyridyl -alanine)(D-Abu(tetrazol-5-yl))(2- hydroxy-L-phenylalanine)(2-(trifluoromethoxy)-phenylalanine)] 196 A_17_399 nc[(D-Alanine)(3 -pyridyl -alanine)(D-Abu(tetrazol-5- yl))(homoTyr)(2-(trifluoromethoxy)-phenylalanine)]

[0184] 197 A_17_403 nc[(D-Glutamine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-L-phenylalanine)(L-2-pyridyl-alanine)]

[0185] 198 A_17_404 nc[(D-Glutamine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-L-phenylalanine)(L-4-pyridyl-alanine)]

[0186] 199 A_17_405 nc[(D-Glutamine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(3-3- diphenyl-L-alanine)(L-(7-azaTrp)]

[0187] 200 A_17_407 nc[(D-Cyclopropylglycine)(L-3-pyridyl-alanine)(D-Abu(tetrazol- 5-yl))((2S)-4-pyrid-4-yl-2-aminobutyric-acid)(2-(trifluoromethyl)- L-phenylalanine)l

[0188] 201 A_17_411 nc[(D-Alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(3-3- diphenyl-L-alanine)(beta-(7-methoxy-coumarin-4-yl)-Ala)l

[0189] 202 A_17_413 nc[(D-Alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(Cys- [Meta-Xylene-mercaptoacetic-acid])(2-(trifluoromethyl)-L- phenylalanine)!

[0190] 203 A_17_414 nc[(D-Alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-L-phenylalanine)(3-3-diphenyl-L-alanine)]

[0191] 204 A_17_415 nc[(D-Glutamine)(L-Allothreonine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-L-phenylalanine)(2-(trifluoromethoxy)-L- phenylalanine)]

[0192] 205 A_17_417 nc[(D-Glutamine)(L-Allothreonine)(D-Abu(tetrazol-5-yl))(3-3- diphenyl-L-alanine)(( 1 -naphthyl) -L-alanine)]

[0193] 206 A_17_418 nc[(D-Alanine)(L-Cyclopropylalanine)(D-Cys(5-Methyl-2H- tetrazole))(2-(trifluoromethoxy)-L-phenylalanine)(2-

[0194]

[0195] (trifluoromethyl)-L-phenylalanine)]A_17_419 nc[(D-Alanine)(3-methoxy-L-phenylalanine)(D-Cys(5-Methyl-2H- tetrazole))(3-3-diphenyl-L-alanine)(2-(trifluoromethyl)-L- phenylalanine)]

[0196] A_17_420 nc[(D-Glutamine)(L-Cyclopropylalanine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-L-phenylalanine)(( 1 -naphthyl)-L-alanine)] A_17_422 nc[(D-Glutamine)(L-Cyclopropylalanine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-L-phenylalanine)(L-2-indanylglycine)] A_17_423 nc[(D-Glutamine)(L-Allothreonine)(D-Abu(tetrazol-5-yl))(2-nitro- phenylalanine)(( 1 -naphthyl)-L-alanine)]

[0197] A_17_424 nc[(D-Glutamine)(L-Allothreonine)(D-Abu(tetrazol-5-yl))(2-nitro- phenylalanine)(2-(trifluoromethyl)-L-phenylalanine)] A_17_425 nc[(D-Glutamine)(L-Allothreonine)(D-Abu(tetrazol-5-yl))(2-nitro- phenylalanine) (3-3 -diphenyl -L-alanine)]

[0198] A_17_426 nc[(D-Glutamine)(L-Allothreonine)(D-Abu(tetrazol-5-yl))(2-nitro- phenylalanine)(L-homophenylalanine)]

[0199] A_17_427 nc[(D-Leu(3S-OH))(L-Allothreonine)(D-Abu(tetrazol-5-yl))(3-3- diphenyl-L-alanine)(( 1 -naphthyl) -L-alanine)]

[0200] A_17_506 nc[(D-Glutamine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-l-5-yl))(2- (trifluoromethoxy)-L-phenylalanine)(L-(7-azaTrp) )] A_17_507 nc[(D-Glutamine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(2- nitro-phenylalanine)(2-(trifluoromethyl)-L-phenylalanine)] A_17_508 nc[(D-Cyclopropylglycine)(L-3-pyridyl-alanine)(D-Abu(tetrazol- 5-yl))(3-3-diphenyl-L-alanine)(2-(trifluoromethyl)-L- phenylalanine)]

[0201] A_17_509 nc[(D-Cyclopropylglycine)(L-3-pyridyl-alanine)(D-Abu(tetrazol- 5-yl))(5-bromo-2-fluoro-L-phenylalanine)(L-(7-azaTrp)] A_17_510 nc[(D-Alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(3-3- diphenyl-L-alanine)(L-(7-azaTrp)]

[0202] A_17_514 nc[(D-Ala)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-L-phenylalanine)(L-(7-azaTrp) )] A_17_515 nc [(D-Ala)(L-3 -pyridyl-alanine)(D-Abu(tetrazol-5 -yl))(3 -3 - diphenyl-L-alanine)(3-(4-Quinolyl))-L-alanine)]

[0203] A_17_516 nc [(D-Ala)(L-3 -pyridyl-alanine)(D-Abu(tetrazol-5 -yl))(3 -3 - diphenyl-L-alanine)(L-homophenylalanine)] A_17_517 nc[(D-Ala)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(PhosphoTyr)(2-(trifluoromethyl)-L-phenylalanine)] A_17_518 nc[(D-Alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(Tyr(PEG3Me)))(L-2-indanylglycine)]

[0204] A_17_519 nc[(D-Alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(Tyr(PEG7Me)))(L-2-indanylglycine)]

[0205] A_17_521 nc[(D-4-pyridyl-alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(Tyr(3-5-di-Iodo(PEG3Me)))(L-2-indanylglycine)] A_17_522 nc [(D-Allothreonine)(L-3 -pyridyl -alanine)(D-Abu(tetrazol-5 - yl))(Tyr(3-5-di-Iodo(PEG3Me)))(l-naphthyl)-L-alanine)] A_17_523 nc[(D-Glutamine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(2- nitro-phenylalanine)(L-(7-azaTrp) ]

[0206] A_17_524 nc[(D-4-pyridyl-alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(Phe(bR-OH)))( 1 -naphthyl) -L-alanine)]

[0207]

[0208] A_17_526 nc[(D-4-pyridyl-alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl)) (Tyr(3 -5 -di-Iodo(PEG3 Me)) ( 1 -naphthyl) -L-alanine)] A_17_527 nc[(D-Glutamine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-L-phenylalanine)(3-(4-Quinolyl))-L-alanine)] A_17_528 nc[(D-Cyclopropylglycine)(L-Allothreonine)(D-Abu(tetrazol-5- yl))(3-3-diphenyl-L-alanine)(2-(trifluoromethyl)-L-phenylalanine)] A_17_529 nc[(D-Cyclopropylglycine)(L-Allothreonine)(D-Abu(tetrazol-5- yl))(3-3-diphenyl-L-alanine)((l-naphthyl)-L-alanine)] A_17_530 nc[(D-Cyclopropylglycine)(L-3-pyridyl-alanine)(D-Abu(tetrazol- 5-yl))(Cys-[Meta-Xylene-mercaptoacetic-acid])(2- (trifluoromethyl)-L-phenylalanine)]

[0209] A_17_531 nc[(D-4-pyridyl-alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl)) (Cy s- [Meta-Xylene -mercaptoacetic -acid] ) (2-(trifluoromethyl) - L-phenylalanine)]

[0210] A_17_532 nc[(D-Cyclopropylglycine)(L-3-pyridyl-alanine)(D-Abu(tetrazol- 5 -y 1) ) (3 -3 -diphenyl -L-alanine)(3 -(4-Quinolyl))-L-alanine)] A_17_533 nc[(D-Cyclopropylglycine)(L-Cyclopropylalanine)(D- Abu(tetrazol-5-yl))(3-3-diphenyl-L-alanine)(2-(trifluoromethyl)-L- phenylalanine)]

[0211] A_17_534 nc[(D-Cyclopropylglycine)(L-3-pyridyl-alanine)(D-Abu(tetrazol- 5-yl))(3-3-diphenyl-L-alanine)(2-(trifluoromethoxy)-L- phenylalanine)]

[0212] A_17_535 nc[(D-Cyclopropylglycine)(L-3-pyridyl-alanine)(D-Abu(tetrazol- 5 -y 1) ) (3 -3 -diphenyl -L-alanine)(L-homophenylalanine)] A_17_536 nc[(D-Cyclopropylglycine)(L-3-pyridyl-alanine)(D-Abu(tetrazol- 5-yl))(2-nitro-phenylalanine)(2-(trifluoromethyl)-L- phenylalanine)]

[0213] A_17_537 nc[(D-Cyclopropylglycine)(L-3-pyridyl-alanine)(D-Abu(tetrazol- 5-yl))(2-methoxy-L-phenylalanine)(2-(trifluoromethyl)-L- phenylalanine)]

[0214] A_17_538 nc[(D-Alanine)(L-Cyclopropylalanine)(D-Cys(5-Methyl-2H- tetrazole))(2-methoxy-L-phenylalanine)(2-(trifluoromethyl)-L- phenylalanine)]

[0215] A_17_539 nc[(D-Cyclopropylglycine)(L-3-pyridyl-alanine)(D-Cys(5-Methyl- 2H-tetrazole))(3-3-diphenyl-L-alanine)(2-(trifluoromethyl)-L- phenylalanine)]

[0216] A_17_540 nc[(D-Alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(Tyr(3- 5-di-Iodo(PEG3Me)))(L-2-indanylglycine)]

[0217] A_17_541 nc[(D-Alanine)(L-Cyclopropylalanine)(D-Cys(5-Methyl-2H- tetrazole))(Tyr(3-5-di-Iodo(PEG3Me)))(2-(trifluoromethyl)-L- phenylalanine)]

[0218] A_17_542 nc [(D-Cyclopropylglycine)(L-Cyclopropylalanine)(D-Cys(5 - Methyl-2H-tetrazole))(2-(trifluoromethoxy)-L-phenylalanine)(2- (trifluoromethyl)-L-phenylalanine)]

[0219] A_17_543 nc [(D-Cyclopropylglycine)(L-Cyclopropylalanine)(D-Cys(5 - Methyl-2H-tetrazole))(Tyr(3-5-di-Iodo(PEG3Me)))(2- (trifluoromethyl)-L-phenylalanine)]

[0220] A_17_544 nc[(D-Glutamine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(Tyr(3-5-di-Iodo(PEG3Me)))(3-(4-Quinolyl))-L-alanine)] A_17_545 nc[(D-Glutamine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(2- nitro-phenylalanine)(3-(4-Quinolyl))-L-alanine)]

[0221]

[0222] A_17_546 nc[(D-Glutamine)(L-Allothreonine)(D-Abu(tetrazol-5-yl))(3-3- diphenyl-L-alanine)(2-(trifluoromethyl)-L-phenylalanine)]] A_17_547 nc[(D-Glutamine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(2- methoxy)-L-phenylalanine)(3-(4-Quinolyl))-L-alanine)] A_17_548 nc[(D-Glutamine)(L-Allothreonine)(D-Abu(tetrazol-5-yl))(2-nitro- phenylalanine)(2-(trifluoromethoxy)-L-phenylalanine)] A_17_549 nc[(D-Glutamine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(Phe(3-5-di-Br))(3-(4-Quinolyl))-L-alanine)]

[0223] A_17_550 nc[(D-Alanine)(Phe(3-OH(PEG3Me))(D-Cys(5-Methyl-2H- tetrazole))(3-3-diphenyl-L-alanine)(2-(trifluoromethyl)-L- phenylalanine)]

[0224] A_17_551 nc[(D-Glutamine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(3-3- diphenyl-L-alanine)(( 1 -naphthyl) -L-alanine)]

[0225] A_17_552 nc[(D-Glutamine)(L-Allothreonine)(D-Abu(tetrazol-5-yl))(3-3- diphenyl-L-alanine)(3-(4-Quinolyl))-L-alanine)]

[0226] A_17_553 nc[(D-Glutamine)(L-Allothreonine)(D-Abu(tetrazol-5-yl))(3-3- diphenyl-L-alanine)(L-homophenylalanine)]

[0227] A_17_554 nc[(D-Glutamine)(L-Allothreonine)(D-Abu(tetrazol-5-yl))(2- methoxy-L-phenylalanine)(( 1 -naphthyl)-L-alanine)] A_17_555 nc[(D-Glutamine)(L-Allothreonine)(D-Abu(tetrazol-5-yl))(Phe(3- 5-di-Br))((l-naphthyl)-L-alanine)]

[0228] A_17_556 nc[(D-Glutamine)(L-Allothreonine)(D-Cys(5-Methyl-2H- tetrazole))(3 -3 -diphenyl -L-alanine)(( 1 -naphthyl)-L-alanine)] A_17_557 nc[(D-Alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(2- nitro-phenylalanine)(3 -3 -diphenyl -L-alanine)]

[0229] A_17_558 nc[(D-2-alpha-Aminobutyric-acid)(Beta-Cyclobutyl-L-Alanine)(D- Abu(tetrazol-5-yl))(Phe(3-5-di-Br))(3-(4-Quinolyl)-L-alanine)] A_17_559 nc[(D-4-pyridyl-alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(Tyr(3-5-di-Iodo(PEG3Me))(L-homophenylalanine)] A_17_562 nc[(D-Glutamine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(2- nitro-phenylalanine)(2,3-difluoro-L-homophenylalanine)] A_17_563 nc[(D-Glutamine)(6-hydroxynorleucine)(D-Abu(tetrazol-5-yl))(3- 3 -diphenyl-L-alanine)(3 -(4-Quinolyl))-L-alanine)] A_17_564 nc[(D-Glutamine)(L-Nle(6-Ome))(D-Abu(tetrazol-5-yl))(3-3- diphenyl-L-alanine)(3-(4-Quinolyl))-L-alanine)]

[0230] A_17_565 nc[(D-Glutamine)(5-methoxy-L-norvaline)(D-Abu(tetrazol-5- yl))(3-3-diphenyl-L-alanine)(3-(4-Quinolyl))-L-alanine)] A_17_600 nc[(D-Alanine)(3 -pyridyl -alanine)(D-Abu(tetrazol-5-yl))(2-nitro- phenylalanine)(2-(trifluoromethoxy)-phenylalanine)] A_17_608 nc[(D-Ala)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(homoPhe(3-OCF3))(2-(trifluoromethyl)-L-phenylalanine)] A_17_609 nc[(D-Ala)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(homoPhe(2-OCF3))(2-(trifluoromethyl)-L-phenylalanine)] A_17_610 nc[(D-Ala)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(homoPhe(4-OCF3))(2-(trifluoromethyl)-L-phenylalanine)] A_17_617 nc[(D-Glutamine)(L-Allothreonine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-L-phenylalanine)( 1 -naphthyl)-L-alanine)]

[0231]

[0232] A_17_625 nc[(D-Glutamine)(L-Allothreonine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-L-phenylalanine)(2,3-difluoro-L- homophenylalanine)]

[0233] A_17_626 nc[(D-Glutamine)(L-Allothreonine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-L-phenylalanine)(2-(trifluoromethyl)-L- phenylalanine)]

[0234] A_17_631 nc[(D-Alanine)(L-Cyclopropylalanine)(D-Abu(tetrazol-5-yl))(2- hydroxy-L-phenylalanine)(2-(trifluoromethoxy)-L-phenylalanine)] A_17_632 nc[(D-Glutamine)(L-Cyclopropylalanine)(D-Abu(tetrazol-5- yl))(2,3-dihydroxy-L-phenylalanine)(2-(trifluoromethyl)-L- phenylalanine)]

[0235] A_17_636 nc[(D-Glutamine)(L-Cyclopropylalanine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-L-phenylalanine)(2-(trifluoromethoxy)-L- phenylalanine)]

[0236] A_17_637 nc[(D-Cyclopropylglycine)(L-Cyclopropylalanine)(D- Abu(tetrazol-5-yl))(2-(trifluoromethoxy)-L-phenylalanine)(2- (trifluoromethoxy)-L-phenylalanine)l

[0237] A_17_638 nc[(D-Alanine)(3-pyridyl-alanine)(D-Cys(5-Methyl-2H- tetrazole))(2-(trifluoromethoxy)-phenylalanine)(2- (trifluoromethoxy) -phenylalanine)]

[0238] A_17_639 nc[(D-Cyclopropylglycine)(3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(2-methoxy-L-phenylalanine)(2-(trifluoromethoxy)-L- phenylalanine)]

[0239] A_17_641 nc[(D-Ala)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-phenylalanine)(Phe(2-CONH2)) A_17_643 nc[(D-Cyclopropylglycine)(3-ethoxy-phenylalanine)(D-Cys(5- Methyl-2H-tetrazole))(2-nitro-phenylalanine)(L- homophenylalanine)]

[0240] A_17_644 nc [(D-Cyclopropylglycine)(L-Allothreonine)(D-Cys(5 -Methyl -2H- tetrazole))(2-nitro-phenylalanine)(3-3-diphenyl-L-alanine)] A_17_646 nc [(D-Cyclopropylglycine)(L-Allothreonine)(D-Cys(5 -Methyl -2H- tetrazole))(2-nitro-phenylalanine)(L-homophenylalanine)] A_17_647 nc[(R-2-aminoheptanoic-acid)(3-ethoxy-phenylalanine)(D-Cys(5- Methyl-2H-tetrazole))(homoPhe(4-OCF3))(L- homophenylalanine)]

[0241] A_17_648 nc[(D-Cyclopropylglycine)(L-Cyclopropylalanine)(D- Abu(tetrazol-5-yl))(2-nitro-phenylalanine)(2-(trifluoromethoxy)-L- phenylalanine)]

[0242] A_17_650 nc[(D-N,N-pyrrolidinylglutamine)(L-3-pyridyl-alanine)(D- Abu(tetrazol-5-yl))(3-3-diphenyl-L-alanine)(2-(trifluoromethyl)-L- phenylalanine)]

[0243] A_17_654 nc[(D-N,N-di-methylglutamine)(L-3-pyridyl-alanine)(D- Abu(tetrazol-5-yl))(3-3-diphenyl-L-alanine)(2-(trifluoromethyl)-L- phenylalanine)]

[0244] A_17_655 nc[(D-N,N-di-methylasparagine)(L-3-pyridyl-alanine)(D- Abu(tetrazol-5-yl))(3-3-diphenyl-L-alanine)(2-(trifluoromethyl)-L- phenylalanine)]

[0245] A_17_428 nc[(D-Glutamine)(Leu(3S-OH))(D-Abu(tetrazol-5-yl))(3-3- diphenyl-L-alanine)(( 1 -naphthyl) -L-alanine)]

[0246] A_17_429 nc[(D-Cyclopropylglycine)(Beta-Cyclobutyl-L-Alanine)(D- Abu(tetrazol-5-yl))(2-(trifluoromethoxy)-L-phenylalanine)(2-

[0247]

[0248] (trifluoromethyl)-L-phenylalanine)]A_17_431 nc[(D-Cyclopropylalanine)(L-Cyclopropylalanine)(D-Cys(5- Methyl-2H-tetrazole))(2-(trifluoromethoxy)-L-phenylalanine)(2- (trifluoromethyl)-L-phenylalanine)]

[0249] A_17_432 nc[(D-Cyclopropylglycine)(Cyclohexylalanine)(D-Abu(tetrazol-5- yl))(2-nitro-phenylalanine)(2-(trifluoromethyl)-L-phenylalanine)] A_17_434 nc[(D-Cyclopropylalanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(3-3-diphenyl-L-alanine)(2-(trifluoromethyl)-L-phenylalanine)] A_17_683 nc[(D-Alanine)(L-Cyclopropylalanine)(D-Abu(tetrazol-5- yl))(homoPhe(4-OCF3))(L-homophenylalanine)]

[0250] A_17_677 nc [(D-Alanine)(2-Amino-3 -(pyrazin-2-yl)propanoic acid)(D- Abu(tetrazol-5-yl))(2-(trifluoromethoxy)-phenylalanine)(2- (trifluoromethoxy) -phenylalanine)]

[0251] A_17_438 nc[(D-Glutamine)(3-(5-pyrimidinyl)-L-alanine)(D-Abu(tetrazol-5- yl))(2-methoxy-L-phenylalanine)(2-(trifluoromethyl)-L- phenylalanine)]

[0252] A_17_571 nc[(D-Cyclopropylglycine)(L-3-pyridyl-alanine)(D-Abu(tetrazol- 5-yl))(pentafluoro-L-phenylalanine)(2-(trifluoromethyl)-L- phenylalanine)]

[0253] A_17_560 nc [(D-Allothreonine)(L-3 -pyridyl -alanine)(D-Abu(tetrazol-5 - yl))(L-4-pyridyl-alanine(3 -5 -di-Br))( 1 -naphthyl)-L-alanine)] A_17_436 nc[(D-Glutamine)(2-Amino-3-(pyrazin-2-yl)propanoic-acid)(D- Abu(tetrazol-5-yl))(2-methoxy-L-phenylalanine)(2- (trifluoromethyl)-L-phenylalanine)]

[0254] A_17_430 nc[(D-Cyclopropylglycine)(homoserine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-L-phenylalanine)(2-(trifluoromethyl)-L- phenylalanine)]

[0255] A_17_688 nc[(D-Cyclopropylglycine)(3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(O-Phenylhomoserine)(2-(trifluoromethyl)-phenylalanine)] A_17_687 nc [(D-Cyclopropylglycine)(2-amino-3 -(3,3- difluorocyclobutyl)propanoic acid)(D-Abu(tetrazol-5-yl))(2- methoxy-L-phenylalanine)(2-(trifluoromethyl)-L-phenylalanine)l A_17_437 nc [(D-Glutamine)(2-amino-3 -(5 -fluoro-3 -yl)propanoic-acid)(D- Abu(tetrazol-5-yl))(2-methoxy-L-phenylalanine)(2- (trifluoromethyl)-L-phenylalanine)]

[0256] A_17_573 nc[(D-4-pyridyl-alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(3 -3 -diphenyl -L-alanine)(3 -(4-Quinolyl)-L-alanine)] A_17_575 nc[(D-Glutamine)(L-Allothreonine)(D-Abu(tetrazol-5-yl))(Phe(3- 5 -di-Br))(3 -(4-Quinolyl)-L-alanine)]

[0257] A_17_576 nc[(D-Glutamine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-L-phenylalanine)(2-Amino-3-[6- (trifluoromethyl)]pyridin-3 -y 1)]

[0258] A_17_442 nc[(D-Cyclopropylglycine)(Beta-Cyclobutyl-L-Alanine)(D- Abu(tetrazol-5-yl))(2-6-di-F-(3-pyridyl)alanine)(2- (trifluoromethyl)-L-phenylalanine)]

[0259] A_17_577 nc[(D-Allothreonine)(2-Amino-3-(pyrazin-2-yl)propanoic-acid)(D- Abu(tetrazol-5-yl))(L-4-pyridyl-alanine(3-5-di-Br))(l-naphthyl)-L- alanine)]

[0260] A_17_701 nc[(D-4-pyridyl-alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(2-(trifluoromethoxy)-L-phenylalanine)(l-naphthyl)-L-

[0261]

[0262] alanine)]311 A_17_702 nc[(D-4-pyridyl-alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(2-(trifluoromethoxy)-L-phenylalanine)(3-(4-Quinolyl)-L- alanine)!

[0263] 312 A_17_585 nc[(D-4-pyridyl-alanine)(beta-(pyrimidin-5-yl)-L-alanine)(D- Abu(tetrazol-5-yl))(2-methoxy-L-phenylalanine)(2- (trifluoromethyl)-L-phenylalanine)l

[0264] 313 A_17_675 nc[(D-Glutamine)(2-Amino-3-(pyrazin-2-yl)propanoic acid)(D- Abu(tetrazol-5-yl))(2-(trifluoromethoxy)-L-phenylalanine)(3-(4- Quinolyl) -L-alanine)]

[0265] 314 A_17_579 nc[(D-Cyclopropylglycine)(3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(2-OCH3-Pal(3))(2-(trifluoromethoxy)-L-phenylalanine)] 315 A_17_706 nc[(D-Cyclopropylglycine)(2-Amino-3-(pyrazin-2-yl)propanoic acid)(D-Abu(tetrazol-5-yl))(2-methoxy-L-phenylalanine)(2- (trifluoromethoxy)-L-phenylalanine)l

[0266] 316 A_17_590 nc[(D-Glutamine)(L-Allothreonine)(D-Cys(5-Methyl-2H- tetrazole))(3-3-diphenyl-L-alanine)(3-(4-Quinolyl)-L-alanine)] 317 A_17_583 nc[(D-Allothreonine)(HomoSerine)(D-Abu(tetrazol-5-yl))(2- (trifluoromethoxy)-L-phenylalanine)(2-(trifluoromethyl)-L- phenylalanine)!

[0267] 318 A_17_582 nc[(D-4-pyridyl-alanine)(beta-(pyrimidin-5-yl)-L-alanine)(D- Abu(tetrazol-5-yl))(2-trifluoromethoxy-L-phenylalanine)(2- (trifluoromethyl)-L-phenylalanine)]

[0268] 319 A_17_704 nc[(D-Cyclopropylglycine)(L-3-pyridyl-alanine)(D-Abu(tetrazol- 5-yl))(2-(trifluoromethoxy)-L-phenylalanine)(Om(Cbz(2-Cl)))] 320 A_17_439 nc[(D-Glutamine)(Beta-(pyridazin-4-yl)-L-alanine)(D- Abu(tetrazol-5-yl))(2-methoxy-L-phenylalanine)(2- (trifluoromethyl)-L-phenylalanine)l

[0269] 321 A_17_587 nc[(D-Cyclopropylglycine)(L-3-pyridyl-alanine)(D-Abu(tetrazol- 5 -y 1) ) (3 -3 -diphenyl -L-alanine)(2-CF3-Pal (4))]

[0270] 322 A_17_709 nc[(D-Cyclopropylglycine)(L-Cyclopropylalanine)(D- Abu(tetrazol-5-yl))(2-(trifluoromethoxy)-L-phenylalanine)(2,3- difluoro-L-homophenylalanine)l

[0271] 323 A_17_649 nc[(D-Cyclopropylglycine)(L-3-pyridyl-alanine)(D-Abu(tetrazol- 5 -y 1) ) (3 -3 -diphenyl -L-alanine)(2, 3 -difluoro-L- homophenylalanine)!

[0272] 324 A_17_584 nc[(D-Glutamine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5- yl))(Phe(3-5-di-Br))(Tyr(PEG3Me))]

[0273] 325 A_17_707 nc[(D-Glutamine)(Leu(3S-OH))(D-Abu(tetrazol-5-yl))(3-3- diphenyl-L-alanine)(2,3-difluoro-L-homophenylalanine)]

[0274] 326 A_17_592 nc[(D-Cyclopropylglycine)(L-3-Carbamoylphe)(D-Abu(tetrazol-5- yl))(3-3-diphenyl-L-alanine)(3-(4-Quinolyl))-L-alanine)]

[0275] 327 A_17_720 nc[(D-Alanine)(L-3-pyridyl-alanine)(D-Abu(tetrazol-5-yl))(3-3- diphenyl-L-alanine)(3-CF3-hPal(4))]

[0276] 328 A_17_591 nc[(D-Glutamine)(3-(2-Tetrazolyl)-L-alanine)(D-Abu(tetrazol-5- yl))(3-3-diphenyl-L-alanine)(3-(4-Quinolyl))-L-alanine)]

[0277]

[0278] nc= N to C cyclization

[0279] Table 2: Exemplary peptidomimetics by compound and position number.

[0280] Comp. Position 1 Position 2 Position 3 Position 4 Position 5

[0281]

[0282] No.D-Gln Pal(3) D-Abu(tetrazol- Phe(2-OMe) Phe(2-CF3) 5-yl)

[0283] D-Gly(cPr) Pal(3) D-Abu(tetrazol- Nva(Ph) Phe(2-CF3)

[0284] 5-yl)

[0285] D-Gln Pal(3) D-Abu(tetrazol- Nva(Ph) L-(7-azaTrp)

[0286] 5-yl)

[0287] D-aThr aThr D-Abu(tetrazol- Tyr(3-5-di-Iodo) Gly(indan-2-yl) 5-yl)

[0288] D-aThr aThr D-Abu(tetrazol- L-Phe(2-OCF3) Phe(2-CF3)

[0289] 5-yl)

[0290] D-Abu(tetrazol- D-Ala Pal(3) L-Phe(2-OCF3) L-Phe(2-OCF3)

[0291] 5-yl)

[0292] Pal(3) D-Abu(tetrazol- Phe(2-OH) L-Phe(2-OCF3) D-Ala

[0293] 5-yl)

[0294] Pal(3) D-Abu(tetrazol- D-Ala homoTyr L-Phe(2-OCF3)

[0295] 5-yl)

[0296] D-Gln Pal(3) D-Abu(tetrazol- L-Phe(2-OCF3) Pal(2)

[0297] 5-yl)

[0298] D-Abu(tetrazol- D-Gln Pal(3) L-Phe(2-OCF3) Pal(4)

[0299] 5-yl)

[0300] D-Abu(tetrazol- D-Gln Pal(3) Dip L-(7-azaTrp) 5-yl)

[0301] D-Abu(tetrazol- D-Gly(cPr) Pal(3) Phe(2-CF3) Abu(4-pyridyl)

[0302] 5-yl)

[0303] beta-(7-methoxy- D-Abu(tetrazol- Pal(3) Dip D-Ala

[0304] coumarin-4-yl)-Ala 5-yl)

[0305] D-Abu(tetrazol- Cys-[Meta-Xylene- Pal(3) Phe(2-CF3) D-Ala

[0306] mercaptoacetic-acid] 5-yl)

[0307] D-Abu(tetrazol- Pal(3) L-Phe(2-OCF3) Dip D-Ala

[0308] 5-yl)

[0309] D-Abu(tetrazol- D-Gln aThr L-Phe(2-OCF3) L-Phe(2-OCF3) 5-yl)

[0310] D-Abu(tetrazol- D-Gln aThr Dip 1-Nal 5-yl)

[0311] D-Cys(5- Ala(cPr) Methyl-2H- L-Phe(2-OCF3) Phe(2-CF3) D-Ala

[0312] tetrazole)

[0313] D-Cys(5- Methyl-2H- Dip Phe(2-CF3) D-Ala Phe(3-OMe)

[0314] tetrazole)

[0315] D-Abu(tetrazol- D-Gln Ala(cPr) Phe(2-OMe) 1-Nal

[0316] 5-yl)

[0317] D-Abu(tetrazol- D-Gln Ala(cPr) Gly(indan-2-yl) Phe(2-OMe)

[0318] 5-yl)

[0319] D-Abu(tetrazol- D-Gln aThr Phe(2-NO2) 1-Nal

[0320] 5-yl)

[0321] D-Abu(tetrazol- D-Gln aThr Phe(2-NO2) Phe(2-CF3) 5-yl)

[0322] D-Abu(tetrazol- D-Gln aThr Phe(2-NO2) Dip

[0323] 5-yl)

[0324] D-Abu(tetrazol- D-Gln aThr Phe(2-NO2) hPhe

[0325] 5-yl)

[0326] D-Leu(3S- D-Abu(tetrazol- aThr Dip 1-Nal OH) 5-yl)

[0327] D-Abu(tetrazol- D-Gln Pal(3) L-Phe(2-OCF3) L-(7-azaTrp) 5-yl)

[0328] D-Abu(tetrazol- D-Gln Pal(3) Phe(2-NO2) Phe(2-CF3) 5A1) _

[0329]

[0330] D-Gly(cPr) Pal(3) D-Abu(tetrazol- Dip Phe(2-CF3)

[0331] 5-yl)

[0332] D-Gly(cPr) Pal(3) D-Abu(tetrazol- 5-bromo-2 -fluoroL-(7-azaTrp)

[0333] 5-yl) phenylalanine

[0334] Pal(3) D-Abu(tetrazol- D-Ala Dip L-(7-azaTrp)

[0335] 5-yl)

[0336] D D Pal(3) -Abu(tetrazol- -Ala L-Phe(2-OCF3) L-(7-azaTrp)

[0337] 5-yl)

[0338] Pal(3) D-Abu(tetrazol- 3-(4-Quinolyl)-L- D-Ala Dip

[0339] ala 5-yl) nine

[0340] Pa D-Abu(tetrazol- D-Ala l(3) Dip hPhe

[0341] 5-yl)

[0342] D-Abu Pal(3) (tetrazol- D-Ala Phospho Tyr Phe(2-CF3)

[0343] 5-yl)

[0344] D-Abu(tetrazol- Pal(3) Gly(indan-2-yl) D-Ala Tyr(PEG3Me)

[0345] 5-yl)

[0346] D-Abu(tetrazol- Pal(3) Gly(indan-2-yl) D-Ala Tyr(PEG7Me)

[0347] 5-yl)

[0348] D-Abu(tetrazol- Tyr(3-5-di- D-Pal(4) Pal(3) Gly(indan-2-yl)

[0349] Iodo(PEG3Me)) 5-yl)

[0350] D-Abu(tetrazol- Tyr(3-5-di- D-aThr Pal(3) 1-Nal Iodo(PEG3Me)) 5-yl)

[0351] D-Abu(tetrazol- D-Gln Pal(3) Phe(2-NO2) L-(7-azaTrp) 5-yl)

[0352] D-Abu(tetrazol- D-Pal(4) Pal(3) Phe(bR-OH) 1-Nal

[0353] 5-yl)

[0354] D-Abu(tetrazol- Tyr(3-5-di- D-Pal(4) Pal(3) 1-Nal Iodo(PEG3Me) 5-yl)

[0355] 3-(4-Quinolyl))-L- D-Abu(tetrazol- D-Gln Pal(3) L-Phe(2-OCF3)

[0356] alanine 5-yl)

[0357] D-Abu(tetrazol- D-Gly(cPr) aThr Dip Phe(2-CF3) 5-yl)

[0358] D-Abu(tetrazol- D-Gly(cPr) aThr Dip 1-Nal

[0359] 5-yl)

[0360] D-Abu(tetrazol- Cys-[Meta-Xylene- D-Gly(cPr) Pal(3) Phe(2-CF3) mercaptoacetic-acidl 5-yl)

[0361] D-Abu(tetrazol- Cys-[Meta-Xylene- D-Pal(4) Pal(3) Phe(2-CF3) mercaptoacetic-acidl 5-yl)

[0362] 3-(4-Quinolyl))-L- D-Abu(tetrazol- D-Gly(cPr) Pal(3) Dip

[0363] alanine 5-yl)

[0364] D-Abu(tetrazol- D-Gly(cPr) Ala(cPr) Dip Phe(2-CF3) 5-yl)

[0365] D-Abu(tetrazol- D-Gly(cPr) Pal(3) Dip L-Phe(2-OCF3) 5-yl)

[0366] D-Abu(tetrazol- D-Gly(cPr) Pal(3) Dip hPhe

[0367] 5-yl)

[0368] D-Abu(tetrazol- D-Gly(cPr) Pal(3) Phe(2-NO2) Phe(2-CF3) 5-yl)

[0369] D-Abu(tetrazol- D-Gly(cPr) Pal(3) Phe(2-CF3) Phe(2-OMe)

[0370] 5-yD

[0371] D-Cys(5- Ala(cPr) Methyl-2H- Phe(2-CF3) D-Ala Phe(2-OMe)

[0372] tetrazole)

[0373] D-Cys(5- D-Gly(cPr) Pal(3) Methyl-2H- Dip Phe(2-CF3) tetrazole)

[0374] D-Abu(tetrazol- Tyr(3-5-di- Pal(3) Gly(indan-2-yl) D-Ala 5A1) _ Iodo(PEG3Me))

[0375]

[0376] D-Cys(5- Ala(cP Tyr(3-5-di- D-Ala r) Methyl-2H- Phe(2-CF3) Iodo(PEG3Me))

[0377] tetrazole)

[0378] D-Cys(5- D-Gly(cPr) Ala(cPr) Methyl-2H- L-Phe(2-OCF3) Phe(2-CF3) tetrazole)

[0379] D-Cys(5- D-Gly(cPr) Ala(cPr) Methyl-2H- Tyr(3-5-di- Phe(2-CF3) Iodo(PEG3Me))

[0380] tetrazole)

[0381] 3-(4-Quinolyl))-L- D-Gln Pal(3) D-Abu(tetrazol- Tyr(3-5-di- 5-yl) Iodo(PEG3Me)) alanine

[0382] D- 3-(4-Quinolyl))-L- D-Gln Pal(3) Abu(tetrazol- Phe(2-NO2)

[0383] 5-yl) alanine

[0384] D-Gln aThr D-Abu(tetrazol- Dip Phe(2-CF3)

[0385] 5-yl)

[0386] 3-(4-Quinolyl))-L- D-Gln Pal(3) D-Abu(tetrazol- Phe(2-OMe)

[0387] 5-yl) alanine

[0388] D-Gln aThr D-Abu(tetrazol- Phe(2-NO2) L-Phe(2-OCF3)

[0389] 5-yl)

[0390] 3-(4-Quinolyl))-L- D-Gln Pal(3) D-Abu(tetrazol- Phe(3-5-di-Br)

[0391] 5-yD alanine Phe(3- D-Cys(5- D-Ala OH(PEG3Me) Methyl-2H- Dip Phe(2-CF3) ) tetrazole)

[0392] D-Gln Pal(3) D-Abu(tetrazol- Dip 1-Nal

[0393] 5-yl)

[0394] 3-(4-Quinolyl))-L- D-Gln aThr D-Abu(tetrazol- Dip

[0395] 5-yl) alanine

[0396] D-Gln aThr D-Abu(tetrazol- Dip hPhe

[0397] 5-yl)

[0398] D-Gln aThr D-Abu(tetrazol- Phe(2-OMe) 1-Nal

[0399] 5-yl)

[0400] D-Gln aThr D-Abu(tetrazol- Phe(3-5-di-Br)

[0401] 5-yl) 1-Nal

[0402] D-Cys(5- D-Gln aThr Methyl-2H- Dip 1-Nal tetrazole)

[0403] D-Abu(tetrazol- D-Ala Pal(3) Phe(2-NO2) Dip

[0404] 5-yl)

[0405] D-A 3-(4-Quinolyl))-L- D Ala(cBu) bu(tetrazol- -Abu Phe(3-5-di-Br)

[0406] 5-yl) alanine

[0407] D-Pal(4) Pal(3) D-Abu(tetrazol- Tyr(3-5-di- hPhe

[0408] 5-yl) Iodo(PEG3Me)

[0409] D-Gln Pal(3) D-Abu(tetrazol- Phe(2-NO2) hPhe(2-3-diF)

[0410] 5-yl)

[0411] 3-(4-Quinolyl))-L- D-Gln L-Nle(6-OH) D-Abu(tetrazol- Dip

[0412] 5-yl) alanine

[0413] D-Abu(tetra 3-(4-Quinolyl))-L- D-Gln zol- L-Nle(6-Ome) Dip

[0414] 5-yl) alanine

[0415] 3-(4-Quinolyl) D-Gln D-Abu(tetrazol- )-L- Nva(OMe) Dip

[0416] 5-yl) alanine Pal(3) D-Abu(tetrazol- D-Ala Phe(2-NO2) L-Phe(2-OCF3)

[0417] 5-yl)

[0418] D Pal(3) D-Abu(tetrazol- -Ala homoPhe(3-OCF3) Phe(2-CF3)

[0419] 5-yl)

[0420] D-Ala Pal(3) D-Abu(tetrazol- homoPhe(2-OCF3) Phe(2-CF3)

[0421] 5-yl)

[0422] D-Abu(tetrazol- D-Ala Pal(3) homoPhe(4-OCF3) Phe(2-CF3)

[0423]

[0424] 5-yDD-Abu(tetrazol- D-Gln aThr L-Phe(2-OCF3) 1-Nal

[0425] 5-yl)

[0426] D-Abu(tetrazol- D-Gln aThr L-Phe(2-OCF3) hPhe(2-3-diF)

[0427] 5-yl)

[0428] D-Abu(tetrazol- D-Gln aThr L-Phe(2-OCF3) Phe(2-CF3)

[0429] 5-yl)

[0430] D-Abu(tetrazol- D-Ala Ala(cPr) Phe(2-OH) L-Phe(2-OCF3)

[0431] 5-yl)

[0432] D-Abu(tetrazol- D-Gln Ala(cPr) Phe(2-3-di-OH) Phe(2-CF3)

[0433] 5-yl)

[0434] D-Abu(tetrazol- D-Gln Ala(cPr) L-Phe(2-OCF3) L-Phe(2-OCF3)

[0435] 5-yl)

[0436] D-Abu(tetrazol- D-Gly(cPr) Ala(cPr) L-Phe(2-OCF3) L-Phe(2-OCF3)

[0437] 5-yl)

[0438] D-Cys(5- D-Ala Pal(3) Methyl-2H- L-Phe(2-OCF3) L-Phe(2-OCF3) tetrazole)

[0439] D-Abu(tetrazol- D-Gly(cPr) Pal(3) Phe(2-OMe) L-Phe(2-OCF3)

[0440] 5-yl)

[0441] D-Abu(tetrazol- D-Ala Pal(3) L-Phe(2-OCF3) Phe(2-CONH2)

[0442] 5-yD

[0443] D-Cys(5- 3 -ethoxy -L- D-Gly(cPr) Methyl-2H- Phe(2-NO2) hPhe phenylalanine

[0444] tetrazole)

[0445] D-Cys(5- D-Gly(cPr) aThr Methyl-2H- Phe(2-NO2) Dip tetrazole)

[0446] D-Cys(5- D-Gly(cPr) aThr Methyl-2H- Phe(2-NO2) hPhe tetrazole)

[0447] D-Cys(5- 3 -ethoxy -L- D-Nle(Me) Methyl-2H- homoPhe(4-OCF3) hPhe phenylalanine

[0448] tetrazole)

[0449] D-Gly(cPr) Ala(cPr) D-Abu(tetrazol- Phe(2-NO2) L-Phe(2-OCF3)

[0450] 5-yl)

[0451] D-Abu(tetrazol- D-Gln(Pyr) Pal(3) Dip Phe(2-CF3)

[0452] 5-yl)

[0453] D-Abu(tetrazol- D-Gln(NMe2) Pal(3) Dip Phe(2-CF3)

[0454] 5-yl)

[0455] D-Abu(tetrazol- D-Asn(NMe2) Pal(3) Dip Phe(2-CF3)

[0456] 5-yl)

[0457] D-Abu(tetrazol- D-Gln Leu(3S-OH) 5-yl) Dip 1-Nal D-Abu(tetrazol- D-Gly(cPr) Ala(cBu) 5-yD L-Phe(2-OCF3) Phe(2-CF3) D-Cys(5- Methyl-2H- D-Ala(cPr) Ala(cPr) tetrazole) L-Phe(2-OCF3) Phe(2-CF3) D-Abu(tetrazol- D-Gly(cPr) Cha 5-yl) Phe(2-NO2) Phe(2-CF3) D-Abu(tetrazol- D-Ala(cPr) Pal(3) 5-yl) Dip Phe(2-CF3) D-Abu(tetrazol- D-Ala Ala(cPr) 5-yD homoPhe(4-OCF3) hPhe

[0458] 2-Amino-3- (pyrazin-2- yl)propanoic- D-Abu(tetrazol-

[0459]

[0460] D-Ala acid 5-yD L-Phe(2-OCF3) L-Phe(2-OCF3)3-(5- pyrimidinyl)- D-Abu(tetrazol- D-Gln L-alanine 5-yl) Phe(2-OMe) Phe(2-CF3) D-Abu(tetrazol- D-Gly(cPr) Pal(3) 5-yl) Phe(F5) Phe(2-CF3) D-Abu(tetrazol- L-4-pyridyl- D-aThr Pal(3) 5-yD alanine(3-5-di-Br) 1-Nal

[0461] 2-Amino-3- (pyrazin-2- yl)propanoic- D-Abu(tetrazol- D-Gln acid 5-yl) Phe(2-OMe) Phe(2-CF3) D-Abu(tetrazol- D-Gly(cPr) Hse 5-yl) L-Phe(2-OCF3) Phe(2-CF3) D-Abu(tetrazol- D-Gly(cPr) Pal(3) 5-yl) Hse(Ph) Phe(2-CF3)

[0462] 3-3-diF- D-Abu(tetrazol- D-Gly(cPr) Ala(cBu) 5-yD Phe(2-OMe) Phe(2-CF3)

[0463] 2-amino-3-(5- fluoropyridin- 3- yl)propanoic- D-Abu(tetrazol- D-Gln acid 5-yl) Phe(2-OMe) Phe(2-CF3) D-Abu(tetrazol- 3-(4-Quinolyl)-L- D-Pal(4) Pal(3) 5-yl) Dip alanine

[0464] D-Abu(tetrazol- 3-(4-Quinolyl)-L- D-Gln aThr 5-yl) Phe(3-5-di-Br) alanine

[0465] D-Abu(tetrazol- D-Gln Pal(3) 5-yl) L-Phe(2-OCF3) 4-CF3-Pal(3) D-Abu(tetrazol- D-Gly(cPr) Ala(cBu) 5-yl) 2-6-diF-Pal(3) Phe(2-CF3)

[0466] 2-Amino-3- (pyrazin-2- yl)propanoic- D-Abu(tetrazol- L-4-pyridyl- D-aThr acid 5-yl) alanine(3-5-di-Br) 1-Nal

[0467] D-Abu(tetrazol- D-Pal(4) Pal(3) 5-yl) L-Phe(2-OCF3) 1-Nal

[0468] D-Abu(tetrazol- 3-(4-Quinolyl)-L- D-Pal(4) Pal(3) 5-yl) L-Phe(2-OCF3) alanine

[0469] 3-(5- pyrimidinyl)- D-Abu(tetrazol- D-Pal(4) L-alanine 5-yD Phe(2-OMe) Phe(2-CF3)

[0470] 2-Amino-3- (pyrazin-2- yl)propanoic- D-Abu(tetrazol- 3-(4-Quinolyl)-L- D-Gln acid 5-yl) L-Phe(2-OCF3) alanine

[0471] D-Abu(tetrazol- D-Gly(cPr) Pal(3) 5-yD 2-OCH3-Pal(3) L-Phe(2-OCF3)

[0472] 2-Amino-3- (pyrazin-2- yl)propanoic- D-Abu(tetrazol- D-Gly(cPr) acid 5-yl) Phe(2-OMe) L-Phe(2-OCF3)

[0473] D-Cys(5- Methyl-2H- 3-(4-Quinolyl)-L- D-Gln aThr tetrazole) Dip alanine

[0474] D-Abu(tetrazol- D-aThr Hse 5-yl) L-Phe(2-OCF3) Phe(2-CF3)

[0475] 3-(5- pyrimidinyl)- D-Abu(tetrazol-

[0476]

[0477] D-Pal(4) L-alanine 5-yD L-Phe(2-OCF3) Phe(2-CF3)D-Abu(tetrazol- 319 D-Gly(cPr) Pal(3) 5-yl) L-Phe(2-OCF3) Om(Cbz(2-Cl))

[0478] 4- Pyridazinealan D-Abu(tetrazol- 320 D-Gln ine 5-yl) Phe(2-OMe) Phe(2-CF3)

[0479] D-Abu(tetrazol- 321 D-Gly(cPr) Pal(3) 5-yl) Dip 2-CF3-Pal(4)

[0480] D-Abu(tetrazol- 322 D-Gly(cPr) Ala(cPr) 5-yl) L-Phe(2-OCF3) hPhe(2-3-diF)

[0481] D-Abu(tetrazol- 323 D-Gly(cPr) Pal(3) 5-yl) Dip hPhe(2-3-diF)

[0482] D-Abu(tetrazol- 324 D-Gln Pal(3) 5-yl) Phe(3-5-di-Br) Tyr(PEG3Me)

[0483] D-Abu(tetrazol- 325 D-Gln Leu(3S-OH) 5-yl) Dip hPhe(2-3-diF)

[0484] Phe(3- D-Abu(tetrazol- 3-(4-Quinolyl)-L- 326 D-Gly(cPr) CONH2) 5-yl) Dip alanine

[0485] D-Abu(tetrazol- 327 D-Ala Pal(3) 5-yl) Dip 3-CF3-hPal(4) 3-(2- Tetrazolyl)-L- D-Abu(tetrazol- 3-(4-Quinolyl)-L-

[0486]

[0487] 328 D-Gln alanine 5-yl) Dip alanine

[0488] According to some embodiments, the peptidomimetic does not bind Leu97A and / or Leu97B of the IL-17A protein. According to some embodiments, the peptidomimetic according to the invention does not bind the backbone of Leu97A and / or Leu97B of the IL-17 protein, via a bis amide of the peptidomimetic.

[0489] According to some embodiments, the present invention provides a head-to-tail cyclic penta-peptidomimetic that inhibits the interaction between an interleukin 17 (IL- 17) and an IL-17 receptor (IL-17R), wherein:

[0490] the amino acid at position 1 is selected from the group consisting of D-Ala, D- Gly(cPr), D-Gln, D-Pal(4), D-aThr, D-Ala(cPr), D-Nle(Me), D-Leu(3 S-OH); the amino acid at position 2 is selected from the group consisting of 2-Amino-3- (pyrazin-2-yl)propanoic-acid, 3-(2-Tetrazolyl)-L-alanine, 3-(5-pyrimidinyl)-L- alanine, 3-3-diF-Ala(cBu), 3 -ethoxy -L-phenylalanine, Ala(cBu), Ala(cPr), Cha, Hse, Leu(3S-OH), Pal(3), Phe(3-CONH2), Phe(3-OH(PEG3Me)), Phe(3-OMe), and aThr; the amino acid at position 3 is selected from the group consisting of D-Abu(tetrazol- 5-yl) and D-Cys(5-Methyl-2H-tetrazole);

[0491] the amino acid at position 4 is selected from the group consisting of 2-6-diF-Pal(3), Cys-[Meta-Xylene-mercaptoacetic-acid], Dip, Hse(Ph), L-4-pyridyl-alanine(3-5-di- Br), L-Phe(2-OCF3), Nva(Ph), Phe(2-NO2), Phe(2-OMe), Phe(3-5-di-Br), Phe(F5),Phe(bR-OH), Tyr(3-5-di-Iodo), Tyr(3-5-di-Iodo(PEG3Me)), homoPhe(2-OCF3), homoPhe(3-OCF3), and homoPhe(4-OCF3); and

[0492] the amino acid at position 5 is selected from the group consisting of 1-Nal, 2-CF3- Pal(4), 3-(4-Quinolyl)-L-alanine, Dip, Gly(indan-2-yl), L-(7-azaTrp), Gly(indan-2- yl), L-Phe(2-OCF3), Orn(Cbz(2-Cl)), Phe(2-CF3), Tyr(PEG3Me), hPhe, and hPhe(2- 3-diF).

[0493] According to some embodiments, the cyclic peptidomimetic is Compound No. 194. Compound No. 194, also known as A_17_370, is shown below,

[0494]

[0495] F

[0496] Compound No. 194.

[0497] Position 1 of Compound No. 194 is D-Ala, position 2 is Pal(3), position 3 is D-Abu(tetrazol-5-yl), position 4 is L-Phe(2-OCF3) and position 5 is L-Phe(2-OCF3)). The compound showed an average p(ICso) value of 7.4 from the AlphaLISA and ELISA assays and a p(ICso) of 6.1 from the cell-based assay as indicated by inhibition of IL-8 production, both for inhibition of the IL-17A / IL-17RA complex. Additionally, the compound showed kinetic solubility of 3.4pM and an Exposed Polar Surface Area (EPSA) of 139A2.

[0498] According to some embodiments, the cyclic peptidomimetic is Compound No. 205. Compound No. 205, also known as A_17_417, is shown below,

[0499]

[0500] Compound No.205.

[0501] Position 1 of Compound No. 205 is D-Gln, position 2 is aThr, position 3 is D-Abu(tetrazol-5-yl), position 4 is Dip, and position 5 is 1-Nal. The compound showed a p(ICso) value of 7 from the AlphaLISA assay and a p(ICso) of 6.2 from the cell-based assay as indicated by inhibition of IL-8 production, both for inhibition of the IL-17A / IL-17RA complex. Additionally, the compound showed kinetic solubility of 24.4pM and an EPSA of 172A2.According to some embodiments, the cyclic peptidomimetic is Compound No. 216. Compound No. 216, also known as A_17_507, is shown below,

[0502]

[0503] Compound No. 216.

[0504] Position 1 of Compound No. 216 is D-Gln, position 2 is Pal(3), position 3 is D-Abu(tetrazol-5-yl), position 4 is Phe(2-NO2), and position 5 is Phe(2-CF3). The compound showed a p(ICso) value of 7.2 from the AlphaLISA assay and a p(ICso) of 6.1 from the cell-based assay as indicated by inhibition of IL-8 production, both for inhibition of the IL-17A / IL-17RA complex. Additionally, Compound No. 216 showed a kinetic solubility of 14.3pM.According to some embodiments, the cyclic peptidomimetic is Compound No. 217. Compound No. 217, also known as A_17_508, is shown below,

[0505]

[0506] Compound No.217.

[0507] Position 1 of Compound No. 217 is D-Gly(cPr), position 2 is Pal(3), position 3 is D-Abu(tetrazol-5-yl), position 4 is Dip, and position 5 is Phe(2-CF3)). The compound showed an average p(ICso) value of 7.4 from the AlphaLISA and ELISA assays and a p(ICso) of 6.4 from the cell-based assay as indicated by inhibition of IL-8 production, both for inhibition of the IL-17A / IL-17RA complex. Additionally, the compound showed kinetic solubility of 12.1pM and an EPSA of 153 A2.According to some embodiments, the cyclic peptidomimetic is Compound No. 226. Compound No. 226, also known as A_17_ 521, is shown below,

[0508]

[0509] Compound No. 226.

[0510] Position 1 of Compound No. 226 is D-Pal(4), position 2 is Pal(3), position 3 is D- Abu(tetrazol-5-yl), position 4 is Tyr(3-5-di-Iodo(PEG3Me)), and position 5 is Gly(indan-2-yl). The compound showed a pQCso) value of 7.2 from the AlphaLISA assay and a pQCso) of 6.3 from the cell-based assay as indicated by inhibition of IL-8 production, both for inhibition of the IL-17A / IL-17RA complex. Additionally, Compound No. 226 showed a kinetic solubility of 24.3pM.According to some embodiments, the cyclic peptidomimetic is Compound No. 236. Compound No. 236, also known as A_17_ 532, is shown below,

[0511]

[0512] Compound No.236.

[0513] Position 1 of Compound No. 236 is D-Gly(cPr), position 2 is Pal(3), position 3 is D- Abu(tetrazol-5-yl), position 4 is Dip, and position 5 is 3-(4-Quinolyl))-L-alanine.

[0514] Compound 236 was synthesized by solid phase peptide synthesis using 2-chlorotrityl chloride (CTC) resin (0.2 mmol scale) and HATU / DIPEA (Hexafluorophosphate Azabenzotri azole Tetramethyl Uronium / M-V-Diisopropylethylamine) coupling chemistry. The linear intermediate was cleaved from the resin, yielding 92 mg of material with a purity of 56%. Subsequent N-to-C cyclization was carried out by treating the linear intermediate with PyAOP (7-Azabenzotriazol-l-yl-oxy)tris(pyrrolidino)phosphonium hexafluorophosphate) (1.5 equiv) and DIPEA (3.0 equiv) in DMF at room temperature for 1 hour. Purification yielded 9.6 mg of Compound 236, nc[DGly(cPr)-Pal(3)-DAbu(tetrazol-5-yl)-Dip-(3-(4-Quinolyl)-L-Ala)], with a final purity of 81.9%.

[0515] The compound showed a p(ICso) value of 6.9 from the AlphaLISA assay and a p(ICso) of 6.0 from the cell-based assay as indicated by inhibition of IL-8 production, both for inhibition of the IL-17A / IL-17RA complex. Additionally, Compound No. 236 showed a kinetic solubility of 31 pM.According to some embodiments, the cyclic peptidomimetic is Compound No. 291. Compound No. 291, also known as A_17_429, is shown below,

[0516]

[0517] Compound No.291.

[0518] Position 1 of Compound No. 291 is D-Gly(cPr), position 2 is Ala(cBu), position 3 is D-Abu(tetrazol-5-yl), position 4 is L-Phe(2-OCF3), and position 5 is Phe(2-CF3). The compound showed an average p(ICso) value of 7.4 from the AlphaLISA and ELISA assays and a p(ICso) of 6.2 from the cell-based assay as indicated by inhibition of IL-8 production, both for inhibition of the IL-17A / IL-17RA complex.According to some embodiments, the cyclic peptidomimetic is Compound No. 292. Compound No. 292, also known as A_17_431, is shown below,

[0519]

[0520] Compound No. 292.

[0521] Position 1 of Compound No. 292 is D-Ala(cPr), position 2 is Ala(cPr), position 3 is D-Cys(5-Methyl-2H-tetrazole), position 4 is L-Phe(2-OCF3), and position 5 is Phe(2-CF3). The compound showed an average p(ICso) value of 7.4 from the AlphaLISA and ELISA assays and a pQCso) of 6.3 from the cell-based assay as indicated by inhibition of IL-8 production, both for inhibition of the IL-17A / IL-17RA complex. The compound showed an EPSA of 149A2.According to some embodiments, the cyclic peptidomimetic is Compound No. 293. Compound No. 293, also known as A_17_432, is shown below,

[0522]

[0523] Compound No.293.

[0524] Position 1 of Compound No. 293 is D-Gly(cPr), position 2 is Cha, position 3 is D- Abu(tetrazol-5-yl), position 4 is Phe(2-NO2), and position 5 is Phe(2-CF3). The compound showed an average p Cso) value of 7.2 from the AlphaLISA and ELISA assays and a pQCso) of 6.5 from the cell-based assay as indicated by inhibition of IL-8 production, both for inhibition of the IL-17A / IL-17RA complex. The compound showed an EPSA of 147A2.According to some embodiments, the cyclic peptidomimetic is Compound No. 294. Compound No. 294, also known as A_17_434, is shown below,

[0525]

[0526] Compound No. 294.

[0527] Position 1 of Compound No. 294 is D-Ala(cPr), position 2 is Pal(3), position 3 is D- Abu(tetrazol-5-yl), position 4 is Dip, and position 5 is Phe(2-CF3). The compound showed an average pQCso) value of 7.4 from the AlphaLISA and ELISA assays and a pQCso) of 6.3 from the cell-based assay as indicated by inhibition of IL-8 production, both for inhibition of the IL-17A / IL-17RA complex. The compound showed an EPSA of 146A2and a kinetic solubility of 2pM.According to some embodiments, the cyclic peptidomimetic is Compound No. 296. Compound No. 296, also known as A_17_677, is shown below,

[0528]

[0529] Compound No. 296.

[0530] Position 1 of Compound No. 294 is D-Ala, position 2 is 2-Amino-3-(pyrazin-2-yl)propanoic-acid, position 3 is D-Abu(tetrazol-5-yl), position 4 is Phe(2-OCF3), and position 5 is Phe(2-OCF3). The compound showed an average p(ICso) value of 7.1 from the AlphaLISA and ELISA assays and a p(ICso) of 6.2 from the cell-based assay as indicated by inhibition of IL-8 production, both for inhibition of the IL-17A / IL-17RA complex. The compound showed an EPSA of 132A2.According to some embodiments, the cyclic peptidomimetic is Compound No. 298. Compound No. 298, also known as A_17_571, is shown below,

[0531]

[0532] Compound No. 298.

[0533] Position 1 of Compound No. 298 is D-Gly(cPr), position 2 is Pal(3), position 3 is D- Abu(tetrazol-5-yl), position 4 is Phe(F5), and position 5 is Phe(2-CF3). The compound showed an average p(ICso) value of 7.1 from the AlphaLISA and ELISA assays and a p(ICso) of 5.7 from the cell-based assay as indicated by inhibition of IL-8 production, both for inhibition of the IL-17A / IL-17RA complex. The compound showed a kinetic solubility of 1 IpM.According to some embodiments, the cyclic peptidomimetic is Compound No. 310. Compound No. 310, also known as A_17_701, is shown below,

[0534]

[0535] Compound No.310.

[0536] Position 1 of Compound No. 310 is D-Pal(4), position 2 is Pal(3), position 3 is D- Abu(tetrazol-5-yl), position 4 is L-Phe(2-OCF3), and position 5 is 1-Nal. The compound showed an average p(ICso) value of 7.4 from the AlphaLISA and ELISA assays and a p(ICso) of 6.2 from the cell-based assay as indicated by inhibition of IL-8 production, both for inhibition of the IL-17A / IL-17RA complex. The compound showed a kinetic solubility of 2.3 pM.According to some embodiments, the cyclic peptidomimetic is Compound No. 319. Compound No. 319, also known as A_17_704, is shown below,

[0537]

[0538] Compound No.319.

[0539] Position 1 of Compound No. 319 is D-Gly(cPr), position 2 is Pal(3), position 3 is D- Abu(tetrazol-5-yl), position 4 is L-Phe(2-OCF3), and position 5 is Orn(Cbz(2-Cl). The compound showed an average p(ICso) value of 7.3 from the AlphaLISA and ELISA assays and a p(ICso) of 6.1 from the cell-based assay as indicated by inhibition of IL-8 production, both for inhibition of the IL-17A / IL-17RA complex.According to some embodiments, the cyclic peptidomimetic is Compound No. 322. Compound No. 322, also known as A_17_709, is shown below,

[0540]

[0541] Compound No.322.

[0542] Position 1 of Compound No. 322 is D-Gly(cPr), position 2 is Ala(cPr), position 3 is D- Abu(tetrazol-5-yl), position 4 is L-Phe(2-OCF3), and position 5 is hPhe(2-3-diF). The compound showed an average p(ICso) value of 7.4 from the AlphaLISA and ELISA assays and a p(ICso) of 6.6 from the cell-based assay as indicated by inhibition of IL-8 production, both for inhibition of the IL-17A / IL-17RA complex.According to some embodiments, the cyclic peptidomimetic is Compound No. 323. Compound No. 323, also known as A_17_649, is shown below,

[0543]

[0544] Compound No.323.

[0545] Position 1 of Compound No. 323 is D-Gly(cPr), position 2 is Pal(3), position 3 is D- Abu(tetrazol-5-yl), position 4 is Dip, and position 5 is hPhe(2-3-diF). The compound showed an average p(ICso) value of 7.3 from the AlphaLISA and ELISA assays and a p(ICso) of 6.1 from the cell-based assay as indicated by inhibition of IL-8 production, both for inhibition of the IL-17A / IL-17RA complex. Additionally, the compound showed a kinetic solubility of 6.5pM.

[0546] Potency

[0547] According to some embodiments, the peptidomimetic is characterized by an IL- 17 inhibitory activity, defined as p(ICso) (i.e., inhibition of IL-17-IL-17R interaction, measured as indicated below) of 5 or above. The p(ICso) value of a peptidomimetic, as referred to herein, is as determined by the results of at least one of ELISA, AlphaLISA, Microscale Thermophoresis (MST), a combination thereof, or by any methods known in the art to determine inhibition or the dissociation constant (Kd) of a biological interaction. According to some further embodiments, the peptidomimetic is characterized by an IL-17 inhibitory activity of p(ICso)=5.5 or above, p(ICso)=6 or above, p(ICso)=6.5 or above, p(ICso)=7 or above, orp(ICso)=7.5 or above. Each possibility represents a separate embodiment of the invention. According to some embodiments, the peptidomimetic is characterized by an IL- 17 inhibitory activity of between 4 and 8.5, including each value within the specified range. According to some embodiments, the peptidomimetic is characterized by an IL- 17 inhibitory activity of between 5.5 and 8, including each value within the specified range. According to some embodiments, the peptidomimetic is characterized by an IL-17 inhibitory activity of between 6.5 and 8, including each value within the specified range. According to some embodiments, the peptidomimetic is characterized by an IL-17 inhibitory activity of between 7 and 8, including each value within the specified range. The inhibitory activity is measured for at least one of IL-17A-IL-17R interaction, IL-17F-IL-17R interaction, and IL-17AF-IL-17R interaction. According to some embodiments, the p(ICso) is determined by a single method. According to some embodiments, the p(ICso) is determined by AlphaLisa. According to some embodiments, the p(ICso) is the average p(ICso) as determined by AlphaLisa and ELISA. According to some embodiments, the p(ICso), as determined by AlphaLisa, is at least 6.4. According to some embodiments, the p(ICso), as determined by AlphaLisa, is at least 6.5. According to some embodiments, the p(ICso), as determined by AlphaLisa, is at least 6.7. According to some embodiments, the p(ICso), as determined by AlphaLisa, is at least 6.9. According to some embodiments, the p(ICso), as determined by AlphaLisa, is at least 7.0. According to some embodiments, the average p(ICso) as determined by AlphaLisa and ELISA is 6.7. According to some embodiments, the average p(ICso) as determined by AlphaLisa and ELISA is 6.8. According to some embodiments, the average p(ICso) as determined by AlphaLisa and ELISA is 6.9. According to some embodiments, the average p(ICso) as determined by AlphaLisa and ELISA is 7.0.

[0548] According to some embodiments, the p(ICso) is determined by measuring the reduction of IL-8 in cells, following incubation with a cyclic penta-peptidomimetic. IL-8 levels are used as a readout for IL-17 levels; when IL-17 activation is inhibited (e.g., by a cyclic pentapeptidomimetic of the present invention), IL-8 levels are reduced. According to some embodiments, the peptidomimetic is characterized by an IL-17 inhibitory activity of p(ICso)=5, as determined by the reduction of IL-8 levels in cells. According to some embodiments, the peptidomimetic is characterized by an IL-17 inhibitory activity of p(ICso)=5.5, as determined by the reduction of IL-8 levels in cells. According to some embodiments, the peptidomimetic is characterized by an IL-17 inhibitory activity of p(ICso)=6.O, as determined by the reduction of IL-8 levels in cells. According to some embodiments, the peptidomimetic is characterizedby an IL-17 inhibitory activity of p(ICso)=5.5, 5.6, 5.7, 5.8, 5.9, or 6.0, as determined by the reduction of IL-8 levels and a p(ICso), as determined by AlphaLisa, of at least 6.7, 6.8, 6.9, or 7.0. Each possibility represents a separate embodiment. According to some embodiments, the peptidomimetic is characterized by an IL-17 inhibitory activity of p(ICso)=5.5, 5.6, 5.7, 5.8, 5.9, or 6.0, as determined by the reduction of IL-8 levels in cells and an average p(ICso), as determined by AlphaLisa and ELISA of at least 6.7, 6.8, 6.9, or 7.0. Each possibility represents a separate embodiment. According to some embodiments, the peptidomimetic is characterized by an IL-17 inhibitory activity of p(ICso)= 6.0, as determined by the reduction of IL-8 levels in cells and an average p(ICso), as determined by AlphaLisa and ELISA of at least 7.0.

[0549] The peptidomimetics of the present invention may also be characterized by their kinetic solubility. Kinetic solubility measures how quickly and how much a compound dissolves under specific conditions, capturing a snapshot of dissolution before the system reaches equilibrium. In drug development, it serves as a fast and cost-effective early screening tool to flag compounds at risk of poor bioavailability, assay interference, or formulation challenges. The kinetic solubility may be determined by any method known in the art. According to some embodiments, the kinetic solubility is determined as described herein. According to some embodiments, the cyclic peptidomimetic has a kinetic solubility of 2 pM or greater, 5 pM or greater, 10 pM or greater, 20 pM or greater, or 30 pM or greater. Each possibility represents a separate embodiment.

[0550] The peptidomimetics of the present invention may also be characterized by their Exposed Polar Surface Area (EPSA). EPSA is an experimentally measured form of polar surface area (PSA), determined chromatographically, that captures a molecule's conformationdependent polarity rather than relying on 2D computational estimates. It is particularly valuable for large, flexible molecules like macrocycles, where intramolecular hydrogen bonding can mask polar groups and allow membrane permeability that computational PSA would not predict. In drug development, EPSA helps more accurately forecast passive membrane permeability and oral bioavailability, especially for compounds in the beyond-rule-of-5 space. Its experimental basis makes it a more reliable guide for molecular optimization than calculated PSA alone. EPSA may be determined by any method known in the art. According to some embodiments, EPSA is determined as described herein. According to some embodiments, the cyclic peptidomimetic has an Exposed Polar Surface Area (EPSA) that is in a range of about 130 A2to about 200 A2, including each value within the specified range. According to someembodiments, the cyclic peptidomimetic has an EPSA that is in a range of about 130 A2to about 175 A2, including each value within the specified range.

[0551] The peptidomimetics of the present invention may also be characterized by determining their plasma protein binding. As used herein, "plasma protein binding" refers to the extent to which the peptidomimetic is bound to proteins within the blood plasma as determined by a plasma protein binding assay. The bound fraction refers to the fraction of peptidomimetic that is bound to plasma proteins, which contributes to stability of the peptidomimetic in the body. The plasma protein binding may be determined by any method known in the art. According to some embodiments, the plasma protein binding is determined as described herein.

[0552] According to some embodiments, the present invention provides a cyclic penta-peptidomimetic that inhibits the interaction between IL-17 and IL-17R, wherein:

[0553] the amino acid at position 1, counted from the N-terminus of the pentapeptide before cyclization, is selected from the group consisting of D-Gly(cPr), D-Ala(cPr), D-Ala, D-Pal(4), D-Gln, D-aThr, D-Leu(3S-OH), D-Abu, D-Nle(Me), D-Gln(Pyr), D- Gln(NMe2), and D-Asn(NMe2);

[0554] the amino acid at position 2 is selected from the group consisting of Pal(3), Ala(cPr), Ala(cBu), Cha, 2-Amino-3-(pyrazin-2-yl)propanoic-acid, aThr, Phe(3-OMe), Phe(3- OH(PEG3Me)), L-Nle(6-0H), L-Nle(6-0me), Nva(OMe), 3 -ethoxy -L-phenylalanine, Leu(3S-OH), 3-(5-pyrimidinyl)-L-alanine, Hse, 3-3-diF-Ala(cBu), 2-amino-3-(5- fluoropyri din-3 -yl)propanoic-acid, 4-Pyridazinealanine, PheQ-CONFE), and 3-(2- Tetrazolyl)-L-alanine;

[0555] the amino acid at position 3 is selected from the group consisting of D-Abu(tetrazol- 5-yl) and D-Cys(5-Methyl-2H-tetrazole));

[0556] the amino acid at position 4 is selected from the group consisting of L-Phe(2-OCF3), Dip, Phe(2-NO2), Phe(F5), Phe(2-OMe), Nva(Ph), Tyr(3-5-di-Iodo), Phe(2-OH), homoTyr, Abu(4-pyridyl), Cys-[Meta-Xylene-mercaptoacetic-acid], 5-bromo-2- fluoro-phenylalanine, PhosphoTyr, Tyr(PEG3Me), Tyr(PEG?Me), Tyr(3-5-di- Iodo(PEG3Me)), Phe(bR-OH), Phe(3-5-di-Br), homoPhe(3-OCF3), homoPhe(2- OCF3), homoPhe(4-OCF3), Phe(2-3-di-OH), L-4-pyridyl-alanine(3-5-di-Br), Hse(Ph), 2-6-diF-Pal(3), and 2-OCH3-Pal(3); and

[0557] the amino acid at position 5 is selected from the group consisting of Phe(2-CF3), L- Phe(2-OCF3), 1-Nal, hPhe(2-3-diF), Om(Cbz(2-Cl)), L-(7-azaTrp), Gly(indan-2-yl),Pal(2), Pal(4), beta-(7-methoxy-coumarin-4-yl)-Ala, hPhe, 3 -(4-Quinolyl)-L- Alanine, Phe(2-CONH2), 4-CF3-Pal(3), 2-CF3-Pal(4), Tyr(PEG3Me), 3-CF3-hPal(4), and Dip wherein the p(ICso), as determined by AlphaLisa, is at least 6.5.

[0558] According to some embodiments, the p(ICso), as determined by AlphaLisa, is at least 6.7 and the peptidomimetic is selected from Compound Nos. 222, 291, 217, 247, 253, 255, 206, 215, 230, 256, 264, 279, 322, 323, 227, 234, 241, 243, 244, 246, 259, 268, 272, 280, 282, 292, 294, 310, 194, 204, 226, 242, 245, 263, 277, 293, 319, 326, 189, 190, 192, 203, 207, 216, 233, 238, 239, 257, 271, 278, 290, 296, 213, 240, 285, 297, 298, 299, 205, 211, 214, 249, 252, 254, 260, 269, 283, 306, 208, 221, 231, 236, 270, 301, 303, 308, 321, 324, 328, 193, 199, 218, 235, 250, 258, 265, 274, 295, 309, 318, 320, 209, 210, 220, 288, 305, 311, 314, 315, and 316.

[0559] According to some embodiments, the present invention provides a head-to-tail cyclic penta-peptidomimetic that inhibits the interaction between an interleukin 17 (IL- 17) and an IL-17 receptor (IL-17R), wherein:

[0560] the amino acid at position 1 is selected from the group consisting of D-Ala, D- Gly(cPr), D-Gln, D-Pal(4), D-aThr, D-Ala(cPr), D-Nle(Me), D-Leu(3S-OH); the amino acid at position 2 is selected from the group consisting of 2-Amino-3- (pyrazin-2-yl)propanoic-acid, 3-(2-Tetrazolyl)-L-alanine, 3-(5-pyrimidinyl)-L- alanine, 3-3-diF-Ala(cBu), 3 -ethoxy -L-phenylalanine, Ala(cBu), Ala(cPr), Cha, Hse, Leu(3S-OH), Pal(3), Phe(3-CONH2), Phe(3-OH(PEG3Me)), Phe(3-OMe), and aThr; the amino acid at position 3 is selected from the group consisting of D-Abu(tetrazol- 5-yl) and D-Cys(5-Methyl-2H-tetrazole);

[0561] the amino acid at position 4 is selected from the group consisting of 2-6-diF-Pal(3), Cys-[Meta-Xylene-mercaptoacetic-acid], Dip, Hse(Ph), L-4-pyridyl-alanine(3-5-di- Br), L-Phe(2-OCF3), Nva(Ph), Phe(2-NO2), Phe(2-OMe), Phe(3-5-di-Br), Phe(F5), Phe(bR-OH), Tyr(3-5-di-Iodo), Tyr(3-5-di-Iodo(PEG3Me)), homoPhe(2-OCF3), homoPhe(3-OCF3), and homoPhe(4-OCF3); and

[0562] the amino acid at position 5 is selected from the group consisting of 1-Nal, 2-CF3- Pal(4), 3-(4-Quinolyl)-L-alanine, Dip, Gly(indan-2-yl), L-(7-azaTrp), Gly(indan-2- yl), L-Phe(2-OCF3), Orn(Cbz(2-Cl)), Phe(2-CF3), Tyr(PEG3Me), hPhe, and hPhe(2- 3-diF)

[0563] wherein the p(ICso), as determined by AlphaLisa, is at least 6.9.According to some embodiments, the p(ICso), as determined by AlphaLisa, is at least 6.9 and the peptidomimetic is selected from CompoundNos. 222, 291, 217, 247, 253, 255, 206, 215, 230, 256, 264, 279, 322, 323, 227, 234, 241, 243, 244, 246, 259, 268, 272, 280, 282, 292, 294, 310, 194, 204, 226, 242, 245, 263, 277, 293, 319, 326, 189, 190, 192, 203, 207, 216, 233, 238, 239, 257, 271, 278, 290, 296, 213, 240, 285, 297, 298, 299, 205, 211, 214, 249, 252, 254, 260, 269, 283, 306, 208, 221, 231, 236, 270, 301, 303, 308, 321, 324, and 328.

[0564] According to some embodiments, the p(ICso), as determined by AlphaLisa, is at least 7.0 and the peptidomimetic is selected from CompoundNos. 222, 291, 217, 247, 253, 255, 206, 215, 230, 256, 264, 279, 322, 323, 227, 234, 241, 243, 244, 246, 259, 268, 272, 280, 282, 292, 294, 310, 194, 204, 226, 242, 245, 263, 277, 293, 319, 326, 189, 190, 192, 203, 207, 216, 233, 238, 239, 257, 271, 278, 290, 296, 213, 240, 285, 297, 298, 299, 205, 211, 214, 249, 252, 254, 260, 269, and 283.

[0565] According to some embodiments, the p(ICso), as determined by the average of the AlphaLisa and ELISA p(ICso) values, is at least 7 and the peptidomimetic is selected from Compound Nos. 247, 253, 206, 279, 222, 291, 217, 255, 322, 292, 294, 310, 194, 263, 230, 323, 241, 243, 246, 280, 319, 189, 234, 244, 245, 277, 293, 203, 216, 278, 290, 240, 227, 268, 272, 204, 226, 190, 296, 297, 252, 231, 301, 242, 326, 192, 207, 233, 257, 271, 298, 269, 306, and 304.

[0566] According to some embodiments, the p(ICso), as determined by the average of the AlphaLisa and ELISA p(ICso) values, is at least 7, the p(ICso) as determined by inhibition of IL-8 release is at least 6.0 and the peptidomimetic is selected from Compound Nos. 246, 233, 322, 280, 293, 278, 204, 217, 241, 277, 301, 292, 294, 203, 226, 231, 279, 291, 255, 310, 243, 296, 206, 194, 230, 323, 319, 189, 216, 242, 253, and 240.

[0567] According to some embodiments, the p(ICso), as determined by the average of the AlphaLisa and ELISA p(ICso) values, is at least 7. According to some embodiments, the p(ICso), as determined by the average of the AlphaLisa and ELISA p(ICso) values, is between 7 and 7.8. According to some embodiments, the IC50 is between about 10 and 100 nM. According to some embodiments, the p(ICso), as determined by the average of the AlphaLisa and ELISA p(ICso) values, is at least 7 and the amino acid at position 1 is a D-amino acid. According to some embodiments, the p(ICso), as determined by the average of the AlphaLisa and ELISA p(ICso) values, is at least 7 and the amino acid at position 1 is selected from the group consisting of D-Gly(cPr), D-Ala(cPr), D-Ala, D-Pal(4), D-Gln, D-aThr, D-Leu(3 S-OH), D-Abu, D-Nle(Me), D-Gln(Pyr), D-Gln(NMe2), and D-Asn(NMe2).

[0568] According to some embodiments, the p(ICso), as determined by the average of the AlphaLisa and ELISA p(ICso) values, is at least 7 and the amino acid at position 3 position 3 is composed of negatively charged or partially negatively charged residues of D chirality. According to some embodiments, the p(ICso), as determined by the average of the AlphaLisa and ELISA p(ICso) values, is at least 7 and the amino acid at position 3 is selected from the group consisting of D-Abu(tetrazol-5-yl) and D-Cys(5-Methyl-2H-tetrazole)). According to some embodiments, the p(ICso), as determined by the average of the AlphaLisa and ELISA p(ICso) values, is at least 7 and the amino acid at position 3 is D-Abu(tetrazol-5-yl).

[0569] According to some embodiments, the p(ICso), as determined by an AlphaLisa value of least 6.9 and the amino acid at position 2 is a 6-member aromatic ring with a hydrogen bond accepting moiety as either a part of the aromatic ring or directly attached to it. According to some embodiments, the p(ICso), as determined by an AlphaLisa value of at least 6.9 and the amino acid at position 2 is selected from the group consisting of 2-Amino-3-(pyrazin-2-yl)propanoic-acid, 3-(2-Tetrazolyl)-L-alanine, 3-(5-pyrimidinyl)-L-alanine, 3-3-diF-Ala(cBu), 3 -ethoxy -L-phenylalanine, Ala(cBu), Ala(cPr), Cha, Hse, Leu(3S-OH), Pal(3), Phe(3-CONH2), Phe(3-OH(PEG3Me)), Phe(3-OMe), and aThr. According to some embodiments, the p(ICso), as determined an AlphaLisa value is at least 7 and the amino acid at position 4 comprises modified phenylalanine residues of L chirality. According to further embodiments, the modified phenylalanine residues comprise volume-filling moieties. According to some embodiments, the p(ICso), as determined by the an AlphaLisa value of at least 7 and the amino acid at position 4 is selected from the group consisting of 2-6-diF-Pal(3), Cys-[Meta-Xylene-mercaptoacetic-acid], Dip, Hse(Ph), L-4-pyridyl-alanine(3-5-di-Br), L-Phe(2-OCF3), Nva(Ph), Phe(2-NO2), Phe(2-OMe), Phe(3-5-di-Br), Phe(F5), Phe(bR-OH), Tyr(3-5-di-Iodo), Tyr(3-5-di-Iodo(PEG3Me)), homoPhe(2-OCF3), homoPhe(3-OCF3), and homoPhe(4-OCF3).

[0570] According to some embodiments, the p(ICso), as determined by an AlphaLisa value of at least 7 and the amino acid at position 5 comprises a single 6-membered aromatic ring or a double aromatic ring. According to further embodiments, the amino acid at position 5 comprises homoaromatic or heteroaromatic rings. According to some embodiments, the p(ICso), as determined by anAlphaLisa value ofat least 6.9 and the amino acid at position 5 is selected from the group consisting of 1-Nal, 2-CF3-Pal(4), 3-(4-Quinolyl)-L-alanine, Dip, Gly(indan-2-yl),L-(7-azaTrp), Gly(indan-2-yl), L-Phe(2-OCF3), Orn(Cbz(2-Cl)), Phe(2-CF3), Tyr(PEG3Me), hPhe, and hPhe(2-3-diF).

[0571] Any peptidomimetics as disclosed herein can be modified by the substitution of one or more residues at different, possibly selective, sites within the peptide chain, if not otherwise stated. Such substitutions may be of a conservative nature, for example, where one amino acid is replaced by an amino acid having similar structure and characteristics, such as where a hydrophobic amino acid is replaced by another hydrophobic amino acid. Even more conservative would be replacement of amino acids of the same or similar size and chemical nature, such as where leucine is replaced by isoleucine. In studies of sequence variations in families of naturally occurring homologous proteins, certain amino acid substitutions are more often tolerated than others, and these often show a correlation with similarities in size, charge, polarity, and hydrophobicity between the amino acid and its replacement, and such is the basis for defining “conservative substitutions".

[0572] Conservative substitutions are defined, according to some embodiments, as exchanges within one of the following five groups: Group 1 -small aliphatic, nonpolar or slightly polar residues (Ala, Ser, Thr, Pro, Gly); Group 2-polar, negatively charged residues and their amides (Asp, Asn, Glu, Gin); Group 3 -polar, positively charged residues (His, Arg, Lys); Group 4-large, aliphatic, nonpolar residues (Met, Leu, He, Vai, Cys); and Group 5-large, aromatic residues (Phe, Tyr, Trp).

[0573] Less conservative substitutions might involve the replacement of one amino acid by another that has similar characteristics but is somewhat different in size, such as replacement of an alanine by an isoleucine residue. Highly non-conservative replacements might involve substituting an acidic amino acid for one that is polar, or even for one that is basic in character.

[0574] Pharmaceutical and cosmetic compositions and uses thereof

[0575] According to some further embodiments, the present invention provides a pharmaceutical composition comprising a compound and / or salt of one of the embodiments of the peptidomimetics as described herein above, and at least pharmaceutically acceptable carrier, diluent and / or excipient.

[0576] Compounds of the present invention are potent inhibitors of the interaction of IL-17A, IL-17F, and IL-17AF with IL- 17 receptor, and upon administration to a patient in need thereof, may provide therapeutic benefits while avoiding certain problems associated for example with inhibitory antibodies for IL- 17. As such, compounds of the present invention are believed to beuseful for the treatment, prevention, and / or improving symptoms of diseases or conditions in which excessive IL- 17 mediated signaling plays a role, including relief of certain immunologically- or inflammatory-mediated symptoms. Such conditions include, for example, psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, inflammatory bowel disease (IBD), COPD, age-associated skin condition, and allograft rejection.

[0577] According to some particular embodiments of the invention, there is provided a pharmaceutical composition for treating psoriasis, comprising at least one peptidomimetic according to the invention as described hereinabove, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, or diluents. In a further embodiment the invention provides a pharmaceutical composition for treating rheumatoid arthritis, comprising at least one peptidomimetic according to the invention as described hereinabove, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, or diluents. In another embodiment the invention provides a pharmaceutical composition for treating multiple sclerosis, comprising at least one peptidomimetic according to the invention as described hereinabove, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, or diluents.

[0578] The peptidomimetics and / or compositions disclosed herein may also be used in combination with one or more other active ingredients. In certain embodiments, the compounds may be administered in combination, or sequentially, with another therapeutic agent. Such other therapeutic agents include those known for treatment, prevention, or amelioration one or more symptoms associated with, for example, inflammation or autoimmune disease.

[0579] In certain further embodiments, combinations of 2 or more of the peptidomimetics disclosed herein may be used in treatment of a subject in need thereof. The combination may include formulating a composition comprising 2 or more different peptidomimetics, or administration of two separate compositions.

[0580] According to further embodiments, the present invention provides a method for treating a patient suffering from an IL- 17 associated disease, condition, or disorder, namely, a disease, condition, or disorder in which elevated levels of IL-17A, IL-17F and / or IL-17AF play a role.According to some embodiments, the IL-17 associated disease, condition, or disorder is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, COPD, age-associated skin condition, and / or allograft rejection, the method comprising administering to a patient in need thereof an effective amount of at least one peptidomimetic according to the invention as described hereinabove, or a pharmaceutically acceptable salt thereof.

[0581] According to some particular embodiments, the method of treating a patient suffering from a disease or condition associated with elevated levels of IL-17A (and / or IL-17F / IL-17AF) comprises a preliminary step of determining whether the patient has an elevated level of one or more IL-17-induced chemokine, cytokine or effector, and, if the result is in the affirmative, administering to the patient an effective amount of at least one peptidomimetic according to the present invention, or of a composition comprising such a peptidomimetic, to treat the disease or condition. The measured IL-17A dependent chemokine, cytokine or effector may be one or more of IL-8, Gro-alpha (i.e., Cxcll gene), IL-1 A, TNF-alpha, IL-6, IL-22, S100a7a, CK-16, and IL-lbeta.

[0582] Further, the present invention provides a method of treating psoriasis, comprising administering to a patient in need thereof an effective amount of at least one peptidomimetic according to the invention as described hereinabove, or a pharmaceutically acceptable salt thereof. Further, the present invention provides a method of treating rheumatoid arthritis, comprising administering to a patient in need thereof an effective amount of at least one peptidomimetic according to the invention as described hereinabove, or a pharmaceutically acceptable salt thereof. Further, the present invention provides a method of treating multiple sclerosis, comprising administering to a patient in need thereof an effective amount of at least one peptidomimetic according to the invention as described hereinabove, or a pharmaceutically acceptable salt thereof. Further, the present invention provides a method of treating spondyloarthritis, comprising administering to a patient in need thereof an effective amount of at least one peptidomimetic according to the invention as described hereinabove, or a pharmaceutically acceptable salt thereof.

[0583] Any stage and severity of plaque psoriasis may be treated with the compositions of the present invention, including mild, moderate, and severe stages. According to some embodiments, the disease is moderate to severe plaque psoriasis. According to someembodiments, the disease is moderate plaque psoriasis. According to other embodiments, the disease is severe plaque psoriasis.

[0584] In specific embodiments, the compositions of the present invention are administered to a subject suffering from psoriasis, as part of a treatment regimen that includes additional therapies and treatment for psoriasis. The additional therapies and treatments may include but are not limited to topical corticosteroids, Acitretin, vitamin D analogs, methotrexate, and cyclosporine.

[0585] In human therapeutics, the physician will determine the dosage regimen that is most appropriate according to a preventive or curative treatment and according to the age, weight, stage of the disease and other factors specific to the subject to be treated. The amount of active ingredient in the pharmaceutical composition provided herein, which will be effective in the prevention or treatment of the IL- 17 associated disease will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disease or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject. The active ingredient may be administered at once or may be divided into a number of smaller doses to be administered at intervals of time.

[0586] According to some particular embodiments, administration of the pharmaceutical composition is local, parenteral, or enteral. Each possibility represents a separate embodiment. According to some embodiments, administration of the pharmaceutical composition is topical, intravenous, or oral. According to some embodiments, administration of the pharmaceutical composition is topical. According to some embodiments, administration of the pharmaceutical composition is intravenous. According to some embodiments, administration of the pharmaceutical composition is oral. According to some embodiments, administration of the pharmaceutical composition is by injection, infusion, inhalation or as a nasal spray. According to some embodiments, administration of the pharmaceutical composition is intradermal or subcutaneous. According to some embodiments, administration of the pharmaceutical composition is locally to the dermis. According to some embodiments, administration of the pharmaceutical composition is by electroporation, using methods and devices known in the art.

[0587] According to some embodiments, administration of the pharmaceutical composition is topical. According to some embodiments, administration of the pharmaceutical composition isintravenous. According to some embodiments, administration of the pharmaceutical composition is oral. Other administration routes known in the art are also contemplated.

[0588] In one embodiment, the present invention provides at least one peptidomimetic as described hereinabove, or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis. In another particular embodiment the invention provides at least one peptidomimetic as described hereinabove, or a pharmaceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis. In another particular embodiment the invention provides at least one peptidomimetic as described hereinabove, or a pharmaceutically acceptable salt thereof, for use in treating multiple sclerosis. In another particular embodiment the invention provides at least one peptidomimetic as described hereinabove, or a pharmaceutically acceptable salt thereof, for use in treating spondyloarthritis. In another particular embodiment the invention provides at least one peptidomimetic as described hereinabove, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, IBD, COPD, age-associated skin condition, and / or allograft rejection.

[0589] In yet another embodiment, the present invention provides the use of at least one peptidomimetic as described hereinabove, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of psoriasis. In yet another embodiment, the present invention provides the use of at least one peptidomimetic as described hereinabove, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of rheumatoid arthritis. In yet another embodiment, the present invention provides the use of at least one peptidomimetic as described hereinabove, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of multiple sclerosis. In yet another embodiment, the present invention provides the use of at least one peptidomimetic as described hereinabove, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of spondyloarthritis. In yet another embodiment, the present invention provides the use of at least one peptidomimetic as described hereinabove, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of disease or disorder selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis(PPP), atopic dermatitis, asthma, IBD, COPD, age-associated skin condition, and / or allograft rejection.

[0590] According to some embodiments, the peptidomimetic is selected from the compounds (Comp.) presented in Tables 1 and 2.

[0591] According to some embodiments, a cosmetic composition is provided, comprising at least one cyclic penta-peptidomimetic as disclosed herein above, and at least one cosmetically acceptable excipient, salt, or carrier.

[0592] The term ‘cosmetically acceptable’ as used herein refers to all carriers and / or excipients and / or diluents and / or salts conventionally used in cosmetic compositions and that do not abrogate the beneficial activity and properties of the peptide of the present invention.

[0593] According to other embodiments, a cosmetic composition is provided, comprising at least one cyclic penta-peptidomimetic as disclosed herein above, and at least one dermatologically acceptable excipient, salt, or carrier.

[0594] The term “dermatologically acceptable” as used herein refers to a carrier and / or an excipient and / or a diluent and / or a salt that does not cause significant irritation to the skin and that do not abrogate the beneficial activity and properties of the peptide of the present invention. Suitable dermatologically acceptable carriers within the scope of the present invention include, but are not limited to, a thickener, a filler, a moisturizer, an emulsifier, a humectant, a surfactant, a buffering or pH adjusting agent, a film forming agent, a foaming agent, an anti-foaming agent, a preservative, an anti-oxidant, a fragrance, a solvent, a propellant, a colorant, and a combination or mixture thereof. Each possibility represents a separate embodiment.

[0595] According to some embodiments, the cosmetic composition comprises at least two different cyclic penta-peptidomimetics.

[0596] According to some embodiments, the cosmetic composition comprises at least one additional ingredient. Ingredients that may be included in the compositions of the present invention include but are not limited to vitamins and vitamin derivatives such as, for example vitamin A, vitamin B, vitamin D, vitamin E, vitamin K and derivatives thereof including, for example, a tocopherol; and various plant extracts such as, for example, shea butter, aloe vera, aloe bar hade nsis. castor oil, citrus limonium. citrus paeadisi. citrus sinensis, elaesis guineensis, etc. The additional ingredient may be an active or an inactive ingredient, so long as the additional ingredient does not impart a deleterious effect on the activity of the peptidomimetic. Additional ingredients that may be included in the compositions of the present invention aresunscreens and tanning agents. Sunscreens include those materials commonly employed to block UV light. Illustrative compounds are the derivatives of PABA, cinnamate and salicylate. For example, octyl methoxycinnamate and 2-hydroxy-4-methoxy benzophenone (also known as oxybenzone) can be used. Octyl methoxycinnamate and 2-hydroxy-4-methoxy benzophenone are also known as parsol MCX and benzophenone-3, respectively. Other ingredients may include coal tar, salicylic acid, ceramides, glycerin, hyaluronic acid, and retinoids.

[0597] According to some embodiments, the at least one additional ingredient is selected from coal tar, salicylic acid, a ceramide, glycerin, hyaluronic acid, a retinoid, a sunscreen, a tanning agent, a vitamin, and a plant extract.

[0598] According to some embodiments, the cosmetic composition is formulated for local administration. According to some embodiments, the local administration is topical administration. According to some embodiments, the local administration is intradermal administration.

[0599] According to some embodiments, the cosmetic composition may be formulated as an oil, a gel, a stick, a lotion, a cream, a milk, an aerosol, a spray, a foam, a mousse, an ointment, liquid drops, nebulized liquid, a liquid wash, an emulsion, a suspension, liposomes, an adhesive patch, and a powder. Each possibility represents a separated embodiment. According to some embodiments, the cosmetic composition is formulated as a lotion, a cream, an ointment, a paste, a gel, a hydrogel and the like, or as powder. Each possibility represents a separated embodiment. According to other embodiments, the cosmetic composition is formulated as a solution, mist, or spray.

[0600] According to some embodiments, the cosmetic composition is for use in the prevention, treatment, alleviation of a cosmetic condition, disorder or disease.

[0601] According to some embodiments, the cosmetic condition comprises a skin disorder or an appearance of the skin.

[0602] According to some embodiments, the cosmetic condition is selected from, but not limited to: acne (particularly mild to moderate, and including post-acne marks), excess oil production (including seborrhoea), enlarged pores, hyperpigmentation (including post-inflammatory hyperpigmentation), melasma, dark spots, sunspots and age spots, age signs and wrinkles (including fine lines and deep wrinkles), loss of skin elasticity, sagging and dull skin, sensitive and reactive skin (e.g., rosacea, or eczema), skin redness and irritation, rosacea-proneskin, eczema and atopic dermatitis marks, barrier dysfunction, dry and dehydrated skin, flaky, rough skin, tightness and discomfort of the skin, xerosis (severe dry skin), dark eye circles and puffy eyes, under-eye pigmentation, puffiness and swelling, fine lines and crepey skin. Each possibility represents a separate embodiment.

[0603] According to some embodiments, the cosmetic condition is associated with psoriasis. According to some embodiments, the cosmetic condition associated with psoriasis is selected from one or more of altered skin texture, skin discoloration, and flaky scalp.

[0604] According to some embodiments, the present invention provides a method for preventing, treating, or alleviating a cosmetic condition or disorder, the method comprising administering an effective amount of a compound according to the present invention, or a cosmetically acceptable salt thereof. According to some embodiments, the present invention provides a method for preventing, treating, or alleviating a cosmetic condition or disorder, the method comprising administering an effective amount of a compound according to the present invention, or a dermatologically acceptable salt thereof.

[0605] According to some embodiments, the cosmetic condition comprises a skin disorder or an appearance of the skin. According to some embodiments, the cosmetic condition comprises a skin disorder or an appearance of the skin related to aging. According to some embodiments, the cosmetic condition is related to psoriasis. According to some embodiments, the cosmetic condition related to psoriasis is selected from skin texture, skin discoloration, and flaky scalp.

[0606] According to some embodiments, the cosmetic composition is administered by local administration. According to some embodiments, the local administration is topical administration. According to some embodiments, the local administration is intradermal administration.

[0607] According to some embodiments, the cosmetic composition is administered as an oil, a gel, a stick, a lotion, a cream, a milk, an aerosol, a spray, a foam, a mousse, an ointment, liquid drops, nebulized liquid, a liquid wash, an emulsion, a suspension, liposomes, an adhesive patch, and a powder. Each possibility represents a separated embodiment. According to some embodiments, the cosmetic composition is administered as a lotion, a cream, an ointment, a paste, a gel, a hydrogel, and the like, or as a powder. Each possibility represents a separated embodiment.

[0608] According to other embodiments, the cosmetic composition is administered as a solution,a mist, or a spray. Each possibility represents a separated embodiment.

[0609] As used herein, the terms "increase" and "decrease" mean, respectively, to cause a statistically significantly (i.e., p < 0.1) increase or decrease of at least 5%.

[0610] As used herein, the recitation of a numerical range for a variable is intended to convey that the variable is equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable is equal to any integer value within the numerical range, including the end-points of the range. Similarly, for a variable which is inherently continuous, the variable is equal to any real value within the numerical range, including the end-points of the range. As an example, and without limitation, a variable which is described as having values between 0 and 2 takes the values 0, 1 or 2 if the variable is inherently discrete, and takes the values 0.0, 0.1, 0.01, 0.001, or any other real values > 0 and < 2 if the variable is inherently continuous.

[0611] As used herein, unless specifically indicated otherwise, the word "or" is used in the inclusive sense of "and / or" and not the exclusive sense of "either / or."

[0612] As used herein, the singular forms “a”, “an”, and “the” include plural forms unless the context clearly dictates otherwise.

[0613] As used herein the term “about” refers to ± 10 %.

[0614] The terms “comprise”, “comprising”, “include”, “including”, “having” and their conjugates mean “including, but not limited to”.

[0615] The following examples are intended to be merely illustrative in nature and to be construed in a non-limitative fashion.

[0616] EXAMPLES

[0617] Methods

[0618] Microscale Thermophoresis

[0619] The dissociation constant (Kd) of the interaction between IL-17 and the peptidomimetics may be measured by Microscale Thermophoresis (MST) using a Monolith NT.115 instrument. Biotinylated Human IL-17A / CTLA-8 Protein, His, Avi tag (ILA-H82Q1, Aero biosystem) is labeled using His-Tag Labeling Kit RED-tris-NTA 2ndGeneration (MO-L018, NanoTemperTechnologies) according to the manufacturer’s instructions. Binding experiments are conducted with 12.5nM of protein in binding buffer (lOmM Hepes pH 7.4, 0.05% Tween20, and 2% DMSO) and peptidomimetics concentrations ranging from 0.031 to 100,000 nM. The interaction affinity and Kd is analyzed using the MO. Control Analysis software (version 2.2.4; NanoTemper Technologies).

[0620] AlphaLISA Assay

[0621] Biotinylated Human IL-17A / CTLA-8 Protein, His, Avi tag (ILA-H82Q1) and IL-17RA / IL-17R Fc Chimera Protein Fc (#177-IR) were purchased from Aero biosystems and R&D Systems respectively; White 384 Opti plate (6007290), Protein A acceptor beads (AL101M), and streptavidin donor beads (67660002) were purchased from Perkin Elmer. Peptidomimetics were first dissolved in 100% DMSO, then diluted in assay buffer (50 mM Hepes, pH 7.4, 150mM NaCl, 5mM CaCl2, 0.01% BSA, 0.05% Tween20) in 6 concentrations and then incubated with IL-17A at 0.746nM for Ih. 40 microliter of hIL-17R Fc at 8nM was added to the plate for 1 hour incubation. After the incubation, the samples were transferred to a White 384 Opti plate in 20 microliter triplicates. Detection step was performed by first adding 10 microliter of Protein A acceptor beads for 1 hour and then 10 microliter of streptavidin donor beads at 20 microgram / ml final concentration. The plate was incubated for one hour at room temperature, then read on the Victor Nivo Multimode plate reader (Perkin Elmer). Positive controls (maximum signal) were wells with IL- 17 without peptide, and negative control (minimum signal) were wells with assay buffer. A standard curve was prepared usingl2 concentrations. The relative IC50 values were determined using a four-parameter logistic. In the four-parameter logistic, bottom and top are defined as the plateaus of the curve, and H is the Hill Slope. Percent inhibition was determined by fitting the calculated AlphaLISA signal values to a standard 4-parameter logistic and non-linear regression analysis was performed using Prism software.

[0622] Indirect competitive ELISA (termed “ELISA”)

[0623] Coating buffer (BUF030A), blocking buffer (ELISA Sin block BUF034B), and TMB (BUF054B) were purchased from Bio Rad; and Pierce high sensitivity streptavidin - HRP (TS-21130) was obtained from Thermo Fisher.

[0624] High binding plates (CL3590, Thermo) were coated with 8nM rhIL-17 in coating buffer and incubated overnight at 25°C. Plates were washed 3x times by adding 300 pl of assay buffer (50 mM Hepes, pH 7.4, 150mMNaCl, 5mMCaCl2, 0.05% Tween 20, 0.01 %BSA, 2% DMSO)per well. Blocking buffer (150 pl / well) was added for incubation of 2 hours, while the peptides were preincubated for 1 hour with hIL-17A at 0.24 nM. Each peptide was tested at 8 different concentrations. As a positive control (maximum signal), wells were incubated with IL-17 without inhibitor, and as a negative control (minimum signal), wells were incubated with assay buffer and ELISA reagents. After the blocking step, wells were washed 3 times and 100 microliters of peptide:IL-17A complex were added to precoated plates in duplicate. After 1 hour of incubation, wells were washed and HRP (100 pl per well; 40 ng / ml) was added. After incubation and washing, TMB substrate was added (100 pl / well), and, following development of blue color, absorbance at 655 nm (ODess) values were obtained using a Victor Nivo Multimode plate reader (PerkinElmer). In each experiment, a standard curve was prepared from 12 concentrations. Percent inhibition was determined by fitting the calculated signal values to a standard 4-parameter logistic and non-linear regression analysis was performed using Prism software.

[0625] Primary Keratinocytes Cell Assay

[0626] This cell-based assay is used to determine the IL-17 inhibitory activity of the compounds of the invention by measuring the reduction in IL-8 release from cells. Primary keratinocytes were cultured in a 384 well plate at 3,500 cells per well in a serum-free medium (C-20021, Promocell). 24h after seeding, peptides were added to the cells at 7 different concentrations. Following the addition of the peptides, cells were treated with Human IL-17A (ILA-H82Q1, 3 ng / ml final concentration) and TNF-a (TNA-H4211, lOng / ml final concentration), or with TNF-a alone. Following 48 h of incubation, culture medium was collected from the cells and analyzed for IL-8 levels using AlphaLISA kit (AL224F, Perkin Elmer).

[0627] Percent of inhibition was determined by fitting the calculated signal values to a standard 4-parameter logistic and non-linear regression analysis using Prism software.

[0628] Kinetic Solubility Assay

[0629] Kinetic solubility was determined using the shake-flask method followed by HPLC-UV analysis. Test compounds were prepared as 10 mM stock solutions in 100% DMSO, and approximately 100 pL of stock solution was used per assay. Aliquots of each stock solution (10 uL) were added to assay buffer (490 uL) pre-dispensed in Mini-Uniprep filter vials, using the buffer specified for the study. Samples were vortexed for 2 min and then incubated at room temperature on an orbital shaker for 24 h. After incubation, samples were filtered directly using the syringeless filter device, and aliquots of the filtrate were transferred to a 96-deep-well platefor analysis. The concentration of dissolved compound in the filtrate was quantified by HPLC-UV Three calibration standards were injected from low to high concentration before analysis of the kinetic solubility samples, and test samples were injected in duplicate. Solubility results were calculated and reported in pM and ug / mL using the molecular weights.

[0630] Experimental polar surface area assay

[0631] Experimental polar surface area (EPSA) was measured by supercritical fluid chromatography using an Agilent 1260 SFC Infinity II system equipped with UV and MS detection. Separation was performed on a Phenomenex Chirex (S)-VAL (R)-NEA column (4.6 x 250 mm, 5 pm) maintained at 40 °C, with a flow rate of 4 mL / min, a backpressure regulator set to 140 BarG, a detection wavelength of 220 nm, and an injection volume of 5 pL. Mobile phase A consisted of CO2 and mobile phase B consisted of MeOH containing 20 mM ammonium formate. The gradient was run from 95:5 to 40:60 (A:B) over 9 min. Samples were prepared at 2 mg / mL in DMSO and sonicated prior to analysis. EPSA values were determined using a calibration curve generated from a set of reference compounds with known EPSA values analyzed under identical conditions. The EPSA of each peptide was calculated based on its retention time relative to the standard compounds, with earlier elution corresponding to lower effective polarity in the SFC system.

[0632] Plasma Protein Binding Assay

[0633] Plasma protein binding (PPB) was determined using an equilibrium dialysis method. Test compounds were spiked into pooled plasma at a final concentration of 2 pM. Aliquots of 150 pL of compound-spiked plasma were loaded into one side of a 96-well equilibrium dialysis plate, while an equal volume of dialysis buffer (100 mM sodium phosphate, 150 mM NaCl, pH 7.4 ± 0.1) was added to the opposite side. A plasma aliquot was collected prior to incubation for recovery assessment. The plate was incubated at 37 °C in a humidified atmosphere with 5% CO2 for 4 h to allow equilibration. Following incubation, samples were collected from both plasma and buffer compartments. Plasma samples were diluted with blank buffer and buffer samples with blank plasma to ensure matrix matching, then quenched with a stop solution containing an internal standard. Samples were analyzed by LC-MS / MS, and compound concentrations were determined based on analyte -to-internal standard peak area ratios. The fraction unbound, fraction bound, and recovery were calculated from the measured concentrations in plasma and buffer compartments.Example 1: Identification of IL-17 inhibitory cyclic peptidomimetics

[0634] In an attempt to produce small molecules that operate as stable and effective inhibitors of IL-17-IL-17R interaction, an Al-based algorithm performed virtual screening on the unbound structure of Interleukin- 17A homodimer (PDB: 4HR9), centered at a dynamic radius grid around Gin 94 of chain A of IL-17. Following the virtual screening, peptides comprising 5 amino acids linked by peptide bonds, were generated by the software, wherein the AA in each position was selected from a pool of about 600 different AAs that were selected by the software as potentially suitable for forming an IL- 17 inhibitory peptidomimetic. The peptidomimetics which received the highest estimated IL- 17 binding scores in the algorithm (out of about 10° possibilities) were synthesized by WuXi AppTec, using Fmoc chemistry, and were screened for inhibition of IL-17-IL-17R interaction. To this end, the peptidomimetics were subjected to an AlphaLISA Assay and to an indirect competitive ELISA assay at various concentrations (6 and 8 different concentrations, respectively), according to the protocols set out in the Methods section hereinabove. The response curves of the different cyclic peptidomimetic concentrations were then used to determine 50% Inhibitory Concentration (IC50) values for each peptidomimetic. For convenience of presentation, the IC50 values are shown in Table 3 as p(ICso) values, attained by the formula:

[0635] p(ICso) = -1 *log(ICso), using abase 10 logarithm.

[0636] Out of the tested peptidomimetic compounds, 140 peptidomimetics were found to inhibit IL- 17 with a p(IC5o)>=5.O, as determined by AlphaLISA. Some of the peptidomimetics were found to inhibit IL- 17 with a p(IC5o)>=6.9, as determined by AlphaLISA and / or with an average p(IC5o)>=7.O, calculated from the AlphaLisa and ELISA results.

[0637] Exemplary results of the AlphaLISA are presented in Figures 2A-2D. Exemplary results of the indirect competitive ELISA are presented in Figures 3A-3D.

[0638] Example 2: Inhibition of IL-17-IL-17R interaction in keratinocytes

[0639] Following establishment of the inhibitory effectivity of the peptidomimetics under in vitro conditions, the peptidomimetics were further examined for their ability to alter cellular activity by preventing activation of the IL- 17 receptor in cell culture. Primary keratinocytes were cultured in a 384 well plate with 3,500 cells per well in a serum-free medium (C-20021, Promocell). 24h after seeding, cyclic penta-peptidomimetics were added to the cells, at 7 different concentrations. Following the addition of the cyclic peptidomimetics, cells weretreated with Human IL-17A (ILA-H82Q1, 3 ng / ml final concentration) and TNF-a (TNA-H4211, lOng / ml final concentration), or with TNF-a alone. Incubation with TNF-a alone served as a background for the synergistic activation of IL-17A and TNF-a. Following 48h of incubation, culture medium was collected from the cells and analyzed for IL-8 levels (as a readout for IL- 17 inhibition) using an AlphaLISA kit (AL224F, Perkin Elmer). Percent of inhibition was determined by fitting the calculated signal values to a standard 4-parameter logistic and non-linear regression analysis was performed using Prism software.

[0640] Graphs representing the IL-8 level reduction as a function of the rise in concentration in the cell culture medium of exemplary peptidomimetics are shown in Figures 4A-4D. The p(ICso) values of each of the examined peptidomimetic, calculated based on the IL-8 reduction curves at the different cyclic peptidomimetic concentrations, are set out in Table 3.

[0641] Table 3: In-vitro IL-17A inhibitory activity of selected peptidomimetics

[0642] No. pIC(50) IL- pIC(50) AVG p(IC50) IL-17A

[0643] 17A IL-17A pIC(50) (IL-8 reduction)

[0644] (AlphaLisa) (ELISA)

[0645] 189 7.2 7.3 7.3 6.1

[0646] 190 7.2 7.1 7.1 - 191 6.1 - - - 192 7.2 6.7 7.0 5.8

[0647] 193 6.8 6.4 6.6 0.0

[0648] 194 7.3 7.4 7.4 6.1

[0649] 195 6.5 6.9 6.7 0.0

[0650] 196 5.9 - - - 197 5.6 - - - 198 5.6 - - - 199 6.8 - - - 200 6.4 - - 0

[0651] 201 6.6 7.3 6.9 5.6

[0652] 202 5.8 5.8 5.8 0.0

[0653] 203 7.2 7.1 7.2 6.3

[0654] 204 7.3 6.9 7.1 6.5

[0655] 205 7.0 6.5 6.8 6.2

[0656] 206 7.5 7.7 7.6 6.1

[0657] 207 7.2 6.9 7.0 0

[0658] 208 6.9 6.1 6.5 -

[0659]

[0660] 6.7 6.2 6.4 0 6.7 6.3 6.5 5.4 7.0 6.3 6.6 5.5 6.1 - - 0 7.1 5.3 6.2 5.4 7.0 - - - 7.5 6.3 6.9 5.8 7.2 7.2 7.2 6.1 7.6 7.3 7.4 6.4 6.8 7.0 6.9 6.0 6.5 5.0 5.7 0 6.7 5.5 6.1 5.3 6.9 6.9 6.9 5.4 7.7 7.1 7.4 5.8 5.5 - - - 6.3 5.3 5.8 - 5.4 0 2.7 0 7.3 7.0 7.1 6.3 7.4 6.9 7.1 5.9 5.0 - - - 6.6 6.3 6.5 5.7 7.5 7.1 7.3 6.1 6.9 7.4 7.1 6.3 6.6 6.2 6.4 5.7 7.2 6.8 7.0 6.7 7.4 6.9 7.2 5.3 6.8 6.1 6.5 5.4 6.9 - - 6.0 6.3 5.8 6.0 - 7.2 - - 6.1 7.2 - - 6.0 7.1 7.3 7.2 6.0 7.4 7.2 7.3 6.4 7.3 6.7 7.0 6.1 7.4 7.3 7.3 6.2 7.4 7.1 7.2 5.7

[0661]

[0662] 7.3 7.1 7.2 5.7 7.4 7.2 7.3 6.7 7.6 7.5 7.6 - 6.6 - - 5.5 7.0 6.3 6.6 - 6.8 6.6 6.7 5.7 6.6 - - - 7.0 7.2 7.1 - 7.6 7.7 7.6 6.0 7.0 - - - 7.6 7.2 7.4 6.2 7.5 6.4 6.9 - 7.2 6.7 7.0 - 6.8 6.6 6.7 - 7.4 6.2 6.8 5.8 7.0 6.6 6.8 5.7 6.5 5.6 6.1 - 5.6 - - - 7.3 7.5 7.4 5.9 7.5 - - - 6.8 - - - 6.6 - - - 6.6 - - - 7.4 6.7 7.1 5.6 7.0 6.9 7.0 5.6 6.9 6.7 6.8 5.8 7.2 6.8 7.0 5.9 7.4 6.8 7.1 5.8 6.5 6.9 6.7 6.6 6.8 6.6 6.7 6.0 6.3 4.9 5.6 0 4.9

[0663] 7.3 7.0 7.2 6.4 7.2 7.3 7.2 6.5 7.5 7.4 7.5 6.2 7.4 7.2 7.3 6.6

[0664]

[0665] 6.4 5.3 5.8 0 7.4 - - - 7.0 6.3 6.7 5.8 5.9 - 5.9 - 7.1 - - - 6.5 5.8 6.1

[0666] 6.4 6.2 6.3 5.6 6.7 6.6 6.6 5.9 6.4 5.8 6.1

[0667] 7.2 7.3 7.2 5.7 7.7 7.2 7.4 6.2 7.4 7.3 7.4 6.3 7.3 7.2 7.2 6.5 7.4 7.4 7.4 6.3 6.8 6.3 6.6

[0668] 7.2 7.1 7.1 6.2 7.1 7.1 7.1 5.8 7.1 6.9 7.0 5.7 7.1 6.8 6.9 5.8 6.5 6.3 6.4 5.6 6.9 7.3 7.1 6.4 6.2 6.9 6.5 5.3 6.9 6.7 6.8 5.6 6.4 7.5 7.0 5.9 6.7 6.4 6.6 5.6 7.0 7.0 7.0 5.8 6.4 5.7 6.1 5.4 6.9 6.7 6.8 5.8 6.8 6.4 6.6 5.6 7.4 7.4 7.4 6.2 6.7 6.9 6.8 6.2 6.6 6.5 6.6 5.6 6.5 6.3 6.4 5.5 6.7 6.5 6.6 5.7 6.7 6.7 6.7 6.2 6.7 - - 5.5

[0669]

[0670] 317 6.5 7.0 6.7 5.9

[0671] 318 6.8 6.9 6.8 6.3

[0672] 319 7.3 7.4 7.3 6.1

[0673] 320 6.8 - - - 321 6.9 6.7 6.8 5.7

[0674] 322 7.5 7.4 7.4 6.6

[0675] 323 7.5 7.1 7.3 6.1

[0676] 324 6.9 6.8 6.9 5.5

[0677] 325 6.5 5.8 6.1 0

[0678] 326 7.3 6.7 7.0 5.9

[0679] 327 6.5 6.5 6.5 - 328 6.9 6.7 6.8 -

[0680]

[0681] [0] indicates a peptidomimetic that did not reach 50% inhibition at the maximal concentration (~10pM) and is hence presumed inactive.

[0682] [-] assay not performed

[0683] As is shown in Table 3, the inhibitory activity of the tested peptidomimetics in cell culture was generally correlated with the level of inhibitory activity identified by AlphaLISA and ELISA. Selected peptidomimetics, e.g., Compound Nos. 291, 292, 293, 294, 296, 298, 310, 319, 322, 323, 205, 217, 194, 216, 226, and 236, were characterized by an inhibition of IL-17A of at least 6.0, as determined by the reduction of IL-8 levels in cells, along with a p(ICso) of at least 6.9, as determined by AlphaLisa and / or an average p(ICso) of 7.0, as calculated from the AlphaLisa and ELISA values.

[0684] Example 3: Inhibition of IL-17AF and IL-17F interaction with IL-17R

[0685] As homodimers of IL-17A and of IL-17F, as well as heterodimers of IL-17AF, are all capable of binding and activating the IL-17R, it was next tested whether the peptidomimetics which presented effective IL-17A binding, would also be effective at preventing IL-17F-IL-17R and IL-17AF-IL-17R interactions. AlphaLISA was performed for a representative group of peptidomimetics, selected from the 140 active cyclic penta-peptidomimetics, on IL-17F homodimers and IL-17AF heterodimers, according to the protocol hereinabove, and with each peptidomimetic measured at 6 different concentrations. The p(ICso) values of each of the selected cyclic penta-peptidomimetics were then calculated based on the response curves of the different cyclic peptidomimetic concentrations and are set out in Table 4.Table 4: In-vitro peptidomimetic IL-17F and IL-17AF inhibitory activity Compound p(ICso)

[0686] No. IL-17A IL-17F IL-17AF

[0687] 189 7.2 6.9 —

[0688] 194 7.3 7.7 7.7

[0689] 206 7.5 — 7.4

[0690] 215 7.5 5.5 6.0

[0691] 216 7.2 >6 7.0

[0692] 217 7.6 7.1 7.3

[0693] 219 6.5 — 7.0

[0694] 221 6.9 >6 >5.5

[0695] 222 7.7 6.4 7.3

[0696] 226 7.3 6.9 7.6

[0697] 227 7.4 7.2 7.4

[0698] 230 7.5 6.4 6.5

[0699] 231 6.9 — 7.0

[0700]

[0701] [— ] assay not performed

[0702] As can be clearly seen from Table 4, the selected peptidomimetics were found to be potent at inhibiting the binding of IL-17A, IL-17F and / or IL-17AF to IL-17R. It is noted however, that Compound 230 is specific to IL-17A while Compound No. 226 is specific to IL-17Aand IL-17AF.

[0703] Example 4: Characterization of cyclic Deptidomimetics

[0704] Several cyclic peptidomimetic compounds of the present invention were selected to undergo additional characterization. Specifically, selected compounds were assessed as to their binding to plasma proteins, their kinetic solubility, as well as their exposed polar surface area (EPSA). These experiments were performed as described hereinabove.

[0705] Plasma protein binding (PPB) assay measures the extent to which a drug binds to blood proteins (primarily albumin and a- 1 -acid glycoprotein), thereby determining the unbound fraction which is available for pharmacological activity, metabolism, and excretion.Table 5: Plasma protein binding of selected compounds.

[0706] Compound %Unbound %SD %Bound %Recovery %SD No. Unbound Recovery 217 4.43 0.89 95.57 88.65 6.55 194 3.86 0.41 96.14 80.61 6.07 205 13.39 0.69 86.61 96.33 6.15 231 41.78 6.04 58.22 80.81 5.31 255 8.46 0.87 91.54 82.17 5.76 226 2.11 0.11 97.89 118.86 5.48

[0707]

[0708] The results of the PPB assay are presented in Table 5. Plasma protein binding analysis showed that the cyclic peptidomimetics were predominantly bound to plasma proteins, consistent with substantial association with albumin. This binding profile is favorable because it is expected to protect the compounds in circulation and support systemic persistence, while still leaving a measurable unbound fraction available for interaction with the target protein in the bloodstream. Overall, the results indicate a balanced plasma binding profile, with sufficient protein association to support stability and exposure, together with a residual free fraction that may contribute to pharmacological activity.

[0709] Additionally, compounds were assessed for their kinetic solubility and EPSA values. The experiments were performed as described hereinabove. As can be seen in Table 6, the highest EPSA compound (205, 172 A2) shows the best kinetic solubility (24.4 pM), which supports the general principle that polar surface area enhances water interaction. However, and without wishing to be bound to any mechanism or theory, the relationship between EPSA and kinetic solubility appears to have a threshold effect where other physicochemical properties (molecular flexibility, crystal packing, lipophilicity) likely dominate solubility behavior in the 140-155 A2EPSA range.

[0710] Table 6: Kinetic solubility and EPSA of select compounds.

[0711] Compound No. Kinetic solubility (pM) EPSA (A2)

[0712] 194 3.4 139

[0713] 205 24.4 172

[0714] 216 14.3 - 217 12.1 153

[0715]

[0716] 226 24.3 - 236 31 - 292 - 149

[0717] 293 not detected 147

[0718] 294 2 146

[0719] 296 - 132

[0720] 298 11 - 310 2.3 -

[0721]

[0722] [-]= not performed

[0723] Example 5: Structure-activity considerations

[0724] A multiparameter optimization was performed in order to improve the potential of the active peptidomimetic identified in the previous rounds for being applicable for intravenous or oral administration. Some of the properties investigated, in addition to the chemical and cellline inhibition potency, included: kinetic solubility, serum stability, exposed polar surface area (EPSA).

[0725] Additional residue options that were offered by the software were included with the potential of improving one or more of the above listed traits.

[0726] Position 1:

[0727] In further modification of the compounds in which D-Gln was shown active in this position, D-N,N-pyrrolidinylglutamine (D-Gln(Pyr)) (as exemplified, for example, in Compound No. 287), D-N,N-di-methylglutamine (D-Gln(NMe2)) (as exemplified, for example, in Compound No. 288) and D-N,N-di-methylasparagine (D-Asn(NMe2)) (as exemplified, for example, in Compound No. 289) were also shown active.

[0728] Compound Nos. 287, 288, and 289 had a p(ICso) value, as determined by AlphaLisa, of 6.4, 6.7, and 6.4, respectively.

[0729] Similarly, the combination of hydrogen bonding and hydrophobic potentials in position 1 also allow the application of (2R,3S)-2-amino-3-hydroxy-4-methylpentanoic acid (D-Leu(3S-OH)) (as exemplified, for example, in Compound No. 214), that showed a p(ICso) value, as determined by AlphaLisa, of 7.0.Position 2:

[0730] Position 2 can contain aromatic rings modified phenylalanine residues, such as Phe(3-OH), Phe(3-OMe) or Phe(3-OEt). It is now shown that a polyethylene glycol (PEG) moiety can be added to the substituted sidechain forming Phe(3-OH(PEG3Me)), as exemplified, for example, in Compound No. 254. Compound No. 254 showed a p(ICso) value, as determined by AlphaLisa, of 7.0.

[0731] Additional compounds having methylated oxygen Nle(6-OH), forming Nle(6-OMe) (as exemplified, for example, in Compound No. 266, with a p(ICso) value, as determined by AlphaLisa of 6.6), are also identified, retaining a similar activity to the former (as exemplified, for example, in Compound No. 265, with a p(ICso) value, as determined by AlphaLisa of 6.8) Another option in this position is 5 -m ethoxy -L-norvaline (Nva(OMe)), that showed similar activity in the same context (as exemplified, for example, in Compound No. 267, with a p(ICso) value, as determined by AlphaLisa, of 6.6.

[0732] Position 4:

[0733] In view of the activity of peptidomimetic comprising 3,5-di-iodo-tyrosine (Tyr(3,5-di-lodo)), and in concurrence to the 3D binding model, it was found that polyethylene glycol (PEG) can be connected to the side chain hydroxy group thereof. Tyr(3-5-di-Iodo(PEG3Me)) in position 4 is exemplified, for example, in Compound No. 226 and Compound No. 227, with a p(ICso) value, as determined by AlphaLisa, of 7.3 and 7.4, respectively.

[0734] Another aspect that was investigated was the effect of distancing the aromatic moiety from the backbone. One way of doing this was through a thioether bond between a cysteine and a meta-Xylene group, which forms another thioether bond to a mercaptoacetic-acid (Cys-[Meta-Xylene-mercaptoacetic-acid]) as exemplified, for example, in Compound No. 234. Compound No. 234 showed a p(ICso) value, as determined by AlphaLisa, of 7.4.

[0735] To avoid the carboxy motif problematic nature in passive membrane passage, in the above molecules, uncharged distancing alternatives were tested: Norvaline-phenyl (Nva(Ph)) (as exemplified, for example, in Compound No. 190) and homophenylalanine with oxygen connected to a CF3 group in position 4 (homoPhe(4-OCF3)) (as exemplified, for example, in Compound No. 285 and Compound No. 271).

[0736] These peptidomimetics showed IL- 17 inhibitory activities, with p(ICso) values, as determined by AlphaLisa, of 7.2, 7.1, and 7.2, for Compound Nos. 190, 285, and 271, respectively.Position 5:

[0737] IL-17 inhibitory activity was also shown when using 3-3-diphenyl-L-alanine (Dip) in position 5 (as exemplified, for example, in Compound No. 203) or homophenylalanine (hPhe) (as exemplified, for example, in Compound No. 222). These peptidomimetics showed IL- 17 inhibitory activities, with p(ICso) values, as determined by AlphaLisa, of 7.2, and 7.7, for Compound Nos. 203 and 222, respectively.

[0738] Example 6: In vivo murine intravenous injection experiment

[0739] The potential of inhibiting IL-17A / IL-17R-induced chemokine release with the peptidomimetics of the invention was investigated, since systemic IL-17A inhibition is a key attribute for IL-17A inhibitory drug candidates. IL-17A is known to induce the production of the chemokine (C-X-C motif) ligand 1 (CXCL1), (encoded by the Cxcll gene), also known as GRO-a.

[0740] To investigate the potential of inhibiting IL-17 / IL-17R-induced chemokine release, mice were administered intravenously with either a vehicle, IL-17A+vehicle (negative control) or the vehicle+IL-17A and a selected compound e.g., Compound Nos.: 125 (A_17_248, disclosed in WO 2025 / 079064), 194 (A_17_370), 205 (A_17_417), 217 (A_17_508), and 231 (A 17 527). As a positive control, the IL- 17 inhibitory antibody ixekizumab was used. The serum levels of GRO-a were used to analyze the inhibition of IL-17A by the selected compounds.

[0741] Mice (5 mice per group) received either the vehicle, the tested compounds (15 mg / kg) or the IL-17 inhibitory antibody (0.8 mg / kg) treatments intravenously, immediately followed by a subcutaneous injection of 3 pg IL-17A (7955-IL-025 / CF). A control group that received the vehicle but was not subsequently injected subcutaneously with IL-17A was included. Ih post IL-17A injection, blood was collected and the serum tested for GRO-a (DY453-05) levels.

[0742] The results are presented in Figure 5. As is demonstrated therein, the groups that received Compound Nos. 125 (labeled 125+IL17A), 194 (labeled 194+IL17A), 205 (labeled 205+IL17A), or 217 (labeled 217+IL17A) all showed reduced of serum levels of GRO-a compared with the negative control (labeled IL-17A+vehicle), with compounds 125, 205, and217 showing statistically significant reduction. The activity of some of the compounds of the present invention in vivo demonstrates the potential of the peptidomimetics in the clinic.

[0743] Example 7: Treatment of psoriasis in vivo with IL-17A inhibiting peptidomimetic For evaluating the therapeutic activity of the peptidomimetics in vivo an Imiquimod (IMQ) mouse psoriasis model is used, which is well-validated with a high dependency on IL-17 for the pathologic outcome. Mice are divided into 4 groups (n=6), according to the respective treatment regimens, as follows: IMQ + DMSO (designated “IMQ + Vehicle”), as a negative control; IMQ + Daivobet (0.5 mg / g betamethasone), Diavobet being an approved drug for treatment of psoriasis (designated “IMQ + Steroid”); IMQ + cyclic pentapeptidomimetic of the present invention; and an untreated control group (designated “no-IMQ”). On days 1-7 of the treatment, the mice groups receive a daily dosage of IMQ (topical), and on days 4-7 the mice receive topical administration of the respective treatment formulations twice-daily, i.e., DMSO, Daivobet, and DMSO + cyclic pentapeptidomimetic (2% v / v), respectively. On day 8 the mice are sacrificed, and skin thickness, expression of genes related to IL- 17 activation, and levels of GRO-a protein in the mouse serum (explained hereinabove), are measured.

Claims

CLAIMS1. A cyclic penta-peptidomimetic that inhibits the interaction between an interleukin 17 (IL- 17) and an IL- 17 receptor (IL-17R), wherein:the amino acid at position 1, counted from the N-terminus of the pentapeptide before cyclization, is selected from the group consisting of: D-Gly(cPr), D-Ala(cPr), D-Ala, D-Pal(4), and D-Gln;the amino acid at position 2 is selected from the group consisting of: Pal(3), Ala(cPr), Ala(cBu), Cha, 2-Amino-3-(pyrazin-2-yl)propanoic-acid, and aThr;the amino acid at position 3 is selected from D-Abu(tetrazol-5-yl) and D- Cy s(5 -Methyl -2H-tetrazol e) ;the amino acid at position 4 is selected from the group consisting of L-Phe(2-OCF3), Dip, Phe(2-NO2), Tyr(3-5-di-Iodo(PEG3Me)), and Phe(F5); andthe amino acid at position 5 is selected from the group consisting of: Phe(2-CF3), L- Phe(2-OCF3), 1-Nal, hPhe(2-3-diF), Gly(indan-2-yl), 3-(4-Quinolyl))-L-alanine, and Orn(Cbz(2-Cl)).

2. The cyclic penta-peptidomimetic according to claim 1, wherein the amino acid at position 3 is D-Abu(tetrazol-5-yl).

3. The cyclic penta-peptidomimetic according to claim 2, wherein:the amino acid at position 1 is selected from D-Gly(cPr), and D-Ala(cPr); the amino acid at position 2 is selected from Pal(3) and Ala(cPr);the amino acid at position 4 is selected from L-Phe(2-OCF3) and Dip; and the amino acid at position 5 is Phe(2-CF3).

4. The cyclic penta-peptidomimetic according to claim 1, selected from the group consisting of: Compound Nos. 291, 292, 293, 294, 296, 298, 310, 319, 322, 323, 205, 217, 194, 216, 226, and 236.

5. The cyclic penta-peptidomimetic according to claim 1 , selected from the group consisting of: Compound Nos. 291, 292, 293, 294, 296, 298, 319, 322, 205, 216, and 226.

6. The cyclic penta-peptidomimetic according to any one of claims 1-5, having an IL-17 inhibitory activity of p(IC5o)=6.9 or above, as determined by AlphaLISA.

7. The cyclic penta-peptidomimetic according to any one of claims 1-5, having an IL-17 inhibitory activity of p(ICso) of 5.5 or above, as determined by inhibition of IL-8 secretion from cells.

8. The cyclic penta-peptidomimetic according to any one of claims 1-7 wherein the cyclic penta-peptidomimetic inhibits the interaction between an IL-17R andi. IL- 17A homodimer;ii. an IL-17F homodimer;iii. an IL- 17AF heterodimer;and any combination thereof.

9. A head-to-tail cyclic penta-peptidomimetic that inhibits the interaction between an interleukin 17 (IL- 17) and an IL- 17 receptor (IL-17R), wherein the head-to-tail cyclic penta-peptidomimetic is selected from Compound Nos. 189 to 328.

10. A pharmaceutical composition comprising at least one cyclic penta-peptidomimetic according to any one of claims 1-9, and at least one excipient, salt or carrier.

11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is formulated for local, parenteral or enteral administration.

12. The pharmaceutical composition according to claim 10 or 11, wherein the pharmaceutical composition is formulated for administration by mouth, injection, infusion, inhalation or as a nasal spray.

13. The pharmaceutical composition according to any one of claims 10-12, wherein the pharmaceutical composition is formulated for intradermal administration, subcutaneous administration, for administration locally to the dermis or for administration by electroporation.

14. The pharmaceutical composition according to any one of claims 10-13, for use in the treatment of an IL- 17 associated disease, condition, or disorder.

15. The pharmaceutical composition for use according to claim 14, wherein the IL- 17 associated disease, condition, or disorder, is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, inflammatorybowel disease, chronic obstructive pulmonary disease (COPD), age-associated skin condition, and allograft rejection.

16. The pharmaceutical composition for use according to claim 15, wherein the psoriasis is plaque psoriasis.

17. A method for treating a patient suffering from an IL-17 associated disease, condition, or disorder, comprising administering to a patient in need thereof an effective amount of at least one cyclic pentapeptide according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof.

18. The method according to claim 17 further comprising providing at least one additional treatment.

19. The method according to claim 18, wherein the at least one additional treatment comprising an anti-inflammatory agent or therapy or an immunosuppressant.

20. The method according to any one of claims 17-19, wherein the IL-17 associated disease, condition, or disorder, is selected from the group consisting of psoriasis, psoriatic arthritis rheumatoid arthritis, spondyloarthritis, multiple sclerosis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, inflammatory bowel disease, COPD, age-associated skin condition, and allograft rejection.

21. A dosage form suitable for administration locally or by injection, infusion, inhalation or as a nasal spray, wherein the dosage form comprises at least one package which contains the pharmaceutical composition according to any one of claims 10-13.

22. A kit comprising at least one container containing the pharmaceutical composition according to any one of claims 10-13 and instructions for using the kit.

23. A cosmetic composition comprising at least one cyclic penta-peptidomimetic according to any one of claims 1-9, and at least one cosmetically acceptable excipient, salt or carrier.

24. The cosmetic composition according to claim 23, wherein the cosmetic composition is formulated as a lotion, a cream, an ointment, a paste, a gel, a hydrogel, a powder, a solution, a mist, or a spray.

25. The cosmetic composition according to claim 23 or 24, wherein the cosmetic composition comprises at least one additional ingredient.

26. The cosmetic composition according to any one of claims 23-25, for use in the prevention, treatment, alleviation of a cosmetic condition or disorder.

27. The cosmetic composition for use according to claim 26, wherein the cosmetic condition or disorder is selected from altered skin texture, skin discoloration, flaky scalp, acne, excess oil production, enlarged pores, hyperpigmentation, melasma, dark spots, sunspots and age spots, age signs and wrinkles, loss of skin elasticity, sagging and dull skin, sensitive and reactive skin, skin redness and irritation, rosacea-prone skin, eczema and atopic dermatitis marks, skin barrier dysfunction, dry and dehydrated skin, flaky skin, rough skin, tightness and discomfort of the skin, xerosis, dark eye circles, puffy eyes, under-eye pigmentation, puffiness and swelling, fine lines, and crepey skin.

28. A method for preventing, treating, or alleviating a cosmetic condition or disorder, the method comprising administering an effective amount of a compound according to any one of claims 1-9, or a cosmetically acceptable salt thereof.

29. The method according to claim 28, wherein the cosmetic condition or disorder is selected from altered skin texture, skin discoloration, flaky scalp, acne, excess oil production, enlarged pores, hyperpigmentation, melasma, dark spots, sunspots and age spots, age signs and wrinkles, loss of skin elasticity, sagging and dull skin, sensitive and reactive skin, skin redness and irritation, rosacea-prone skin, eczema and atopic dermatitis marks, barrier dysfunction, dry and dehydrated skin, flaky skin, rough skin, tightness and discomfort of the skin, xerosis, dark eye circles, puffy eyes, under-eye pigmentation, puffiness and swelling, fine lines, and crepey skin.

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