WO2025051912A1 - New peptides as selective il-23 receptor inhibitors - Google Patents

Abstract

The disclosure relates to IL-23 receptor inhibitor compounds of formula (I), their pharmaceutical compositions, and their medical uses, for example in the treatment of inflammatory bowel diseases such as Crohn's disease.

Description

[TITLE]

NEW PEPTIDES AS SELECTIVE IL-23 RECEPTOR INHIBITORS

[FIELD]

[0001] The disclosure relates to peptide IL-23 receptor inhibitors and their medical use, for example in the treatment of inflammatory bowel diseases such as Crohn's disease. More specifically, the disclosure relates to cyclic peptide compounds useful as IL-23 receptor inhibitors.

[BACKGROUND]

[0002] There is increasing evidence that interleukin-23 (IL-23) cytokine is playing a crucial role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as asthma, rheumatoid arthritis, psoriasis, multiple sclerosis and inflammatory bowel diseases (IBDs), e.g., ulcerative colitis and Crohn's disease. The primary role of IL-23R could be revealed by acute and chronic mouse models of IBD and downstream effector cytokines in disease pathogenesis. Th17 cells, y8 T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells, which are found abundantly in the intestine are adaptive and innate immune cells which express IL-23R. IBD patients have an increased gene expression and IL-23R level at the intestine mucosal surface. There is evidence that IL-23 contributes to this effect by promoting the development of a pathogenic CD4+ T cell population that produces IL-6, IL-17, and tumor necrosis factor (TNF).

[0003] Concentration of IL-23 is increased in the intestine, where it is thought to play a key role in regulating the balance between tolerance and immunity through T-cell- dependent and T-cell-independent pathways of intestinal inflammation. This regulation has effects on T -helper 1 (Th1 ) and Th17-associated cytokines, as well as repressing regulatory T-cell responses in the gut, promoting inflammation. Furthermore, IL-23R polymorphisms have been associated with susceptibility to gut inflammation, further confirming the importance of the IL-23 pathway in intestinal homeostasis.

[0004] Psoriasis is a chronic skin disease with a prevalence in the Caucasian population of about 2%-3% has been shown to be mediated by the body's T cell inflammatory response mechanisms. Via the induction of interleukin-17, activation of macrophages and regulation of T memory cells, IL-23 is one of several interleukins implicated as a key player in the pathogenesis of psoriasis by maintaining chronic autoimmune inflammation. Neutralizing antibodies against IL-23 showed IL-23-dependent inhibition of psoriasis development in animal models of psoriasis while high expression of IL-23 and IL-23R has been demonstrated to be increased in tissues of patients with psoriasis.

[0005] IL-23 is a part of the IL-12 family of cytokines and is composed of a p19 subunit specific to IL-23 and the p40 subunit of IL-12, which is a cytokine involved in the development of interferon-y (IFN-y)-producing T helper 1 (TH1 ) cells. Although IL-23 and IL-12 both contain the p40 subunit, they have different phenotypic properties. While animals with deficiency in IL-12 are susceptible to inflammatory autoimmune diseases, IL-23 deficient animals are resistant, most likely due to a reduced number of CD4+ T cells producing IL-6, IL-17, and TNF in the CNS. IL-23 binds to IL-23R, which is a heterodimeric receptor composed of IL-12R|31 and IL-23R subunits. Binding of IL-23 to IL-23R activates the Jak-Stat signaling molecules, Jak2, Tyk2, Statl , Stat3, Stat4, and Stat 5, although Stat4 activation is substantially weaker and different DNA-binding Stat complexes form in response to IL-23 as compared with IL-12. IL-23R associates constitutively with Jak2 and in a ligand-dependent manner with Stat3. In contrast to IL-12, which acts mainly on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells.

[0006] Based on the biological importance, inhibition of the IL-23 pathway is an attractive option for treatment of IL-23-related diseases and disorders. A number of antibodies that bind to IL-23 or IL-23R have been identified, including ustekinumab, a humanized antibody that binds IL-23, which has been approved for the treatment of psoriasis. More recently, polypeptide inhibitors that bind to IL-23R and inhibit the binding of IL-23 to IL-23R have been identified (see, e.g., US Patent Application Publication No. US2013/0029907). Clinical trials in Crohn's Disease or psoriasis with ustekinumab and briakinumab (which target the common p40 subunit) and tildrakizumab, guselkumab, brazikumab, and risankizumab (which target the unique p19 subunit of IL-23) highlight the potential of IL-23 signaling blockade in treatment of human inflammatory diseases.

[0007] While these findings are promising, challenges remain with respect to identifying stable and selective agents that preferentially target the IL-23 pathway in the intestine, which can be used for the treatment of intestinal inflammation, such as intestinal bowel diseases, including Crohn' s disease, ulcerative colitis and related disorders.

[0008] Irritable bowel disease (IBD) patients with autoimmune inflammation in the intestinal tract can benefit from an oral-to-local treatment where compounds specifically target the IL-23 pathway from the luminal side of the gut. [0009] A problem associated with the use of compounds as an orally administered therapeutic in the treatment of inflammatory diseases and other indications can be their limited stability in the intestinal environment.

[0010] Therefore, in developing new therapeutic molecules, there is a need for variants with improved pharmaceutical properties, for example increased stability against proteases present in the gut and/or increased chemical or physical stability and/or a prolonged half-life in vivo and/or increased potency/efficacy in vivo.

[0011] Also, there remains a need for anti-inflammatory therapies that avoid or alleviate the common systemic side effects of IL-23R based therapies (e.g., defense against infections), thereby achieving an anti-inflammatory effect with improved tolerability.

[0012] US 2013-029907 A1 discloses linear peptide inhibitors of the IL-23 receptor.

[0013] Protagonist's WO 2016/011208 A1 , WO 2017/011820 A2, WO 2018/089693 A2, WO 2018/022937 A1 , WO 2018/136646 A1 and WO 2022/109328 A1 , as well as Sayago et al. (ACS Med. Chem. Lett. 2018, 9,912-916) disclose peptide inhibitors of the IL- 23 receptor for oral administration. A common structural characteristic of the disclosed compounds is a ring formed by 6 amino acids as ring members.

[0014] WO 2013/063468 discloses cyclic peptides which are modified by long chain hydrocarbon groups resulting in amphiphilic molecules useful as drug delivery system including nucleotide delivery to cells.

[0015] WO 2015/179438 A1 also discloses cyclic peptides of a 2 to 10 membered ring formed by amino acids as inhibitors Rac or Rho in a cell or tissue, wherein at least two amino acids are arginine.

[0016] Quiniou et al. (Am J Physiol Regul Integr Comp Physiol, 2014, 307 : R1216- R1230) disclose small peptide non-competitive inhibitors made of D-amino acids.

[0017] Kuchar et al. (Proteins, 2013) disclose IL-23 receptor inhibitors derived from three-helix bundle scaffold of the albumin-binding domain of streptococcal protein G.

[0018] WO 2023/288028 discloses cyclic peptide inhibitors of IL-23 receptor of 16 amino acid residues with a cyclization obtained with a disulfide bond between residues at positions 4 and 9.

[0019] WO 2023/288019 discloses cyclic peptide inhibitors of IL-23 receptor of 16 amino acid residues with a cyclization obtained with a disulfide or thioether bond between residues at positions 4 and 9. [0020] WO 2023/288017 discloses bicyclic peptide inhibitor of IL-23 receptor with bicyclization obtained with a first disulfide or thioether bond between a first pair of amino acid residues and a second amide or thioether bond between a second pair of amino acid residue.

[0021] Therefore, there is still a need for improved IL-23 receptor inhibitor compounds for treating and/or preventing autoimmune or inflammatory disease.

[0022] There is a need for IL-23 receptor inhibitor compounds with improved in vitro and in vivo stability.

[0023] There is a need for IL-23 receptor inhibitor compounds with improved oral bioavailability and/or stability upon oral administration.

[0024] There is a need for IL-23 receptor inhibitor compounds which selectively bind to the IL-23 receptor in the intestine.

[0025] There is a need for compounds with improved IL-23 inhibitor properties.

[0026] There is a need for IL-23 receptor inhibitor compounds with high binding affinity.

[0027] There is a need for compounds able to inhibit the binding of IL-23 to the IL- 23 receptor with an IC50 in the nanomolar range, for example equal or below 50 nM, or again equal or below 20 nM.

[0028] There is a need for IL-23 receptor inhibitor compounds with improved protease stability.

[0029] The disclosure provides peptide compounds of formula (I) that inhibit IL-23 binding, and some embodiments are suitable for oral administration and/or address one or more of the above-referenced needs.

[0030] Therefore, the disclosure provides compounds of formula (I) having affinity to the IL-23 receptor.

[SUMMARY]

[0031] The present disclosure relates to a peptide compound of formula (I):

[0032] X1 (§ 1 )(#1 )-X2(#1 )(@2)-X3-X4-X5-X6-X7-X8-X9(§1 )(@2)-X10-X11 -X12- X13-R1 (I),

[0033] wherein [0034] X1 is absent or is a Butyl moiety and

[0035] when X1 is a Butyl moiety, then (§1) represents an alkyl bond between X1 and X9 and (#1) represents an alkyl bond between X1 and X2, and, in such a case, (@2) are absent, or

[0036] when X1 is absent, then (@2) represents an amide bond between X2 and X9, and, in such a case, (§1 ) and (#1) are absent,

[0037] X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dad, Dae, Dec, Dod, Dpa, Kme, Kme(aAc), Lys(aAc), Nmapt, Nmha and Oca;

[0038] X3 is an amino acid residue selected among a residue of Nak, Trp, Wdm, Wim, Wme, Wcl and Wfl;

[0039] X4 is an amino acid residue selected among a residue of Aib, Gin, Glu, lie, Iva, Leu, Lys, Lys(Ac), Mie, Mly, Mva, Phe, Thr, Trp and Vai;

[0040] X5 is an amino acid residue selected among a residue of Aib, Mkdm, Mie and Thp;

[0041] X6 is an amino acid residue selected among a residue of Trp, Tyr, Yae, Yde and Yme;

[0042] X7 is an amino acid residue selected among a residue of Nak, Nal and Trp;

[0043] X8 is an amino acid residue selected among a residue of Aib, Cba, Cit, Gin, Leu, Lys, Lys(Ac), Mie, Mly, D-Mkdm, Mkdm, Thp, D-Trp and D-Tza;

[0044] X9 is an amino acid residue selected among a residue of Asp, Glu, Kme, Lys and Orn;

[0045] X10 is an amino acid residue selected among a residue of Ala, Asn, Gly and Ser;

[0046] X11 is an amino acid residue selected among a residue of Ala, Asn, Bal, Gly, Hol, Hph, His, lie, Iva, Leu, Mhis, Pal, Pyal, PyEA, Vai, and their corresponding D-forms;

[0047] X12 is absent or is an amino acid residue selected among a residue of Bal, Dnmy, lie, Lys, Mep, Mhis and Sar;

[0048] X13 is absent or is a residue of Lys; and,

[0049] R1 is absent or is selected among -NH₂, -OH and -N(C2H₅)2;

[0050] or a salt or a solvate thereof. [0051] A peptide compound of formula (I) inhibits the binding of interleukin-23 (IL- 23) to an interleukin-23-receptor (IL-23R).

[0052] In some embodiments, a salt or a solvate of a peptide compound of the disclosure is a pharmaceutically acceptable salt or solvate.

[0053] As shown in the Example section, it has been observed that in some embodiments, peptide compounds of general formula (I) have a good solubility in water at various gastrointestinal pH (from pH 1.2 to 7.4), a good stability to pH as low as 1.2, with less than about 20% of purity loss, or even less than 15% purity loss at pH ranging from 1.1 to 7.4. Such capabilities make the peptide compounds of the disclosure usable per oral route, where in the digestive tractus the pH may range from about 7.4, in the mouth, to about 1.2, in the stomach. Further some compounds present good stability in simulated gastric and intestinal fluids, with about at least 50% of peptide compound remaining in a simulated intestinal fluid after 60 min at 37°C. In some embodiments, the peptide compounds of the disclosure have the capacity to inhibit the binding of IL-23 to its IL-23 receptor with IC50 in the nanomolar range, at least below about 20 nM, or at least below about 10 nM. In some embodiments, the peptide compounds of the disclosure have the capacity to inhibit IL-23-induced STAT3 phosphorylation with IC50 in the nanomolar range, at least below about 50 nM, or below about 25 nM, or below about 15 nM, or below about 10 nM, or below about 5 nM, or within the range of from about 0.05 nM or from about 0.1 nM to about 50 nM.

[0054] In some embodiments, a peptide compound of formula (I) has a sequence selected among SEQ ID NO: 1 to 50, or a salt or a solvate thereof, as figured in the Table 2 below.

[0055] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 of about 50 nM or less, or of about 25 nM or less, or of about 15 nM or less, or of about 10 nM or less.

[0056] In some embodiments, peptide compounds of formula (I) have a stability in water at pH of about 1 .2, measured as a purity loss after 24 hrs at 37°C in buffer solution, of about less than 20%, or of about less than 15%, or of about less than 10%.

[0057] In some embodiments, peptide compounds of formula (I) have a stability in water at pH of about 6.5, measured as a purity loss after 24 hrs at 37°C in buffer solution, of about less than 10%, or of about less than 5%, or of about less than 2%. [0058] In some embodiments, peptide compounds of formula (I) have a stability in water at pH of about 7.4, measured as a purity loss after 24 hrs at 37°C in buffer solution, of about less than 10%, or of about less than 5%, or of about less than 2%.

[0059] In some embodiments, peptide compounds of formula (I) have a protease stability, measured as a percentage of remaining of said peptide in simulated intestinal fluids at 60 min and at 37°C, of at least 50%.

[0060] In some embodiments, peptide compounds of formula (I) are for use for treating and/or preventing an autoimmune or an inflammatory disease in a subject in need thereof.

[0061] In some embodiments, the autoimmune or inflammatory disease is selected among inflammatory bowel disease, such as Crohn’s disease and ulcerative colitis, psoriasis, psoriatic arthritis and hidradenitis suppurativa.

[0062] In some embodiments, the disclosure relates to compositions comprising a peptide compound of formula (I) as described herein, or a salt or solvate thereof, in admixture with a carrier. A carrier may be a pharmaceutically acceptable excipient or carrier.

[0063] In some embodiments, the disclosure relates to a pharmaceutical composition comprising at least one peptide compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0064] The disclosure also relates to the use of peptide compounds of formula (I) as described herein for use as a medicament, particularly for the treatment of a condition as described herein.

[0065] In some embodiments, the disclosure relates to the use of a peptide compound of formula (I), for the manufacture of a medicament for treating and/or preventing an autoimmune or an inflammatory disease in a subject in need thereof.

[0066] In some embodiments, the disclosure relates to a method for treating and/or preventing an autoimmune or an inflammatory disease, the method comprising at least a step of administering to said subject a peptide compound of formula (I).

[DETAILED DESCRIPTION]

Definitions

[0067] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press, may provide one of skill with a general dictionary of many of the terms used in this disclosure. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. In case of conflict, the present specification, including definitions, will control. Generally, nomenclature used in connection with, and techniques of, cell and tissue culture, molecular biology, virology, immunology, microbiology, genetics, analytical chemistry, synthetic organic chemistry, medicinal and pharmaceutical chemistry, and protein and nucleic acid chemistry and hybridization described herein are those well- known and commonly used in the art. Enzymatic reactions and purification techniques are performed according to manufacturer’s specifications, as commonly accomplished in the art or as described herein. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0068] Units, prefixes, and symbols are denoted in their International Units System accepted form. Numeric ranges are inclusive of the numbers defining the range. Unless otherwise indicated, amino acid sequences are written left to right in amino to carboxy orientation. The headings provided herein are not limitations of the various aspects of the disclosure. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0069] Although a number of documents are cited herein, this citation does not constitute an admission that any of these documents forms part of the common general knowledge in the art.

[0070] Throughout this specification and embodiments, the words “have” and “comprise,” or variations such as “has,” “having,” “comprises,” or “comprising,” are used interchangeably and have the same meaning.

[0071] It is to be noted that the term “a” or “an” means one or more; for example, “a peptide compound,” is understood to mean one or more peptide compounds. As such, the terms “a” (or “an”), “one or more,” and “at least one” can be used interchangeably herein.

[0072] Furthermore, “and/or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and/or” as used in a phrase such as “A and/or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, o“ C; A or C; A ”r B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0073] The term “approximately” or “about” is used herein to mean approximately, roughly, around, or in the regions of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” can modify a numerical value above and below the stated value by a variance of, e.g., 10 percent, up or down (higher or lower). In some embodiments, the term indicates deviation from the indicated numerical value by ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1 %, ±0.05%, or ±0.01%. In some embodiments, “about” indicates deviation from the indicated numerical value by ±10%. In some embodiments, “about” indicates deviation from the indicated numerical value by ±5%. In some embodiments, “about” indicates deviation from the indicated numerical value by ±4%. In some embodiments, “about” indicates deviation from the indicated numerical value by ±3%. In some embodiments, “about” indicates deviation from the indicated numerical value by ±2%. In some embodiments, “about” indicates deviation from the indicated numerical value by ±1%. In some embodiments, “about” indicates deviation from the indicated numerical value by ±0.9%. In some embodiments, “about” indicates deviation from the indicated numerical value by ±0.8%. In some embodiments, “about” indicates deviation from the indicated numerical value by ±0.7%. In some embodiments, “about” indicates deviation from the indicated numerical value by ±0.6%. In some embodiments, “about” indicates deviation from the indicated numerical value by ±0.5%. In some embodiments, “about” indicates deviation from the indicated numerical value by ±0.4%. In some embodiments, “about” indicates deviation from the indicated numerical value by ±0.3%. In some embodiments, “about” indicates deviation from the indicated numerical value by ±0.1%. In some embodiments, “about” indicates deviation from the indicated numerical value by ±0.05%. In some embodiments, “about” indicates deviation from the indicated numerical value by ±0.01 %.

[0074] Peptide compound. The term “peptide compound” encompasses a singular “peptide compound” as well as plural “peptide compounds,” and refers to a molecule comprising amino acids linked by amide bonds. A peptide compound of the disclosure comprises natural, unnatural amino acids, and building blocks such as a Butyl moiety. A peptide of the disclosure comprises amide and alkyl bonds based on natural and non-natural amino acids, and building blocks engaged in the bond. A peptide compound of the disclosure is cyclized. A peptide compound may comprise additional modifications with functionalized amino acid.

[0075] Amino acids. Amino acids are referred to herein by either their name, their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Therefore, the amino acid sequences disclosed herein contain the conventional one letter and three letter codes for naturally occurring amino acids, as well as generally accepted three letter codes for other non-natural amino acids, such as Aib for a-aminoisobutyric acid, Orn for ornithine or Ahx for 6- aminohexanoic acid.

[0076] The term “amino acid” or “any amino acid” as used here refers to any and all amino acids, including naturally occurring amino acids, modified amino acids, and nonnatural amino acids. It includes both D- and L-amino acids. Natural amino acids include those found in nature, such as, e.g., the 23 amino acids that combine into peptide chains to form the building-blocks of a vast array of proteins. These are primarily L stereoisomers, although a few D-amino acids occur in bacterial envelopes and some antibiotics. Except otherwise indicated, L-amino acids are used throughout the disclosure. D-amino acids are indicated as such.

[0077] Residue. Within the disclosure, the term “residue refers to a moiety within a peptide compound, which results from the binding of an amino acid or a building block to another amino acid or to a building block by forming of amide bonds. Residue is i) what remains of an amino acid after the removal of the elements of water, ii) what remains of a dicarboxylic acid after removal of the OH groups and iii) what remains of a building block with one sole amino group after the removal of one H thereof.

[0078] Amide bond. The expression “amide bond” refers to a bond obtained via the coupling between an amine moiety of an amino acid of a peptide compound of the disclosure with a carboxylic acid moiety of another amino acid of the peptide compound. For example, an amide bond may be obtained between an amine moiety of X2 being Aud, Ade, Add, Atd, Atea, Ahd or Aoa and a carboxylic moiety of the side of chain of X9 being Glu. Alternatively, an amide bond may be obtained between a carboxylic moiety of X2 being Dec, Dod, Oca or Dpa and an amine moiety of the side of chain of X9 being Lys.

[0079] Activity. The term “activity” used with regard to a peptide compound refers to the capability of the peptide compound to inhibit the interleukin-23 receptor. The term “activity” as used herein also refers to the capability of a peptide compound to inhibit the intracellular STAT3 phosphorylation induced by activation of the IL-23 receptor. [0080] Potency. “Potency” is a measure of the ability of a compound to inhibit the interleukin-23 receptor’s activation measured in a cell-based assay, as for example presented in the Examples. Numerically, it may be expressed as the “IC50” value, which is the effective concentration of a compound that inhibits a half maximal increase of response (e.g., phosphorylation of STAT3 induced by the IL-23 receptor activation) in a doseresponse experiment.

[0081] Compounds of the disclosure have interleukin-23 receptor affinity. This term refers to the ability to bind to the interleukin-23 receptor. Peptide compounds of the disclosure can be tested for interleukin-23 receptor affinity or activity using the assays described in Methods and results shown in Tables 8 or 9 herein.

[0082] To inhibit the binding of interleukin-23 to an interleukin-23-receptor. The expression “to inhibit the binding of interleukin-23 to an interleukin-23-receptor” refers to a property of a peptide compound of the disclosure to prevent or reduce the binding of the IL-23 receptor by its ligand IL-23, so as to prevent or reduce activation of a downstream cellular response induced by the binding of IL-23 to its receptor. The capacity of a peptide compound to inhibit the binding of IL-23 to IL-23R is measured by assays disclosed in the Example section. This property is measured as a binding affinity and can be expressed as the “IC50” value, which is the effective concentration of a compound that induces a half maximal decrease of the binding of IL-2.3 to its receptor in a dose-response experiment. In some embodiments, a peptide compound of the disclosure has a binding affinity to the interleukin 23 receptor of 100 nM or below (i.e., IC50 100 nM).

[0083] The expressions “pharmaceutically acceptable solvate” and “pharmaceutically acceptable salt” refer to solvates or salts of peptide compounds of the disclosure which can be used in the formulation of a pharmaceutical composition, and which are physiologically acceptable, i.e., safe and effective for use in mammals. A pharmaceutically acceptable salt or solvate may be suitable for oral administration.

[0084] “Administer” or “administering,” as used herein refers to delivering to a subject a peptide compound or a composition described herein. The peptide compound or the composition can be administered to a subject using methods known in the art. In particular, the peptide compound or composition can be administered orally, sublingually, buccally, nasally, rectally, vaginally or via pulmonary route, or again intravenously, subcutaneously, intramuscularly, or intradermally. In some embodiments, the administration is an oral administration. [0085] Table 1 presents the codes used for amino acids and other building blocks used herein:

Table 1 : Natural, non-natural amino acids and building blocks

[0086] It is appreciated that certain features of the disclosure which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

[0087] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

[0088] The list of sources, ingredients, and components as described hereinafter are listed such that combinations and mixtures thereof are also contemplated and within the scope herein.

[0089] It should be understood that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein. [0090] All lists of items, such as, for example, lists of ingredients include combinations and mixtures thereof.

[0091] Referenced herein may be trade names for components including various ingredients utilized in the present disclosure. Equivalent materials (e.g., those obtained from a different source under a different name or reference number) to those referenced by trade name may be substituted and utilized in the descriptions herein.

Peptide compounds

[0092] In some embodiments, the disclosure relates to a peptide compound capable of binding to IL-23 receptor (IL23-R) and inhibiting or reducing the binding of interleukin-23 (IL-23) to its receptor.

[0093] A peptide compound of the disclosure is a peptide compound of formula (I):

[0094] X1 (§ 1 )(#1 )-X2(#1 )(@2)-X3-X4-X5-X6-X7-X8-X9(§1 )(@2)-X10-X11 -X12- X13-R1 (I),

[0095] wherein

[0096] X1 is absent or is a Butyl moiety and

[0097] when X1 is a Butyl moiety, then (§1 ) represents an alkyl bond between X1 and X9 and (#1 ) represents an alkyl bond between X1 and X2, and, in such a case, (@2) are absent, or

[0098] when X1 is absent, then (@2) represents an amide bond between X2 and X9, and, in such a case, (§1 ) and (#1 ) are absent;

[0099] X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dad, Dae, Dec, Dod, Dpa, Kme, Kme(aAc), Lys(aAc), Nmapt, Nmha and Oca;

[0100] X3 is an amino acid residue selected among a residue of Nak, Trp, Wdm, Wim, Wme, Wcl and Wfl;

[0101] X4 is an amino acid residue selected among a residue of Aib, Gin, Glu, lie, Iva, Leu, Lys, Lys(Ac), Mie, Mly, Mva, Phe, Thr, Trp and Vai;

[0102] X5 is an amino acid residue selected among a residue of Aib, Mkdm, Mie and Thp; [0103] X6 is an amino acid residue selected among a residue of Trp, Tyr, Yae, Yde and Yme;

[0104] X7 is an amino acid residue selected among a residue of Nak, Nal and Trp;

[0105] X8 is an amino acid residue selected among a residue of Aib, Cba, Cit, Gin, Leu, Lys, Lys(Ac), Mie, Mly, D-Mkdm, Mkdm, Thp, D-Trp and D-Tza;

[0106] X9 is an amino acid residue selected among a residue of Asp, Glu, Kme, Lys and Orn;

[0107] X10 is an amino acid residue selected among a residue of Ala, Asn, Gly and Ser;

[0108] X1 1 is an amino acid residue selected among a residue of Ala, Asn, Bal, Gly, Hol, Hph, His, lie, Iva, Leu, Mhis, Pal, Pyal, PyEA, Vai, and their corresponding D-forms;

[0109] X12 is absent or is an amino acid residue selected among a residue of Bal, Dnmy, lie, Lys, Mep, Mhis and Sar;

[0110] X13 is absent or is a residue of Lys; and,

[0111] R1 is absent or is selected among -NH₂, -OH and -N(C2H₅)2;

[0112] or a salt or a solvate thereof.

[0113] The expression “and their corresponding D-forms“ necessarily refers to the amino acid residue comprising an asymmetric carbon atom and for which L and D forms exist. The expression does not apply to amino acid for which such asymmetric carbon atom does not exist, such as glycine (Gly) and PyEA.

[0114] A peptide compound of formula (I) inhibits the binding of interleukin-23 (IL- 23) to an interleukin-23-receptor (IL-23R).

[0115] The term “solvate” when used with regard to a peptide compound of the disclosure intends to refer to an aggregate consisting of a peptide compound with one or more solvent molecules, e.g., organic solvent molecules and/or water. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent. Such solvates are within the scope of the present disclosure.

[0116] The term “salt” when used with respect to a peptide compound of the disclosure intends to refer to an ionic form of a peptide compound of the disclosure, negatively or positively charged, in ionic interaction with positively charged cations or negatively charged anions. Such salts include acid or base addition salts formed with inorganic acids or with organic acids or bases.

[0117] In some embodiments, X1 is a Butyl moiety, and X9 is an amino acid residue selected among a residue of Kme, Lys and Orn.

[0118] In some embodiments, X1 is a Butyl moiety and X9 represents Kme.

[0119] In some embodiments, X1 is absent, X2 is an amino acid residue selected among a residue of Dad, Dae, Dec, Dod, Dpa and Oca, and X9 is an amino acid residue selected among a residue of Kme, Lys and Orn.

[0120] In some embodiments, X1 is absent, X2 is an amino acid residue selected among a residue of Dec, Dod, Dpa and Oca, and X9 is an amino acid residue selected among a residue of Kme, Lys and Orn.

[0121] In some embodiments, X1 is absent, X2 is an amino acid residue selected among a residue of Dec, Dod, Dpa and Oca, and X9 is an amino acid residue selected among Kme and Lys.

[0122] In some embodiments, X1 is absent, X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Kme, Kme(aAc), Lys(aAc), Nmapt and Nmha, and X9 is an amino acid residue selected among a residue of Asp and Glu.

[0123] In some embodiments, X1 is absent, X2 is an amino acid residue selected among Add, Ade, Ahd, Aoa, Atd, Atea and Aud, and X9 is Glu.

[0124] In some embodiments, X1 is a Butyl moiety, and X9 is a residue of Kme, or

X1 is absent, X2 is an amino acid residue selected among a residue of Dad, Dae, Dec, Dod, Dpa and Oca, and X9 is an amino acid residue selected among a residue Kme, Lys, and Orn, or

X1 is absent, X2 is an amino acid residue selected among a residue of Dec, Dod, Dpa and Oca, and X9 is an amino acid residue selected among a residue of Kme and Lys, or

X1 is absent, X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Kme, Kme(aAc), Lys(aAc), Nmapt and Nmha, and X9 is an amino acid residue selected among a residue of Asp and Glu, or

X1 is absent, X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea and Aud, and X9 is a residue of Glu. [0125] In some embodiments, peptide compounds of formula (I) comprise a first group of compounds wherein:

[0126] X1 absent or is a Butyl moiety;

[0127] X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dec, Dod, Dpa, Kme, Kme(aAc), Nmapt, Nmha and Oca;

[0128] X3 is an amino acid residue selected among a residue of Trp, Wdm, Wim and Wme;

[0129] X4 is an amino acid residue selected among a residue of Gin, Leu and Lys(Ac);

[0130] X5 is an amino acid residue selected among a residue of Aib and Thp;

[0131 ] X6 is a residue of Yde;

[0132] X7 is a residue of Nal;

[0133] X8 is an amino acid residue selected among a residue of Aib, Mkdm and Thp;

[0134] X9 is an amino acid residue selected among a residue of Glu, Kme and Lys;

[0135] X10 is an amino acid residue selected among a residue of Asn, Gly and Ser;

[0136] X11 is an amino acid residue selected among a residue of Pal and PyEA;

[0137] X12 is absent or is a residue of Sar;

[0138] X13 is absent;

[0139] R1 is absent or is -NH₂,

[0140] or a salt or a solvate thereof.

[0141] In some embodiments, peptide compounds of formula (I) comprise a first group of compounds wherein:

[0142] X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dec, Dod, Dpa, Kme, Kme(aAc), Nmapt, Nmha and Oca;

[0143] X3 is an amino acid residue selected among a residue of Trp, Wdm, Wim, and Wme;

[0144] X4 is an amino acid residue selected among a residue of Gin, Leu and Lys(Ac);

[0145] X5 is an amino acid residue selected among a residue of Aib and Thp; [0146] X6 is a residue of Yde;

[0147] X7 is a residue of Nal;

[0148] X8 is an amino acid residue selected among a residue of Aib, Mkdm and Thp;

[0149] X9 is an amino acid residue selected among a residue of Glu, Kme and Lys;

[0150] X10 is an amino acid residue selected among a residue of Asn, Gly and Ser;

[0151] X11 is an amino acid residue selected among a residue of Pal and PyEA;

[0152] X12 is absent or is a residue of Sar;

[0153] X13 is absent; and,

[0154] R1 is absent or is -NH₂.

[0155]

[0156] In some embodiments of the first group, peptide compounds of formula (I) inhibit the IL-23-induced STAT3 phosphorylation with an IC50 of less than about 50 nM, or less than about 25 nM, or less about 15 nM, or less than about 10 nM.

[0157] In some embodiments of the first group of peptide compounds of formula (I):

[0158] X10 is a residue of Asn, or

[0159] X10 is an amino acid residue selected among a residue of Gly and Ser and X12 is Sar.

[0160] Peptide compounds of such embodiments have an IC50 for inhibiting IL-23 induced STAT3 phosphorylation of about 25 nM or less, or from about 0.05 nM to about 25 nM.

[0161] In some embodiments of the first group of peptide compounds of formula (I) R1 is NH₂.

[0162] Peptide compounds of such embodiments have an IC50 for inhibiting IL-23 induced STAT3 phosphorylation of about 10 nM or less, or from about 0.05 nM to about 10 nM.

[0163] In some embodiments of the first group of peptide compounds of formula (I):

[0164] R1 is NH₂, and

[0165] when X1 is present, X2 is an amino acid residue selected among a residue of Kme, Nmapt and Nmha; or [0166] when X1 is absent, X2 is an amino acid residue selected among a residue of Add, Ade, Aoa, Atd, Atea, Aud, Dec, Dod and Oca.

[0167] In some embodiments of the first group of peptide compounds of formula (I):

[0168] X10 represents Asn ; or,

[0169] X10 represents an amino acid residue selected among a residue of Gly and Ser and X12 represents Sar; and

[0170] R1 represents NH₂, or

[0171] R1 represents NH₂ and

[0172] when X1 is a butyl moiety, X2 represents an amino acid residue selected among a residue of Kme, Nmapt and Nmha; or

[0173] when X1 is absent, X2 represents an amino acid residue selected among Add, Ade, Aoa, Atd, Atea, Aud, Dec, Dod and Oca.

[0174]

[0175] Peptide compounds of such embodiments have an IC50 for inhibiting IL-23 induced STAT3 phosphorylation of about 5 nM or less, or from about 0.05 nM to about 5 nM.

[0176] In some embodiments, X1 is absent or is a Butyl moiety.

[0177] In some embodiments, X1 is absent.

[0178] In some embodiments, X1 is a Butyl moiety.

[0179] In some embodiments, X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dad, Dae, Dec, Dod, Dpa, Kme, Kme(aAc), Lys(aAc), Nmapt, Nmha and Oca.

[0180] In some embodiments, X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dec, Dod, Dpa, Kme, Kme(aAc), Nmapt, Nmha and Oca.

[0181] In some embodiments, X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dec, Dod, Kme, Kme(aAc), Nmapt, Nmha and Oca. [0182] In some embodiments, X2 is an amino acid residue selected among a residue of Add, Ade, Aoa, Atd, Atea, Aud, Dec, Dod, Kme, Kme(aAc), Nmapt, Nmha and Oca.

[0183] In some embodiments, X2 is a residue of Add.

[0184] In some embodiments, X2 is a residue of Ade.

[0185] In some embodiments, X2 is a residue of Ahd.

[0186] In some embodiments, X2 is a residue of Aoa.

[0187] In some embodiments, X2 is a residue of Atd.

[0188] In some embodiments, X2 is a residue of Atea.

[0189] In some embodiments, X2 is a residue of Aud.

[0190] In some embodiments, X2 is a residue of Dad.

[0191] In some embodiments, X2 is a residue of Dae.

[0192] In some embodiments, X2 is a residue of Dec.

[0193] In some embodiments, X2 is a residue of Dod.

[0194] In some embodiments, X2 is a residue of Dpa.

[0195] In some embodiments, X2 is a residue of Kme.

[0196] In some embodiments, X2 is a residue of Kme(aAc).

[0197] In some embodiments, X2 is a residue of Nmapt.

[0198] In some embodiments, X2 is a residue of Nmha.

[0199] In some embodiments, X2 is a residue of Oca.

[0200] In some embodiments, X3 is an amino acid residue selected among a residue of Nak, Trp, Wdm, Wim, Wme, Wcl and Wfl.

[0201] In some embodiments, X3 is an amino acid residue selected among a residue of Trp, Wdm, Wim and Wme.

[0202] In some embodiments, X3 is an amino acid residue selected among a residue of Trp, Wim and Wme.

[0203] In some embodiments, X3 is a residue of Trp.

[0204] In some embodiments, X3 is a residue of Wdm.

[0205] In some embodiments, X3 is a residue of Wim. [0206] In some embodiments, X3 is a residue of Wme.

[0207] In some embodiments, X4 is an amino acid residue selected among a residue of Aib, Gin, Glu, lie, Iva, Leu, Lys, Lys(Ac), Mie, Mly, Mva, Phe, Thr, Trp and Vai.

[0208] In some embodiments, X4 is an amino acid residue selected among a residue of Gin, Leu and Lys(Ac).

[0209] In some embodiments, X4 is a residue of Gin.

[0210] In some embodiments, X4 is a residue of Leu.

[0211] In some embodiments, X4 is a residue of Lys(Ac).

[0212] In some embodiments, X5 is an amino acid residue selected among a residue of Aib, Mkdm, Mie and Thp.

[0213] In some embodiments, X5 is an amino acid residue selected among a residue of Aib and Thp.

[0214] In some embodiments, X5 is a residue of Aib.

[0215] In some embodiments, X5 is a residue of Thp.

[0216] In some embodiments, X6 is an amino acid residue selected among a residue of Trp, Tyr, Yae, Yde and Yme.

[0217] In some embodiments, X6 is a residue of Yde.

[0218] In some embodiments, X7 is an amino acid residue selected among a residue of Nak, Nal and Trp.

[0219] In some embodiments, X7 is a residue of Nal.

[0220] In some embodiments, X8 is an amino acid residue selected among a residue of Aib, Cba, Cit, Gin, Leu, Lys, Lys(Ac), Mie, Mly, D-Mkdm, Mkdm, Thp, D-Trp and D-Tza.

[0221] In some embodiments, X8 is an amino acid residue selected among a residue of Aib, Mkdm and Thp.

[0222] In some embodiments, X8 is a residue of Aib.

[0223] In some embodiments, X8 is a residue of Mkdm.

[0224] In some embodiments, X8 is a residue of Thp.

[0225] In some embodiments, X9 is an amino acid residue selected among a residue of Asp, Glu, Kme, Lys and Orn. [0226] In some embodiments, X9 is an amino acid residue selected among a residue of Glu, Kme and Lys.

[0227] In some embodiments, X9 is a residue of Glu.

[0228] In some embodiments, X9 is a residue of Kme.

[0229] In some embodiments, X9 is a residue of Lys.

[0230] In some embodiments, X10 is an amino acid residue selected among a residue of Ala, Asn, Gly and Ser.

[0231] In some embodiments, X10 is an amino acid residue selected among a residue of Asn, Gly, and Ser.

[0232] In some embodiments, X10 is a residue of Asn.

[0233] In some embodiments, X10 is a residue of Gly.

[0234] In some embodiments, X10 is a residue of Ser.

[0235] In some embodiments, X11 is an amino acid residue selected among a residue of Ala, Asn, Bal, Gly, Hol, Hph, His, lie, Iva, Leu, Mhis, Pal, Pyal, PyEA, Vai, and their corresponding D-forms.

[0236] In some embodiments, X11 is an amino acid residue selected among a residue of Ala, Asn, Bal, Gly, Hol, Hph, His, lie, Iva, Leu, D-Leu, Mhis, Pal, Pyal, PyEA and Vai.

[0237] In some embodiments, X11 is an amino acid residue selected among a residue of Pal and PyEA.

[0238] In some embodiments, X11 is a residue of Pal.

[0239] In some embodiments, X11 is a residue of PyEA.

[0240] In some embodiments, X12 is absent or is an amino acid residue selected among a residue of Bal, Dnmy, lie, Lys, Mep and Sar.

[0241] In some embodiments, X12 is absent or is a residue of Sar.

[0242] In some embodiments, X12 is absent.

[0243] In some embodiments, X12 is a residue of Sar.

[0244] In some embodiments, X13 is absent or is a residue of Lys.

[0245] In some embodiments, X13 is absent. [0246] In some embodiments, R1 is absent or is selected among a residue of -NH₂, -OH or -N(C₂H₅)₂.

[0247] In some embodiments, R1 is absent or is -NH₂.

[0248] In some embodiments, R1 is absent.

[0249] In some embodiments, R1 is NH₂.

[0250] In some embodiments, peptide compounds of formula (I) comprise a second group of compounds wherein:

[0251] X1 is absent or is a Butyl moiety;

[0252] X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dec, Dod, Dpa, Kme, Kme(aAc), Nmapt, Nmha and Oca;

[0253] X3 is an amino acid residue selected among a residue of Trp, Wim and Wme;

[0254] X4 is an amino acid residue selected among a residue of Gin, Leu and Lys(Ac);

[0255] X5 is an amino acid residue selected among a residue of Aib and Thp;

[0256] X6 is a residue of Yde;

[0257] X7 is a residue of Nal;

[0258] X8 is an amino acid residue selected among a residue of Aib, Mkdm and Thp;

[0259] X9 is an amino acid residue selected among a residue of Glu, Kme and Lys;

[0260] X10 is an amino acid residue selected among a residue of Asn, Gly and Ser;

[0261] X11 is an amino acid residue selected among a residue of Pal and PyEA;

[0262] X12 is absent or is a residue of Sar;

[0263] X13 is absent;

[0264] R1 is absent or is -NH₂.

[0265] In some embodiments of the second group:

[0266] when X2 is a residue of Nmapt, X11 is a residue of PyEA, and X4 is a residue of Gin, then X10 is not a residue of Gly, or [0267] when X2 is a residue of Nmapt, X1 1 is a residue of PyEA, and X10 is a residue of Gly, then X4 is not a residue of Gin,

[0268] when X2 is a residue of Nmha and X11 is a residue of PyEA, then X4 is not a residue of Lys(Ac).

[0269] In some embodiments of the second group, when X2 is a residue of Nmapt, then X1 1 is a residue of Pal.

[0270] In some embodiments of the second group, when X2 is a residue of Nmapt and X1 1 is a residue of PyEA, then X10 is a residue of Ser.

[0271] In some embodiments of the second group, when X2 is a residue of Nmha, then X1 1 is a residue of Pal.

[0272] In some embodiments of the second group, when X2 is a residue of Nmha and X1 1 is a residue of PyEA, then X4 is a residue of Gin.

[0273] In some embodiments of the second group, peptide compounds of formula (I) have an IC50 for inhibiting IL-23 induced STAT3 phosphorylation of about 25 nM or less, or from about 0.05 nM to about 25 nM.

[0274] In some embodiments, peptide compounds of formula (I) comprise a third group of compounds wherein:

[0275] X1 is absent or is a Butyl moiety;

[0276] X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dec, Dod, Dpa, Kme, Kme(aAc), Nmapt, Nmha and Oca;

[0277] X3 is an amino acid residue selected among a residue of Trp, Wim and Wme;

[0278] X4 is an amino acid residue selected among a residue of Gin, Leu and Lys(Ac);

[0279] X5 is an amino acid residue selected among a residue of Aib and Thp;

[0280] X6 is a residue of Yde;

[0281] X7 is a residue of Nal;

[0282] X8 is an amino acid residue selected among a residue of Aib, Mkdm and Thp;

[0283] X9 is an amino acid residue selected among a residue of Glu, Kme and Lys; [0284] X10 is an amino acid residue selected among a residue of Asn, Gly and Ser;

[0285] X11 is an amino acid residue selected among a residue of Pal and PyEA;

[0286] X12 is absent or is a residue of Sar;

[0287] X13 is absent;

[0288] R1 is absent or is -NH₂.

[0289] In some embodiments of the third group,

[0290] when X2 is a residue of Nmapt, X11 is a residue of PyEA, and X4 is a residue of Gin, then X10 is not a residue of Gly, or

[0291 ] when X2 is a residue of Nmapt, X11 is a residue of PyEA, and X4 is a residue of Lys(Ac), then X10 is not a residue of Ser, or

[0292] when X2 is a residue of Nmapt, X11 is a residue of PyEA, and X10 is a residue of Gly, then X4 is not a residue of Gin,

[0293] when X2 is a residue of Nmha, then X11 is not a residue of PyEA.

[0294] In some embodiments of the third group, when X2 is a residue of Nmapt, then X11 is a residue of Pal.

[0295] In some embodiments, peptide compounds of formula (I) comprise a third group of compounds wherein:

[0296] X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dec, Dod, Dpa, Kme, Kme(aAc), Nmapt, Nmha and Oca;

[0297] X3 is an amino acid residue selected among a residue of Trp, Wim and Wme;

[0298] X4 is an amino acid residue selected among a residue of Gin, Leu and Lys(Ac);

[0299] X5 is an amino acid residue selected among a residue of Aib and Thp;

[0300] X6 is a residue of Yde;

[0301] X7 is a residue of Nal;

[0302] X8 is an amino acid residue selected among a residue of Aib, Mkdm and Thp;

[0303] X9 is an amino acid residue selected among a residue of Glu, Kme and Lys;

[0304] X10 is an amino acid residue selected among a residue of Asn, Gly and Ser; [0305] X11 is an amino acid residue selected among a residue of Pal and PyEA;

[0306] X12 is absent or is a residue of Sar;

[0307] X13 is absent;

[0308] R1 is absent or is -NH₂,

[0309] wherein

[0310] when X2 is a residue of Nmapt, X11 is a residue of PyEA, and X4 is a residue of Gin, then X10 is not a residue of Gly, or

[0311] when X2 is a residue of Nmapt, X11 is a residue of PyEA, and X10 is a residue of Gly, then X4 is not a residue of Gin, or

[0312] when X2 is a residue of Nmha and X11 is a residue of PyEA, then X4 is not a residue of Lys(Ac).

[0313]

[0314] In some embodiments of the third group, when X2 is a residue of Nmapt and X11 is a residue of PyEA, then X10 is a residue of Gly and X4 is a residue of Gin or X10 is a residue of Ser and X4 is a residue of Lys(Ac).

[0315] In some embodiments of the third group, when X2 is a residue of Nmha, then X11 is a residue of Pal.

[0316] Peptide compounds of the third group have an IC50 for inhibiting IL-23 induced STAT3 phosphorylation of about 15 nM or less, or from about 0.05 nM to about 15 nM.

[0317] In some embodiments, peptide compounds of formula (I) comprise a fourth group of compounds wherein:

[0318] X1 is absent or is a Butyl moiety;

[0319] X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dec, Dod, Kme, Kme(aAc), Nmapt, Nmha and Oca;

[0320] X3 is an amino acid residue selected among a residue of Trp, Wim and Wme;

[0321] X4 is an amino acid residue selected among a residue of Gin, Leu and Lys(Ac);

[0322] X5 is an amino acid residue selected among a residue of Aib and Thp; [0323] X6 is a residue of Yde;

[0324] X7 is a residue of Nal;

[0325] X8 is an amino acid residue selected among a residue of Aib, Mkdm and Thp;

[0326] X9 is an amino acid residue selected among a residue of Glu, Kme and Lys;

[0327] X10 is an amino acid residue selected among a residue of Asn, Gly and Ser;

[0328] X11 is an amino acid residue selected among a residue of Pal and PyEA;

[0329] X12 is absent or is a residue of Sar;

[0330] X13 is absent;

[0331] R1 is absent or is -NH₂,

[0332] In some embodiments of the fourth group,

[0333] when X2 is a residue of Nmapt, then X11 is not a residue of PyEA, or

[0334] when X2 is a residue of Nmapt and X11 is a residue of PyEA, then X3 is a residue of Wim, X4 is a residue of Gin and X10 is a residue of Ser, or

[0335] when X2 is a residue of Nmha, then X11 is not a residue of PyEA, or

[0336] when X2 is a residue of Aoa or Dec, then X4 is not a residue of Leu.

[0337] In some embodiments of the fourth group, when X2 is a residue of Nmapt, then X11 is a residue of Pal.

[0338] In some embodiments of the fourth group, when X2 is a residue of Nmapt and X11 is a residue of PyEA, then X10 is a residue of Gly X4 is a residue of Gin and X3 is a residue of Wim.

[0339] In some embodiments of the fourth group, when X2 is a residue of Nmha, then X11 is a residue of Pal.

[0340] In some embodiments of the fourth group, when X2 is a residue of Aoa or Dec, then X4 is a residue of Gin.

[0341] In some embodiments, peptide compounds of formula (I) comprise a fourth group of compounds wherein:

[0342] X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dec, Dod, Dpa, Kme, Kme(aAc), Nmapt, Nmha and Oca;

[0343] X3 is an amino acid residue selected among a residue of Trp, Wim and Wme; [0344] X4 is an amino acid residue selected among a residue of Gin, Leu and Lys(Ac);

[0345] X5 is an amino acid residue selected among a residue of Aib and Thp;

[0346] X6 is a residue of Yde;

[0347] X7 is a residue of Nal;

[0348] X8 is an amino acid residue selected among a residue of Aib, Mkdm and Thp;

[0349] X9 is an amino acid residue selected among a residue of Glu, Kme and Lys;

[0350] X10 is an amino acid residue selected among a residue of Asn, Gly and Ser;

[0351] X11 is an amino acid residue selected among a residue of Pal and PyEA;

[0352] X12 is absent or is a residue of Sar;

[0353] X13 is absent; and,

[0354] R1 is absent or is -NH_2;

[0355] wherein

[0356] when X2 is a residue of Nmapt, X11 is a residue of PyEA, and X4 is a residue of Gin, then X10 is not a residue of Gly, or

[0357] when X2 is a residue of Nmapt, X11 is a residue of PyEA, and X4 is a residue of Lys(Ac), then X10 is not a residue of Ser, or

[0358] when X2 is a residue of Nmapt, X11 is a residue of PyEA, and X10 is a residue of Gly, then X4 is not a residue of Gin, or

[0359] when X2 is a residue of Nmha, then X11 is not a residue of PyEA.

[0360] In some embodiments, peptide compounds of formula (I) comprise a fourth group of compounds wherein:

[0361] X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dec, Dod, Kme, Kme(aAc), Nmapt, Nmha and Oca;

[0362] X3 is an amino acid residue selected among a residue of Trp, Wim and Wme;

[0363] X4 is an amino acid residue selected among a residue of Gin, Leu and Lys (Ac);

[0364] X5 is an amino acid residue selected among a residue of Aib and Thp; [0365] X6 is a residue of Yde;

[0366] X7 is a residue of Nal;

[0367] X8 is an amino acid residue selected among a residue of Aib, Mkdm and Thp;

[0368] X9 is an amino acid residue selected among a residue of Glu, Kme and Lys;

[0369] X10 is an amino acid residue selected among a residue of Asn, Gly and Ser;

[0370] X11 is an amino acid residue selected among a residue of Pal and PyEA;

[0371 ] X12 is absent or is a residue of Sar;

[0372] X13 is absent;

[0373] R1 is absent or is -NH₂,

[0374] wherein

[0375] when X2 is a residue of Nmapt, then X11 is not PyEA, or

[0376] when X2 is a residue of Nmapt and X11 is a residue of PyEA, then X3 is a residue of Wim, X4 is a residue of Gin and X10 is a residue of Ser, or

[0377] when X2 is a residue of Nmha, then X11 is not a residue of PyEA, or

[0378] when X2 is a residue of Aoa or Dec, then X4 is not a residue of Leu.

[0379]

[0380] Peptide compounds of the fourth group have an IC50 for inhibiting IL-23 induced STAT3 phosphorylation of about 10 nM or less, or from about 0.05 nM to about 10 nM.

[0381] In some embodiments, peptide compounds of formula (I) comprise a fifth group of compounds wherein:

[0382] X1 is absent or is a Butyl moiety;

[0383] X2 is an amino acid residue selected among a residue of Add, Ade, Aoa, Atd, Atea, Aud, Dec, Dod, Kme, Kme(aAc), Nmapt, Nmha and Oca;

[0384] X3 is an amino acid residue selected among a residue of Trp, Wim and Wme;

[0385] X4 is an amino acid residue selected among a residue of Gin, Leu and Lys (Ac); [0386] X5 is an amino acid residue selected among a residue of Aib and Thp;

[0387] X6 is a residue of Yde;

[0388] X7 is a residue of Nal;

[0389] X8 is an amino acid residue selected among a residue of Aib, Mkdm and Thp;

[0390] X9 is an amino acid residue selected among a residue of Glu, Kme and Lys;

[0391 ] X10 is an amino acid residue selected among a residue of Asn, Gly and Ser;

[0392] X11 is a residue of Pal;

[0393] X12 is a residue of Sar;

[0394] X13 is absent;

[0395] R1 is -NH₂.

[0396] In some embodiments of the fifth group,

[0397] when X2 is a residue of Nmapt and X3 is a residue of Wme, then X8 is not a residue of Mkdm, or

[0398] when X2 is a residue of Aoa, then X4 is not a residue of Leu.

[0399] In some embodiments of the fifth group, when X2 is a residue of Aoa or Dec, then X4 is a residue of Gin.

[0400] In some embodiments, peptide compounds of formula (I) comprise a fifth group of compounds wherein:

[0401 ] X2 is an amino acid residue selected among a residue of Add, Ade, Aoa, Atd, Atea, Aud, Dec, Dod, Kme, Kme(aAc), Nmapt, Nmha and Oca;

[0402] X3 is an amino acid residue selected among a residue of Trp, Wim and Wme;

[0403] X4 is an amino acid residue selected among a residue of Gin, Leu and Lys (Ac);

[0404] X5 is an amino acid residue selected among a residue of Aib and Thp;

[0405] X6 is a residue of Yde;

[0406] X7 is a residue of Nal;

[0407] X8 is an amino acid residue selected among a residue of Aib, Mkdm and

Thp; [0408] X9 is an amino acid residue selected among a residue of Glu, Kme and Lys;

[0409] X10 is an amino acid residue selected among a residue of Asn, Gly and Ser;

[0410] X11 is a residue of Pal;

[0411 ] X12 is a residue of Sar;

[0412] X13 is absent;

[0413] R1 is -NH₂,

[0414] wherein,

[0415] when X2 is a residue of Nmapt and X3 is a residue of Wme, then X8 is not a residue of a residue of Mkdm, or

[0416] when X2 is a residue of Aoa, then X4 is not a residue of a residue of Leu.

[0417]

[0418] Peptide compounds of the fifth group have an IC50 for inhibiting IL-23 induced STAT3 phosphorylation of about 5 nM or less, or from about 0.05 nM to about 5 nM.

[0419] In some embodiments, peptide compounds of formula (I) comprise a sixth group wherein:

[0420] X1 is a Butyl moiety;

[0421] X2 is an amino acid residue selected among a residue of Nmap and Nmha;

[0422] X3 is an amino acid residue selected among a residue of Wdm, Wim and Wme;

[0423] X4 is an amino acid residue selected among a residue of Gin, Leu and Lys(Ac);

[0424] X5 is a residue of Thp;

[0425] X6 is a residue of Yde;

[0426] X7 is a residue of Nal;

[0427] X8 is a residue of Aib;

[0428] X9 is a residue of Kme;

[0429] X10 is a residue of Gly;

[0430] X11 is a residue of PyEA; [0431] X12 is absent;

[0432] X13 is absent;

[0433] R1 is absent.

[0434] In some embodiment of the peptide compounds of the sixth group, when X2 is a residue of Nmha, then X4 is not a residue of Gin.

[0435] Peptide compounds of the sixth group have an IC50 for inhibiting IL-23 induced STAT3 phosphorylation in a range of from about 25 nM to about 50 nM.

[0436] In some embodiments, peptide compounds of formula (I) comprise a seventh group wherein:

[0437] X1 is a Butyl moiety;

[0438] X2 is an amino acid residue selected among a residue of Nmapt and Nmha;

[0439] X3 is an amino acid residue selected among a residue of Wim and Wme;

[0440] X4 is an amino acid residue selected among a residue of Gin and Lys(Ac);

[0441] X5 is a residue Thp;

[0442] X6 is a residue of Yde;

[0443] X7 is a residue of Nal;

[0444] X8 is a residue of Aib;

[0445] X9 is a residue of Kme;

[0446] X10 is an amino acid residue selected among a residue of Gly and Ser;

[0447] X11 is a residue of PyEA;

[0448] X12 is absent;

[0449] X13 is absent;

[0450] R1 is absent.

[0451] In some embodiments of the seventh group, when X2 is a residue of Nmha, then X4 is not a residue of Lys(Ac), or when X2 is a residue of Nmapt, then X4 is not a residue of Gin.

[0452] Peptide compounds of the seventh group have an IC50 for inhibiting IL-23 induced STAT3 phosphorylation in a range of from about 15 nM to about 25 nM. [0453] In some embodiments, peptide compounds of formula (I) comprise an eighth group wherein:

[0454] X1 is absent or is a Butyl moiety;

[0455] X2 is an amino acid residue selected among a residue of Aoa, Dec, Dpa and Nmapt;

[0456] X3 is an amino acid residue selected among a residue of Wim and Wme;

[0457] X4 is an amino acid residue selected among a residue of Gin, Leu and Lys(Ac);

[0458] X5 is a residue of Thp;

[0459] X6 is a residue of Yde;

[0460] X7 is a residue of Nal;

[0461] X8 is an amino acid residue selected among a residue of Aib and Thp;

[0462] X9 is an amino acid residue selected among a residue of Glu, Kme and Lys;

[0463] X10 is an amino acid residue selected among a residue of Asn, Gly and Ser;

[0464] X11 is an amino acid residue selected among a residue of Pal and PyEA;

[0465] X12 is absent or is a residue of Sar;

[0466] X13 is absent;

[0467] R1 is absent or is a residue of -NH₂.

[0468] In some embodiments of the peptide compounds of the eighth group, when X2 is a residue of Aoa, then X4 is not a residue of Gin, or when X2 is a residue of Dec, then X4 is not a residue of Gin, or when X2 is a residue of Nmapt, then X8 is a residue of Thp or X3 is a residue of Wim, X10 is a residue of Ser, and X11 is a residue of PyEA.

[0469] Peptide compounds of the eighth group have an IC50 for inhibiting IL-23 induced STAT3 phosphorylation in a range of from about 10 nM to about 15 nM.

[0470] In some embodiments, peptide compounds of formula (I) comprise a ninth group wherein:

[0471] X1 is absent or is a Butyl moiety; [0472] X2 is an amino acid residue selected among a residue of Ahd and Nmapt;

[0473] X3 is an amino acid residue selected among a residue of Wim and Wme;

[0474] X4 is a residue of Gin;

[0475] X5 is a residue of Thp;

[0476] X6 is a residue of Yde;

[0477] X7 is a residue of Nal;

[0478] X8 is an amino acid residue selected among a residue of Aib or Mkdm;

[0479] X9 is an amino acid residue selected among a residue of Glu and Kme;

[0480] X10 is an amino acid residue selected among a residue of Asn and Ser;

[0481] X11 is an amino acid residue selected among a residue of Pal and PyEA;

[0482] X12 is absent or is a residue of Sar;

[0483] X13 is absent;

[0484] R1 is absent or is -NH₂.

[0485] In some embodiments of the ninth group, when X2 is a residue of Nmpat, then X3 is a residue of Wim and X11 is a residue of PyEA, or X8 is a residue of Mkdm.

[0486] Peptide compounds of the ninth group have an IC50 for inhibiting IL-23 induced STAT3 phosphorylation in a range of from about 5 nM to about 10 nM.

[0487] In some embodiments, peptide compounds of formula (I) comprise a tenth group wherein:

[0488] X1 is absent or is a Butyl moiety;

[0489] X2 is an amino acid residue selected among a residue of Aoa, Nmapt and Nmha;

[0490] X3 is an amino acid residue selected among a residue of Trp, Wim and Wme;

[0491] X4 is an amino acid residue selected among a residue of Gin and Lys(Ac);

[0492] X5 is a residue of Thp;

[0493] X6 is a residue of Yde;

[0494] X7 is a residue of Nal; [0495] X8 is a residue of Aib;

[0496] X9 is an amino acid residue selected among a residue of Glu and Kme;

[0497] X10 is an amino acid residue selected among a residue of Asn, Gly and Ser;

[0498] X11 is a residue of Pal;

[0499] X12 is a residue of Sar;

[0500] X13 is absent;

[0501] R1 is -NH₂.

[0502] In some embodiments of the tenth group, when X2 is a residue of Nmha, then X4 is not a residue of Gin and/or X10 is not a residue of Asn, or when X2 is a residue of Nmapt, then X3 is not a residue of Wim, or when X2 is a residue of Nampt and X3 is a residue of Wme, then X10 is not a residue of Ser.

[0503] Peptide compounds of the tenth group have an IC50 for inhibiting IL-23 induced STAT3 phosphorylation in a range of from about 3 nM to about 5 nM.

[0504] In some embodiments, peptide compounds of formula (I) comprise an eleventh group wherein

[0505] X1 is a Butyl moiety;

[0506] X2 is an amino acid residue selected among a residue of Nmapt and Nmha;

[0507] X3 is an amino acid residue selected among a residue of Trp, Wim and Wme;

[0508] X4 is an amino acid residue selected among a residue of Gin and Lys(Ac);

[0509] X5 is a residue of Aib;

[0510] X6 is a residue of Yde;

[0511] X7 is a residue of Nal;

[0512] X8 is an amino acid residue selected among a residue of Aib and Thp;

[0513] X9 is a residue of Kme;

[0514] X10 is an amino acid residue selected among a residue of Gly and Ser;

[0515] X11 is a residue of Pal;

[0516] X12 is a residue of Sar;

[0517] X13 is absent; [0518] R1 is -NH₂-

[0519] In some embodiments of the eleventh group, when X2 is a residue of Nmapt, then X8 is a residue of Thp or X3 is not a residue of W, or X3 is a residue of Wim and X10 is a residue of Gly, or X3 is a residue of Wme and X10 is a residue of Ser, or when X2 is a residue of Nmha, then X4 is not a residue of Lys(Ac).

[0520] Peptide compounds of the eleventh group have an IC50 for inhibiting IL-23 induced STAT3 phosphorylation in a range of from about 2 nM to about 3 nM.

[0521] In some embodiments, peptide compounds of formula (I) comprise a twelfth group wherein:

[0522] X1 is absent or is a Butyl moiety;

[0523] X2 is an amino acid residue selected among a residue of Ade, Atd, Atea, Aud and Nmapt;

[0524] X3 is a residue of Wim;

[0525] X4 is an amino acid residue selected among a residue of Gin, Leu and Lys(Ac);

[0526] X5 is a residue of Thp;

[0527] X6 is a residue of Yde;

[0528] X7 is a residue of Nal;

[0529] X8 is an amino acid residue selected among a residue of Aib and Mkdm;

[0530] X9 is an amino acid residue selected among a residue of Glu and Kme;

[0531] X10 is an amino acid residue selected among a residue of Asn and Ser;

[0532] X11 is a residue of Pal;

[0533] X12 is a residue of Sar;

[0534] X13 is absent;

[0535] R1 is -NH₂.

[0536] In some embodiments of the twelfth group, when X2 is a residue of Nmapt, then X4 is not a residue of Gin, or X8 is not a residue of Aib, or X10 is not a residue of Asn, or when X2 is a residue of Ade, then X4 is not a residue of Gin, or when X2 is a residue of Aud, then X4 is a residue of Leu. [0537] Peptide compounds of the twelfth group have an IC50 for inhibiting IL-23 induced STAT3 phosphorylation in a range of from about 1 nM to about 2 nM.

[0538] In some embodiments, peptide compounds of formula (I) comprise a thirteenth group wherein:

[0539] X1 is absent or is a Butyl moiety;

[0540] X2 is an amino acid residue selected among a residue of Add, Ade, Aud, Dec, Dod and Oca;

[0541] X3 is an amino acid residue selected among a residue of Wim and Wme;

[0542] X4 is an amino acid residue selected among a residue of Gin and Lys(Ac);

[0543] X5 is an amino acid residue selected among a residue of Aib and Thp;

[0544] X6 is a residue of Yde;

[0545] X7 is a residue of Nal;

[0546] X8 is an amino acid residue selected among a residue of Aib, Mkdm and Thp;

[0547] X9 is an amino acid residue selected among a residue of Glu, Kme and Lys;

[0548] X10 is a residue of Asn;

[0549] X11 is a residue of Pal;

[0550] X12 is a residue of Sar;

[0551] X13 is absent;

[0552] R1 is -NH₂.

[0553] In some embodiment of the thirteenth group, when X2 is a residue of Nmapt or Nmha, then X8 is not a residue Mkdm.

[0554] Peptide compounds of the thirteenth group have an IC50 for inhibiting IL-23 induced STAT3 phosphorylation in a range of from about 0.05 nM to about 1 nM.

[0555] In some embodiments, a peptide compound of formula (I) is represented by a sequence selected among SEQ ID NO: 1-50, or a salt or a solvate thereof, as figured in the Table 2 below. [0556] In some embodiments, a peptide compound of formula (I) is represented by a sequence selected among SEQ ID NO: 1-22, 24, 26-48 and 50, or a salt or a solvate thereof.

[0557] In some embodiments, a peptide compound of formula (I) is represented by a sequence selected among SEQ ID NO: 1 -21 , 24, 26-36, 38-48 and 50, or a salt or a solvate thereof.

[0558] In some embodiments, a peptide compound of formula (I) is represented by a sequence selected among SEQ ID NO: 1 -8, 10-14, 16, 18-21 , 24, 26-36, 39-47 and 50, or a salt or a solvate thereof.

[0559] In some embodiments, a peptide compound of formula (I) is represented by a sequence selected among SEQ ID NO: 1-2, 4-8, 10-14, 16, 18-21 , 24, 26-35, 39-44, 46- 47 and 50, or a salt or a solvate thereof.

[0560] In some embodiments, a peptide compound of formula (I) is represented by a sequence selected among SEQ ID NO: 1 -2, 4-5, 7-8, 10-14, 16, 18-21 , 26, 28-29, 31-35, 39-40, 43-44, 46-47 and 50, or a salt or a solvate thereof.

[0561] In some embodiments, a peptide compound of formula (I) is represented by a sequence selected among SEQ ID NO: 1-2, 4-5, 7-8, 10-14, 16, 18-21 , 31 -35, 39, 44, 46- 47 and 50, or a salt or a solvate thereof.

[0562] In some embodiments, a peptide compound of formula (I) is represented by a sequence selected among SEQ ID NO: 4, 11 , 16, 18, 19 and 50, or a salt or a solvate thereof.

In some embodiments, a peptide compound of formula (I) is represented by a sequence selected among

SEQ ID NO: 1-22, 24, 26-48 and 50, or a salt or a solvate thereof; or

SEQ ID NO: 1-21 , 24, 26-36, 38-48 and 50, or a salt or a solvate thereof; or

SEQ ID NO: 1 -8, 10-14, 16, 18-21 , 24, 26-36, 39-47 and 50, or a salt or a solvate thereof; or

SEQ ID NO: 1-2, 4-8, 10-14, 16, 18-21 , 24, 26-35, 39-44, 46-47 and 50, or a salt or a solvate thereof; or

SEQ ID NO: 1-2, 4-5, 7-8, 10-14, 16, 18-21 , 26, 28-29, 31-35, 39-40, 43-44, 46- 47 and 50, or a salt or a solvate thereof; or

[0564] (§1 ) represent an alkyl bond between X1 and X9 and (#1 ) represents an alkyl bond between X1 and X2.

[0565] (@2) represents an amide bond between X2 and X9. [0566] (Ac) indicates acetylation of the amino acid residue, e.g., Lys(Ac) or

Kme(aAc).

[0567] Peptide compounds of the disclosure display affinity for the interleukin-23 receptor and the ability to prevent or reduce the binding of IL-23 to its receptor. [0568] The binding of peptide compounds of the disclosure to interleukin-23 prevents, reduces or inhibits the intracellular signal transduction pathway resulting in Th 17 cell activation.

[0569] Peptide compounds of the disclosure can be tested for interleukin-23 receptor affinity or inhibitor activity using the assays described in the Examples section and the results shown in Tables 8 and 9 herein.

[0570] Peptide compounds of formula (I) have a binding affinity to the interleukin 23 receptor determined using the method described in the Examples (i.e., Human ELISA IL23/IL23R) of 100 nM or less (i.e., IC50 <= 100 nM), or of 50 nM or less (i.e., IC50 <= 50.0 nM), or of 20 nM or less (i.e., IC50 <= 20.0 nM), or of 10 nM or less (i.e., IC50 < =10.0 nM), or of 5 nM or less (i.e., IC50 <= 5.0 nM), or of 1 nM or less (i.e., IC50 <= 1 -0 nM).

[0571] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 of about 50 nM or less, or of about 25 nM or less, or of about 15 nM or less, or of about 10 nM or less, or of about 5 nM or less, or of about 3 nM or less, or of about 2 nM or less, or of about 1 nM or less.

[0572] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 in the range of from about 0.01 nM to about 50 nM, or from about 0.05 nM to about 50 nM, or from about 0.1 nM to about 50 nM.

[0573] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 in the range of from about 0.01 nM to about 25 nM, or from about 0.05 nM to about 25 nM, or from about 0.1 nM to about 25 nM.

[0574] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 in the range of from about 0.05 nM to about 50 nM, or from about 0.05 nM to about 25 nM, or from about 0.05 nM to about 15 nM, or from about 0.05 nM to about 10 nM, or from about 0.05 nM to about 5 nM, or from about 0.05 nM to about 3 nM, or from about 0.05 nM to about 2 nM, or from about 0.05 nM to about 1 nM.

[0575] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 in the range of from about 0.1 nM to about 50 nM, or from about 0.1 nM to about 25 nM, or from about 0.1 nM to about 15 nM, or from about 0.1 nM to about 10 nM, or from about 0.1 nM to about 5 nM, or from about 0.1 nM to about 3 nM, or from about 0.1 nM to about 2 nM, or from about 0.1 nM to about 1 nM.

[0576] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 ranging from about 0.01 nM to about 50 nM.

[0577] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 ranging from about 0.01 nM to about 25 nM.

[0578] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 ranging from about 0.01 nM to about 20 nM.

[0579] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 ranging from about 0.01 nM to about 15 nM.

[0580] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 ranging from about 0.01 nM to about 10 nM. [0581] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 ranging from about 0.01 nM to about 8 nM.

[0582] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 ranging from about 0.01 nM to about 6 nM.

[0583] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 ranging from about 0.01 nM to about 5 nM.

[0584] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 ranging from about 0.01 nM to about 4 nM.

[0585] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 ranging from about 0.01 nM to about 3 nM.

[0586] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 ranging from about 0.01 nM to about 2 nM.

[0587] In some embodiments, peptide compounds of formula (I) inhibit the IL-23- induced STAT3 phosphorylation with an IC50 ranging from about 0.01 nM to about 1 nM.

[0588] In a further embodiment, peptide compounds of formula (I) are sufficiently chemically stable in aqueous solution at different pH. Stability in aqueous solution is measured as a purity loss after 24 hrs at 37°C in buffer solution.

[0589] In some embodiments, peptide compounds of formula (I) have chemical stability in aqueous solution at pH ranging from about 1 to about 8.5, or from about 1 .2 to about 7.4 as exemplified in the Examples.

[0590] In some embodiments, peptide compounds of formula (I) are stable in aqueous solution at a pH of about 1 , 1 .2, 1 .5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.4, 7.5, 8, 8.5 or 9.

[0591] In some embodiments, peptide compounds of formula (I) are stable in aqueous solution at a pH of 1 .2, 6.5 or 7.4.

[0592] The stability of a peptide compound of formula (I) is determined by measure of the relative purity loss as described in the Example section.

[0593] In some embodiments, peptide compounds of formula (I) have a stability in water at pH of about 1 .2, measured as a purity loss after 24 hrs at 37°C, of about 20% or less or of about 15% or less, or of about 10% or less, with respect to the control, at 37°C at 0 hour. [0594] In some embodiment, peptide compounds of formula (I) have a stability in water at pH of about 1 .2, measured as a purity loss after 24 hrs at 37°C, of about 20% or less, with respect to the control, at 37°C at 0 hour.

[0595] Peptide compounds of formula (I) have a stability in water at pH of about

1 .2, measured as a purity loss after 24 hrs at 37°C, of about 15% or less.

[0596] Peptide compounds of formula (I) have a stability in water at pH of about

1.2, measured as a purity loss after 24 hrs at 37°C, of about 10% or less, with respect to the control at 37°C at 0 hour.

[0597] Peptide compounds of formula (I) have a stability in water at pH of about

6.5, measured as a purity loss after 24 hrs at 37°C, of about 10% or less, or of about 5% or less, or of about 2% or less, with respect to the control at 37°C at 0 hour.

[0598] Peptide compounds of formula (I) have a stability in water at pH of about

6.5, measured as a purity loss after 24 hrs at 37°C, of about 10% or less, with respect to the control at 37°C at 0 hour.

[0599] Peptide compounds of formula (I) have a stability in water at pH of about

6.5, measured as a purity loss after 24 hrs at 37°C, of about 5% or less, with respect to the control at 37°C at 0 hour.

[0600] Peptide compounds of formula (I) have a stability in water at pH of about

6.5, measured as a purity loss after 24 hrs at 37°C, of about 2% or less, with respect to the control at 37°C at 0 hour.

[0601] Peptide compounds of formula (I) have a stability in water at pH of about

7.4, measured as a purity loss after 24 hrs at 37°C, of about 10% or less, or of about 5% or less, or of about 2% or less, with respect to the control at 37°C at 0 hour.

[0602] Peptide compounds of formula (I) have a stability in water at pH of about

7.4, measured as a purity loss after 24 hrs at 37°C, of about 10% or less, with respect to the control at 37°C at 0 hour.

[0603] Peptide compounds of formula (I) have a stability in water at pH of about

7.4, measured as a purity loss after 24 hrs at 37°C, of about 5% or less, with respect to the control at 37°C at 0 hour.

[0604] Peptide compounds of formula (I) have a stability in water at pH of about

7.4, measured as a purity loss after 24 hrs at 37°C, of about 2% or less, with respect to the control at 37°C at 0 hour. [0605] In a further embodiment, peptide compounds of formula (I) are sufficiently stable in the intestinal environment to execute a pharmacological effect.

[0606] Protease stability is measured as a percentage of remaining of peptide compound in simulated intestinal fluids at 60 min and 37°C, of at least 50%.

[0607] Peptide compounds of formula (I) have a protease stability measured as a percentage of remaining of said peptide in simulated intestinal fluids at 60 min and 37°C, of about 50% to about 100%.

[0608] Peptide compounds of formula (I) have a protease stability measured as a percentage of remaining of said peptide in simulated intestinal fluids at 60 min and 37°C, of about 60% to about 95%.

[0609] Peptide compounds of formula (I) have a protease stability measured as a percentage of remaining of said peptide in simulated intestinal fluids at 60 min, 37°C, of about 70% to about 90%.

[0610] In some embodiments, peptide compounds of formula (I) have sufficient stability in gastric or intestinal environment to execute a pharmacological effect. The stability in a gastric or intestinal environment of a peptide of compound of formula (I) is determined as described in the Example section.

Peptide synthesis

[0611] The skilled person is aware of a variety of different methods to prepare peptides. These methods include but are not limited to synthetic approaches. Thus, one way of preparing peptides is the synthesis in solution or on a solid support and subsequent isolation and purification.

[0612] A way to prepare the compounds disclosed herein is solid phase synthesis on a suitable resin. Solid phase peptide synthesis is a well-established methodology (see for example: Stewart and Young, Solid Phase Peptide Synthesis, Pierce Chemical Co., Rockford, III., 1984; E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis. A Practical Approach, Oxford-IRL Press, New York, 1989). Solid phase synthesis is initiated by attaching an N-terminally protected amino acid with its carboxy terminus to an inert solid support carrying a cleavable linker. This solid support can be any polymer that allows coupling of the initial amino acid, e.g., a trityl resin, a chlorotrityl resin, a Wang resin or a Rink resin in which the linkage of the carboxy group (or carboxamide for Rink resin) to the resin is sensitive to acid (when Fmoc strategy is used). The polymer support must be stable under the conditions used to deprotect the a-amino group during the peptide synthesis. In a further aspect a Fmoc synthesis strategy may be applied, and Rink resins may be used. In another aspect a Fmoc synthesis strategy may be applied, and Wang resins may be used.

[0613] After the N-terminally protected first amino acid has been coupled to the solid support, the a-amino protecting group of this amino acid is removed. The remaining protected amino acids are then coupled one after the other or with a preformed dipeptide, tripeptide or tetrapeptide, in the order represented by the peptide sequence using appropriate amide coupling reagents, for example BOP, HBTU, HATU or DIC (N,N’- diisopropylcarbodiimide) / HOBt (1 -hydroxybenzotriazole), wherein BOP, HBTU and HATU are used with tertiary amine bases. Alternatively, the liberated N-terminus can be functionalized with groups other than amino acids, for example carboxylic acids.

[0614] Usually, reactive side-chain groups of the amino acids are protected with suitable blocking groups. These protecting groups are removed after the desired peptides have been assembled. They are removed concomitantly with the cleavage of the desired product from the resin under the same conditions. Protecting groups and the procedures to introduce protecting groups can be found in Protective Groups in Organic Synthesis, 3d ed., Greene, T. W. and Wuts, P. G. M., Wiley & Sons (New York: 1999).

[0615] In some cases, it might be desirable to have side chain protecting groups that can selectively be removed while other side chain protecting groups remain intact. In this case the liberated functionality can be selectively functionalized. For example, a lysine is protected with an ivDde ([1 -(4,4-dimethyl-2,6-dioxocyclohex-1 -ylidene)-3-methylbutyl) protecting group (S.R. Chhabra et al., Tetrahedron Lett. 39, (1998), 1603) which is labile to a very nucleophilic base, for example 4% hydrazine in DMF (dimethyl formamide). Thus, if the N-terminal amino group and all side-chain functionalities are protected with acid labile protecting groups, the ivDde group can be selectively removed using 4% hydrazine in DMF and the corresponding free amino group can then be further modified, e.g., by acylation. The lysine can alternatively be coupled to a protected amino acid and the amino group of this amino acid can then be deprotected resulting in another free amino group which can be acylated or attached to further amino acids.

[0616] Finally, the peptide is cleaved from the resin. This can be achieved by using King’s cocktail (D. S. King, C. G. Fields, G. B. Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266) similar cleavage cocktails known to the person skilled in the art. For example, EDT can be replaced by DODT or a mixture of TIS, water and TFA can be used. The raw material can then be purified by chromatography, e.g., preparative RP-HPLC, if necessary. [0617] All starting materials such as amino acids and chemicals may be ordered from vendors or may be synthesized by methods known from literature.

Cycllzatlon/Lactam formation

[0618] Methods for lactam bond formation are known to the person skilled in the art. Exemplary methods are given in the examples.

[0619] In a further aspect the cyclisation/lactam formation may be carried out after cleavage from the resin.

[0620] In a further aspect the cyclisation/lactam formation may be carried out (in DMF) after cleavage from the resin and subsequent purification of the peptide by methods known to the person skilled in the art, such as preparative HPLC.

[0621] In one aspect of the cyclisation where an amide bond is formed between a primary or a secondary amine group of one amino acid and a carboxylic acid group of another amino acid, the carboxylic acid group may be activated with PyBOP or HATU in the presence of DIPEA in order to form a lactam with the unprotected amine (such as the compounds with SEQ ID NO. 1 -12, 14-21 , 35, 50).

[0622] In another aspect of the cyclisation, where a primary or a secondary amine group of one amino acid may be covalently linked to a primary or a secondary amine group of another amino acid, the cyclisation may be performed with Bis(2,5-dioxopyrrolidin-1 -yl) butanedioate (such as the compounds with SEQ ID NO. 13, 22-34, 36-49).

[0623] In another aspect of the cyclisation, cleavage from Wang resin and subsequent cyclisation with Bis(2,5-dioxopyrrolidin-1 -yl) butanedioate lead to a free carboxylic acid C-terminus. This residue may be activated with HATU in the presence of DIPEA and the addition of 2-(3-pyridyl)ethanamine (PyEA) may lead to peptides with PyEa as terminal end group.

Therapeutic uses

[0624] A further aspect of the present disclosure relates to a peptide compound of formula (I) for use for treating and/or preventing an autoimmune or an inflammatory disease.

[0625] A peptide compound of formula (I) is for use in a subject in need thereof. Herein, the terms “subject”, “individual” and “patient” are used interchangeably. In some exemplary embodiments, the individual or subject is a human. [0626] The present disclosure also relates to a method for treating an autoimmune or an inflammatory disease which comprises at least a step of administering to a patient in need thereof a peptide compound of formula (I).

[0627] The present disclosure also relates to a use of a peptide compound of formula (I) for the manufacture of a medicament for treating an autoimmune or an inflammatory disease.

[0628] The terms “disease” and “disorder” are used interchangeably and intend to refer to any pathological or unhealthy state. In particular, a disease or disorder relates to an autoimmune or an inflammatory disease.

[0629] By “treat” or “treating” is meant to administer a compound or composition or a combination of compounds or compositions to a subject in order to eliminate a disease or disorder; arrest or slow a disease or disorder in a subject; inhibit or slow the development of a new disease or disorder in a subject; decrease the frequency or severity of symptoms and/or recurrences in a subject who currently has or who previously has had a disease or disorder; and/or prolong, i.e., increase, the lifespan of the subject. In particular, the term “treating/treatment of a disease or disorder” includes curing, shortening the duration, ameliorating, slowing down or inhibiting progression or worsening of a disease or disorder or the symptoms thereof.

[0630] By “prevent” or “preventing” is particularly meant to administer a compound or composition or a combination of compounds or compositions to a subject in order to inhibit or delay the onset of a disease or disorder in a subject.

[0631] In some embodiments, the disclosure includes methods of inhibiting IL-23 signaling by a cell expressing IL-23 receptors, comprising contacting the cells with a peptide compound of the formula (I). In some embodiments, the cell is a mammalian cell. In some embodiments, the method is performed in vitro or in vivo. In some embodiments, the inhibition of IL-23 signaling may be determined by measuring changes in phospho-STAT3 levels in the cell.

[0632] In some embodiments, the inhibition of IL-23 binding to IL-23R occurs in particular organs or tissues of the subject, e.g., the stomach, small intestine, large intestine/colon, intestinal mucosa, lamina propria, Peyer’s Patches, mesenteric lymph nodes, or lymphatic ducts.

[0633] Further provided is the use of the peptide compound of formula (I), or a composition comprising the compound of formula (I), in the preparation of a pharmaceutical composition for treating an autoimmune disease or an inflammatory disease. [0634] The autoimmune or inflammatory disease may for example be inflammatory bowel disease, such as Crohn’s disease and ulcerative colitis, psoriasis, psoriatic arthritis and hidradenitis suppurativa.

[0635] In some embodiments, the disease or disorder is autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, inflammatory bowel diseases (IBDs), juvenile IBD, adolescent IBD, Crohn’s disease, sarcoidosis, Systemic Lupus Erythematosus, ankylosing spondylitis (axial spondylarthritis), psoriatic arthritis, or psoriasis. In some embodiments, the disease or disorder is psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, Palmo- Plantar Pustulosis, psoriasis vulgaris, or erythrodermic psoriasis), atopic dermatitis, acne ectopica, ulcerative colitis, Crohn’s disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis/esophagitis, colitis associated with radio- or chemotherapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-1 , chronic granulomatous disease, glycogen storage disease type lb, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich Syndrome, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral- associated enteropathy, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft versus host disease.

Pharmaceutical compositions

[0636] According to another aspect, pharmaceutical compositions are disclosed that include a peptide compound of formula (I), or a salt or a solvate thereof, described herein as an active ingredient. Pharmaceutical compositions of the disclosure comprise at least one peptide compound of formula (I) of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0637] The said excipients are selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.

[0638] Standard acceptable pharmaceutical carriers and their formulations are known to one skilled in the art and described, for example, in Remington: The Science and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro A. R., 2000, Lippencott Williams & Wilkins and in R.C.Rowe et al. (Ed), Handbook of Pharmaceutical excipients, PhP, May 2013 update.

[0639] In these pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intra-tracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I), or its salt or solvate, may be administered in a unit administration form, in a mixture with conventional pharmaceutical excipients, to human beings for the prophylaxis or treatment of the disorders or diseases or conditions that is at least partly influenced by the reduction or inhibition of the IL-23 receptor induced intracellular signaling. A desired effect may be the prevention, reduction or treatment of an inflammatory disease or an autoimmune disease, or at least one of a symptom of such diseases.

Administration units

[0640] The unit administration forms appropriate include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intra-ocular and intranasal administration forms, forms for inhalative, topical, transdermal, sub-cutaneous, intra-muscular or intravenous administration, rectal administration forms and implants.

[0641] When prepared in unit administration form, the pharmaceutical compositions of the disclosure typically contain from 0.01 mg to 1000 mg of the peptide compound of formula (I), or a salt or a solvate thereof, described herein as an active ingredient. Active ingredient. The amount of active ingredient that is combined with one or more excipients to produce a single unit administration form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.01 mg to 0.5 g of active ingredient with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percents by weight of the total composition.

Dosage

[0642] By the oral route, the dose of a peptide compound of formula (I), or a salt or a solvate thereof, described herein as an active ingredient, administered per day may reach about 0.01 to 50 mg/dose, or 0.02 to 1 mg/dose or for example, from 0.0001 to 300 mg/kg body weight daily or 1 to 300 mg/kg body weight daily, taken all at once or in portions. [0643] There may be particular cases in which higher or lower dosages are appropriate; such dosages do not depart from the scope of the disclosure. According to usual practice, the dosage that is appropriate for each patient is determined by the doctor according to the mode of administration and the weight and response of the said patient.

[EXAMPLES]

[0644] The following examples illustrate the embodiments of the disclosure that are presently best known. However, it is to be understood that the following are only exemplary or illustrative of the application of the principles of the present disclosure. Numerous modifications and alternative compositions, methods, and systems is devised by those skilled in the art without departing from the spirit and scope of the present disclosure. Thus, while the present disclosure has been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the most practical and preferred embodiments of the disclosure.

Abbreviations employed are as follows:

[0645] AA: Amino acid

[0646] ACN: Acetonitrile

[0647] Aib: Alpha-amino-isobutyric acid

[0648] Boc: tert-Butyloxycarbonyl

[0649] tBu: tertiary Butyl

[0650] DCM: dichloromethane

[0651] DIC: N,N'-diisopropylcarbodiimide

[0652] DIPEA: N,N-diisopropylethylamine

[0653] DMF: dimethyl formamide

[0654] DODT: 3,6-dioxa-1 ,8-octanedithiol

[0655] DPBS: Dulbecco's phosphate-buffered saline

[0656] EDC: 1 -Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0657] EDT: ethanedithiol

[0658] Fmoc: fluorenylmethyloxycarbonyl

[0659] g: Gram

[0660] HATU: 0-(7-azabenzotriazol-1 -yl)-/V,/V,/V,/V-tetramethyluronium hexafluorophosphate

[0661] HBTU: 2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyl-uronium hexafluorophosphate [0662] HOAt: 1 -hydroxy-7-azabenzotriazole

[0663] HOBt: 1 -hydroxybenzotriazole

[0664] HPLC: High Performance Liquid Chromatography

[0665] LC/MS: Liquid Chromatography/Mass Spectrometry

[0666] mM: millimolar

[0667] MMT: monomethoxy-trityl

[0668] n.a.: Not available

[0669] n.d.: Not determined

[0670] nM: Nanomolar

[0671] NMP N-Methyl-2-pyrrolidone

[0672] PBS: phosphate buffered saline

[0673] Pfp: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl

[0674] PyBOP benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate

[0675] tBu: t- Butyl

[0676] TFA: trifluoroacetic acid

[0677] Trt: trityl/triphenymethyl

[0678] UHPLC: Ultra-High Pressure Liquid Chromatography

[0679] UV: ultraviolet

Materials

[0680] Different Rink-Amide resins (e.g., 4-(2’,4’-Dimethoxyphenyl-Fmoc- aminomethyl)-phenoxyacetamido-norleucylaminomethyl resin, MERCK BIOSCIENCES; 4- [(2,4-Dimethoxyphenyl)(Fmoc-amino)methyl]phenoxy acetamido methyl resin, Agilent Technologies) were used for the synthesis of peptide amides with loadings in the range of 0.2-0.7 mmol/g.

[0681] Fmoc protected natural amino acids were purchased from PROTEIN TECHNOLOGIES INC., SENN CHEMICALS, MERCK BIOSCIENCES, NOVABIOCHEM, IRIS BIOTECH, BACHEM, CHEM-IMPEX INTERNATIONAL or MATRIX INNOVATION. The following standard amino acids were used throughout the syntheses: Fmoc-L-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-L-Asn(Trt)-OH, Fmoc-L-Asp(OtBu)-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-L-Leu-OH, Fmoc-L-Lys(Boc)-OH, Fmoc-L- Phe-OH, Fmoc-L-Ser-OH, Fmoc-L-Trp(Boc)-OH,.

[0682] In addition, the following special amino acids were purchased from the same suppliers as above: Fmoc-Aib-OH, Fmoc-L-Nal-OH, Fmoc-L-Phe(2-Ae-Boc)-OH, Fmoc-L- Yde-OH, Fmoc-L-Phe(4-Ome)-OH, Fmoc-L-Trp(Me)-OH, Fmoc-L-alpha-Me-Leu-OH, Fmoc-beta(4-thiazolyl)-Ala-OH, Fmoc-4-amino-tetrahydropyran-4-carboxylic acid, Fmoc-L- Sar-OH, Fmoc-L-Lys(Ac)-OH, Fmoc-L-Lys(Boc)Me-OH, Fmoc-L-Pal-OH, Fmoc-Ahx-OH, Fmoc-Apt-OH, Fmoc-Atd-OH, Fmoc-Add-OH, Fmoc-Ahd-OH, Fmoc-Aud-OH, Fmoc-Ade- OH, Fmoc-Aoa-OH, Fmoc-Atea-OH, Fmoc-Nmha-OH and Fmoc-Nmapt.

[0683] In addition, the following building blocks were purchased from the same suppliers as above: Fmoc-L-1 -Nal-OH, Fmoc-L-Phe(2-Ae-Boc)-OH, Fmoc-L-Phe(Me)-OH, Fmoc-L-Orn(Boc), Fmoc-L-Wim-OH, Fmoc-L-Wme-OH, Fmoc-L-Wdm-OH, Fmoc-PyEA.

[0684] In addition, the following building blocks were purchased from the same suppliers as above: Dae, Dad, Dod, Dec, Dpa and Oca as di-succinimide ester.

Example 1: General synthesis of peptide compounds

Synthesis of Mkdm

[0685] 470 mg (2S)-6-(tert-butoxycarbonylamino)-2-(9H-fluoren-9- ylmethoxycarbonylamino)hexanoic acid was treated with 5 mL TFA for two hours. Then, 100 mL water were added, and the solution was frozen and lyophilized. The residue was taken up with 10 mL methanol. Then, 129 mg DIPEA, 126 mg NaCNBH3 and 50 mg formaldehyde were added, and the mixture was stirred for one hour. The product was purified by chromatography to give 230 mg yield.

Synthesis of Yde

[0686] The BOC / Fmoc protected Yae was treated with TFA 95% for 2 hours. Then Yae with Fmoc protecting group attached to the alpha amine (1 mmol) was dissolved in a mixture of MeOH / water 1 :1. The pH was adjusted to 6 - 7 with DIPEA. Then, formaldehyde (3 mmol) and NaCNBH3 (2 mmol) were added, and the mixture was stirred for 1 hour at room temperature. The mixture was concentrated and freeze-dried. The resulting oil was purified by chromatography to give Yde. Synthesis of peptide compounds

[0687] The solid phase peptide syntheses were performed on a PRELUDE PEPTIDE SYNTHESIZER (PROTEIN TECHNOLOGIES) or a similar automated synthesizer using standard Fmoc chemistry and HBTU/DIPEA or HATU/DIPEA activation. DMF was used as the solvent.

[0688] Deprotection: 20% piperidine/DMF for 2 x 2.5 min.

[0689] Washes: 7 x DMF.

[0690] Coupling: 5/5/13 200 mM AA / 500 mM HBTU in DMF / 2M DIPEA in NMP 2 x for 20 min. Washes: 5 x DMF.

[0691] HBTU/DIPEA activation was used for all standard couplings.

[0692] For N-terminal acetylated peptides, the N-terminal Fmoc protecting group was removed and the peptide was treated twice with 10% solution of acetic acid anhydride and DIPEA for 20 minutes with shaking.

[0693] The peptides were cleaved from the resin with King’s cleavage cocktail consisting of 82.5% TFA, 5% phenol, 5% water, 5% thioanisole, and 2.5% EDT or a modified cleavage cocktail consisting of 82.5% TFA, 5% phenol, 5% water, 5% thioanisole, and 2.5% DODT. The crude peptides were then precipitated in diethyl or diisopropyl ether, centrifuged, and lyophilized. Peptides were analyzed by analytical HPLC and checked by ESI mass spectrometry. Crude peptides were purified by a conventional preparative RP- HPLC purification procedure.

Synthesis of peptide SEQ. ID NO: 4

[0694] Aud(@2)-Wim-Q-Thp-Yde-Nal-Aib-E(@2)-N-Pal-Sar-NH₂

[0695] Peptide SEQ ID NO: 4 was prepared by using FMOC solid phase peptide synthesis techniques.

[0696] RINK AMIDE AM RESIN LL using Prelude synthesizer and standard Fmoc protection synthesis conditions reported in the literature were used.

[0697] Resin preparation: 0.1 mmol of RINK AMIDE AM RESIN LL (0.345 g, 0.29 mmol / g loading) was transferred to a 25 ml peptide vessel with filter frit. The resin was washed 3x with 4 ml DMF for 5 min. Step I: Coupling of Fmoc-2-(methylamino)acetic acid (Sar):

[0698] For the deprotection of the resin bound Fmoc group 4 ml of 20 % piperidine in DMF was added to the swollen resin and was mixed for 2.5 min by bubbling with nitrogen and then drained. This process was repeated once.

[0699] After deprotection the resin was washed 7x with 4 ml DMF with mixing. A solution of Fmoc-2-(methylamino)acetic acid (2.5 eq, 2.5 ml, 100 mM in DMF) was added to the resin followed by HATLI (5 eq, 1 ml, 500 mM in DMF) and DIPEA (13 eq, 0.65 ml, 2 M in NMP). The mixture was mixed by bubbling with nitrogen for 40 min prior draining. The resin was washed once with 4ml DMF before the coupling process was repeated once. The resin was washed 5x with 4ml DMF by bubbling with N2 prior to starting the next deprotection-coupling cycle.

Step II: Coupling of Fmoc-(2S)-2-Amino-3-(3-oyridyl)orooanoic acid (Pal):

[0700] For the deprotection of the resin bound Fmoc group 4 ml of 20 % piperidine in DMF was added to the swollen resin and was mixed for 2.5 min by bubbling with nitrogen and then drained. This process was repeated once.

[0701] After deprotection the resin was washed 7x with 4 ml DMF with mixing. A solution of Fmoc-(2S)-2-Amino-3-(3-pyridyl)propanoic acid (2.5 eq, 2.5 ml, 100 mM in DMF) was added to the resin followed by HATLI (5 eq, 1 ml, 500 mM in DMF) and DIPEA (13 eq, 0.65 ml, 2 M in NMP). The mixture was mixed by bubbling with nitrogen for 40 min prior draining. The resin was washed once with 4ml DMF before the coupling process was repeated once. The resin was washed 5x with 4ml DMF by bubbling with N2 prior to starting the next deprotection-coupling cycle.

Step III: Coupling of Fmoc-Asn(Trt)-OH (N):

[0702] For the deprotection of the resin bound Fmoc group 4 ml of 20 % piperidine in DMF was added to the swollen resin and was mixed for 2.5 min by bubbling with nitrogen and then drained. This process was repeated once.

[0703] After deprotection the resin was washed 7x with 4 ml DMF with mixing. A solution of Fmoc-Asn(Trt)-OH (5 eq, 2.5 ml, 200 mM in DMF) was added to the resin followed by HATLI (5 eq, 1 ml, 500 mM in DMF) and DIPEA (13 eq, 0.65 ml, 2 M in NMP). The mixture was mixed by bubbling with nitrogen for 40 min prior draining. The resin was washed once with 4ml DMF before the coupling process was repeated once. The resin was washed 5x with 4ml DMF by bubbling with N2 prior to starting the next deprotection-coupling cycle.

Step IV: Coupling of Fmoc-Asp(OtBu)-OH (E):

[0704] For the deprotection of the resin bound Fmoc group 4 ml of 20 % piperidine in DMF was added to the swollen resin and was mixed for 2.5 min by bubbling with nitrogen and then drained. This process was repeated once.

[0705] After deprotection the resin was washed 7x with 4 ml DMF with mixing. A solution of Fmoc-Asp(OtBu)-OH (5 eq, 2.5 ml, 200 mM in DMF) was added to the resin followed by HATLI (5 eq, 1 ml, 500 mM in DMF) and DIPEA (13 eq, 0.65 ml, 2 M in NMP). The mixture was mixed by bubbling with nitrogen for 40 min prior draining. The resin was washed once with 4ml DMF before the coupling process was repeated once. The resin was washed 5x with 4ml DMF by bubbling with N2 prior to starting the next deprotection-coupling cycle.

Step V: Coupling of Fmoc-Aminoisobutyric acid (Alb):

[0706] For the deprotection of the resin bound Fmoc group 4 ml of 20 % piperidine in DMF was added to the swollen resin and was mixed for 2.5 min by bubbling with nitrogen and then drained. This process was repeated once.

[0707] After deprotection the resin was washed 7x with 4 ml DMF with mixing. A solution of Fmoc-Aminoisobutyric acid (2.5 eq, 2.5 ml, 100 mM in DMF) was added to the resin followed by HATLI (5 eq, 1 ml, 500 mM in DMF) and DIPEA (13 eq, 0.65 ml, 2 M in NMP). The mixture was mixed by bubbling with nitrogen for 40 min prior draining. The resin was washed once with 4ml DMF before the coupling process was repeated once. The resin was washed 5x with 4ml DMF by bubbling with N2 prior to starting the next deprotectioncoupling cycle.

Step VI: Coupling of Fmoc-(2S)-2-Amino-3-(2-naohthyl)propanoic acid (Nal):

[0708] For the deprotection of the resin bound Fmoc group 4 ml of 20 % piperidine in DMF was added to the swollen resin and was mixed for 2.5 min by bubbling with nitrogen and then drained. This process was repeated once. [0709] After deprotection the resin was washed 7x with 4 ml DMF with mixing. A solution of Fmoc-(2S)-2-Amino-3-(2-naphthyl)propanoic acid (2.5 eq, 2.5 ml, 100 mM in DMF) was added to the resin followed by HATLI (5 eq, 1 ml, 500 mM in DMF) and DIPEA (13 eq, 0.65 ml, 2 M in NMP). The mixture was mixed by bubbling with nitrogen for 40 min prior draining. The resin was washed once with 4ml DMF before the coupling process was repeated once. The resin was washed 5x with 4ml DMF by bubbling with N2 prior to starting the next deprotection-coupling cycle.

Step _ VII: _ Coupling _ of _ Fmoc-(2S)-2-Amino-3-[4-[2-

(dimethylamino)ethoxylphenyllpropanoic acid (Yde):

[0710] For the deprotection of the resin bound Fmoc group 4 ml of 20 % piperidine in DMF was added to the swollen resin and was mixed for 2.5 min by bubbling with nitrogen and then drained. This process was repeated once.

[0711] After deprotection the resin was washed 7x with 4 ml DMF with mixing. A solution of Fmoc-(2S)-2-Amino-3-[4-[2-(dimethylamino)ethoxy]phenyl]propanoic acid (2.5 eq, 2.5 ml, 100 mM in DMF) was added to the resin followed by HATLI (5 eq, 1 ml, 500 mM in DMF) and DIPEA (13 eq, 0.65 ml, 2 M in NMP). The mixture was mixed by bubbling with nitrogen for 40 min prior draining. The resin was washed once with 4ml DMF before the coupling process was repeated once. The resin was washed 5x with 4ml DMF by bubbling with N₂ prior to starting the next deprotection-coupling cycle.

Step VIII: Coupling of Fmoc-4-Aminotetrahydropyran-4-carboxylic acid (Thp):

[0712] For the deprotection of the resin bound Fmoc group 4 ml of 20 % piperidine in DMF was added to the swollen resin and was mixed for 2.5 min by bubbling with nitrogen and then drained. This process was repeated once.

[0713] After deprotection the resin was washed 7x with 4 ml DMF with mixing. A solution of Fmoc-4-Aminotetrahydropyran-4-carboxylic acid (2.5 eq, 2.5 ml, 100 mM in DMF) was added to the resin followed by HATLI (5 eq, 1 ml, 500 mM in DMF) and DIPEA (13 eq, 0.65 ml, 2 M in NMP). The mixture was mixed by bubbling with nitrogen for 40 min prior draining. The resin was washed once with 4ml DMF before the coupling process was repeated once. The resin was washed 5x with 4ml DMF by bubbling with N2 prior to starting the next deprotection-coupling cycle. Step IX: Coupling of Fmoc-Gln(Trt)-OH (Q):

[0714] For the deprotection of the resin bound Fmoc group 4 ml of 20 % piperidine in DMF was added to the swollen resin and was mixed for 2.5 min by bubbling with nitrogen and then drained. This process was repeated once.

[0715] After deprotection the resin was washed 7x with 4 ml DMF with mixing. A solution of Fmoc-Gln(Trt)-OH (5 eq, 2.5 ml, 200 mM in DMF) was added to the resin followed by HATLI (5 eq, 1 ml, 500 mM in DMF) and DIPEA (13 eq, 0.65 ml, 2 M in NMP). The mixture was mixed by bubbling with nitrogen for 40 min prior draining. The resin was washed once with 4ml DMF before the coupling process was repeated once. The resin was washed 5x with 4ml DMF by bubbling with N2 prior to starting the next deprotection-coupling cycle.

Step X: Coupling of Fmoc-(2S)-2-Amino-3-(7-methyl-1 H-indol-3-yl)oropanoic acid

[0716] For the deprotection of the resin bound Fmoc group 4 ml of 20 % piperidine in DMF was added to the swollen resin and was mixed for 2.5 min by bubbling with nitrogen and then drained. This process was repeated once.

[0717] After deprotection the resin was washed 7x with 4 ml DMF with mixing. A solution of Fmoc-(2S)-2-Amino-3-(7-methyl-1 H-indol-3-yl)propanoic acid (2.5 eq, 2.5 ml, 100 mM in DMF) was added to the resin followed by HATLI (5 eq, 1 ml, 500 mM in DMF) and DIPEA (13 eq, 0.65 ml, 2 M in NMP). The mixture was mixed by bubbling with nitrogen for 40 min prior draining. The resin was washed once with 4ml DMF before the coupling process was repeated once. The resin was washed 5x with 4ml DMF by bubbling with N2 prior to starting the next deprotection-coupling cycle.

Step XI: Coupling of Fmoc-11-Aminoundecanoic acid (Aud):

[0718] For the deprotection of the resin bound Fmoc group 4 ml of 20 % piperidine in DMF was added to the swollen resin and was mixed for 2.5 min by bubbling with nitrogen and then drained. This process was repeated once.

[0719] After deprotection the resin was washed 7x with 4 ml DMF with mixing. A solution of Fmoc-1 1 -Aminoundecanoic acid (2.5 eq, 2.5 ml, 100 mM in DMF) was added to the resin followed by HATLI (5 eq, 1 ml, 500 mM in DMF) and DIPEA (13 eq, 0.65 ml, 2 M in NMP). The mixture was mixed by bubbling with nitrogen for 40 min prior draining. The resin was washed once with 4ml DMF before the coupling process was repeated once. The resin was washed 5x with 4ml DMF by bubbling with N2 prior to starting the next deprotection-coupling cycle.

Resin cleavage

[0720] The constructed peptide was isolated from the resin and protecting groups by cleavage with Kings cocktail followed by precipitation with diethyl ether.

Cyclisation

[0721] The crude peptide was dissolved in DMF (10 mg/ ml) followed by the addition of PyBOP (1 ,2 eq) and DIPEA (4 eq). The mixture was stirred at room temperature for 2 hours until the lactamization was complete. This was followed by purification by RP-HPLC.

[0722] Lyophilization of pure fractions gives the desired product Peptide SEQ ID NO: 4.

Example 2: Peptide cyclisation

Cyclization by amide bond formation

[0723] The crude peptide was dissolved in DMF (10 mg/ ml) followed by the addition of PyBOP (1 ,2 eq) and DIPEA (4 eq). The mixture was stirred at room temperature for 2 hours until the lactamization was complete. Purification was performed by RP-HPLC and lyophilization of the pure fractions.

[0724] Alternatively, the peptide was dissolved in DMF, cooled to 0°C before 20 eq. NaHCOs, 3 eq. HOAT and 2.5eq EDC.HCI was added. The reaction was stirred and allowed to slowly equilibrate to room temperature overnight. NaHCOs was filtered over gravity and the soluble fraction dried under rotary evaporation. The crude cyclic peptide was dissolved in ACN:Water and freeze-dried. The desired cyclic peptide product was isolated by preparative RP-HPLC purification procedure.

[0725] In case of Yae in the sequence, after cleavage from the resin with King’s cleavage cocktail the N-terminus was kept Fmoc protected, the deprotected Yae moiety was protected by BOC-OSu (2 eq.) and diisopropyl-ehtylamin in DMF. Then, the N-terminal Fmoc group was cleaved with piperidine (20 eq.). [0726] After workup and purification with RP-HPLC, the peptide cyclization was performed. Finally, the BOC protecting group was cleaved with TFA (50 eq.). The desired cyclic peptide product was isolated by a conventional preparative RP-HPLC purification procedure.

Cyclization by formation of alkyl bonds with butanedial

[0727] After cleavage from the resin and purification by HPLC, the freeze dried peptide was dissolved in methanol. Sodium cyanoborohydrate (1 eq.), butanedial (1 eq.) and DIPEA (1 eq.) were added and the mixture was stirred for 16 hours. The solvent was evaporated, and the residue purified by HPLC and freeze-dried to give the desired peptide.

Coupling of PyEA to C-terminus

[0728] To a solution of a peptide with a carboxylic acid function at the C-terminus (0.08 mmol) in DMF (20 mL) was added DIPEA (0.25 mmol) and the resulting mixture was stirred for 0.5 h at 0 °C. Then, DEPBT (0.088 mmol) and PyEA (0.08 mmol) were added successively. The mixture was stirred 1 h at 0°C and 1 h at room temperature. The mixture was concentrated in vacuo, diluted with water (500 mL) and lyophilized. The crude product was purified by chromatography.

[0729] By this method peptide compounds obtained are shown in Table 3:

Table 3: Synthesized peptide compounds

Example 3: Analytical HPLC / UHPLC

[0730] Method A: detection at 214 nm

[0731] HPLC: Waters i-class UPLC

[0732] column: Waters ACQUITY UPLC® CSH™ C18 1.7 nm (75x 2.1 mm) at 50 °C solvent: H20+0.05%TFA: ACN+0.045%TFA (flow 0.7 ml/min)

[0733] gradient: 95:5 (0 min) to 95:5 (1 min) to 20:80 (12 min) to 5:95 (12.5 min) to 5:95 (13.5 min) to 95:5 (14 min) to 95:5 (16 min)

[0734] with mass analyser: Waters Xevo G2-XS QTof, electrospray positive ion mode, mass range: 300-3200 m/z, resolution mode

[0735] Method B: detection at 214 nm

[0736] HPLC: Agilent 1290 Infinity II UPLC

[0737] column: Waters ACQUITY UPLC® CSH™ C18 1.7 pm (150 x 2.1 mm) at 50 °C solvent: H2Q+0.05%TFA: ACN+0.035%TFA (flow 0.5 ml/min)

[0738] gradient: 80:20 (0 min) to 80:20 (3 min) to 25:75 (23 min) to 2:98 (23.5 min) to 2:98 (30.5 min) to 80:20 (31 min) to 80:20 (37 min)

[0739] with mass analyser: Agilent 6230 Accurate-Mass TOF, Agilent Dual Jet Stream ESI+, mass range: 300-3200 m/z, extended dynamic range mode (2Ghz)

[0740] Method C: detection at 214 nm

[0741] HPLC: Agilent 1290 Infinity II UPLC

[0742] Column: Waters ACQUITY UPLC® CSH™ C18 1 .7 pm (150 x 2.1 mm) at 50 °C solvent: H2Q+0.05%TFA: ACN+0.045%TFA (flow 0.5 ml/min)

[0743] gradient: 95:5 (0 min) to 95:5 (3 min) to 20:80 (30 min) to 2:98 (30.5 min) to 2:98 (34.5 min) to 95:5 (35 min) to 95:5 (40 min)

[0744] with mass analyser: Agilent 6230 Accurate-Mass TOF, Agilent Dual Jet Stream ESI, mass range: 300-3200 m/z, extended dynamic range mode (2Ghz) Table 4: List of synthesized peptides and comparison of calculated vs. found molecular weight and used HPLC/ UHPLC method.

Example 4: General Preparative HPLC Purification Procedure

[0745] The crude peptides were purified either on an Akta Purifier System, a Jasco semiprep HPLC System, Waters Autopurification System, an Agilent 1100 HPLC system or a similar HPLC system. Preparative RP-C18-HPLC columns of different sizes and with different flow rates were used depending on the amount of crude peptide to be purified, e.g., the following columns have been used: Waters XSelect CSH C18 OBD Prep 5pm 30x250mm, Waters SunFire C18 OBD Prep 5pm 30x250mm, Waters SunFire C18 OBD Prep 5pm 50x150mm, and Phenomenex Luna Prep C185pm 21 .2x250mm. Acetonitrile (B) and water + 0.1% TFA (A) or water + 0.1% FA (A) were employed as eluents. Productcontaining fractions were collected and lyophilized to obtain the purified product, typically as TFA salt.

[0746] Alternatively, the peptides can be isolated as acetate salts via the following procedure: The peptide was dissolved in water and the solution adjusted to pH 7.05 with NaHCO3. Then, the dissolved compound was purified with a RP Kinetex 21 ,2x250 mm (Column Volume CV 88 ml, 5pm, C18, 100A, Akta avant 25): The column was equilibrated with solvent A (3 x CV), the compound was injected and then washed with a mixture of solvent A (95%) and solvent B (5%) with 3 CV. Then, a gradient solvent A:B (95:5) to A:B (20:80) was run with 15 CV. The purified peptide was collected and lyophilized.

Example 5: Solubility testing of example at different pH

[0747] Prior to the solubility measurement of a peptide batch, its purity was determined through UHPLC/MS method A.

[0748] For solubility testing the target concentration was 1 mg pure compound/ml. Therefore, solutions from solid samples were prepared in a buffer system at a concentration of 1 mg/mL compound. The solid samples were obtained by drying down aliquots of a freshly prepared dimethyl sulfoxide stock solution using a THERMO SPEEDVAC vacuum centrifuge. The dry down time was 3 hours.

[0749] The following buffer systems were applied: [0750] Solubility buffer system A) 50 mM HCI pH 1 .2

[0751] Solubility buffer system B) 50 mM phosphate buffer pH 6.5

[0752] Solubility buffer system C) 50 mM phosphate buffer pH 7.4

[0753] UHPLC-UV was performed using analytical method A after 2 hours of gentle agitation from the filtered (0,45pm filter plates) solutions, which were obtained by 10 mins of centrifugation forced filtration at 1500 RCF (relative centrifugal acceleration).

[0754] The solubility was determined by the comparison of the UV peak area of 2 pL-injections of a buffered sample diluted 1 :10 with a standard curve of a dimethyl sulfoxide reference sample of known concentration. The different extinction coefficients were taken into account for the calculation.

[0755] Results are shown in Table 5.

Table 5: Solubility of peptide compounds in buffer formulations

Example 6: Chemical stability assessment of example compounds

[0756] Purity of a peptide batch was determined through UHPLC/MS method A prior to chemical stability measurement. [0757] For stability assessment, the target concentration was 0.5 mg pure compound/ml. Therefore, solutions from solid samples were prepared in a buffer system at a concentration of 0.5 mg/mL compound. The solid samples were obtained by drying down aliquots of a freshly prepared acetonitrile stock solution using a THERMO SPEEDVAC vacuum centrifuge. The dry down time was 3 hours.

[0758] The following buffer systems were applied:

[0759] Solubility buffer system A): 50 mM HCI pH 1.2 + Acetonitrile (3:1).

[0760] Solubility buffer system B): 50 mM phosphate buffer pH 6.5 + Acetonitrile [0761] Solubility buffer system C): 50 mM phosphate buffer pH 7.4 + Acetonitrile (3:1 ).

[0762] Prepared solutions were stored for 24 hours at 2°C and 37°C.

[0763] After this time course, the samples were centrifuged for 15 min at 2500 RCF to create a 1 :5 dilution of the supernatant. Then 2 pl of the dilution were analyzed with UHPLC-UV applying method A.

[0764] The chemical stability was rated through the relative loss of purity calculated by the equation:

[0765] [(purity after 0 hours at 37°C) - (purity after 24 hours at 37°C)] / (purity after 0 hours at 37°C)] *100%

[0766] The purity is calculated as [(peak area peptide) / (total peak area)] * 100%.

[0767] Results are shown in Table 6.

Tables 6: Chemical stability (relative purity loss) of peptide compounds in buffer formulations

Example 7: Protease stability assessment of peptides

[0768] Studies were carried out in simulated intestinal fluid (SIF) and simulated gastric fluid (SGF) to evaluate gastric stability of the peptide compounds disclosed herein. [0769] For clarification, the term “Pepsin-SGF” refers to a solution of simulated gastric fluid containing pepsin whereas “SGF media” refers to a solution of simulated gastric fluid without pepsin. Pepsin-SGF was prepared by dissolving 320 mg Pepsin (Merck Millipore) in 100 mL SGF media concentrate (PROSENSE). [0770] Similarly, the term “Pancreatin-SIF” refers to a solution of simulated intestinal fluid containing pancreatin whereas “SIF-media” refers to a solution of simulated intestinal fluid without pancreatin. Pancreatin-SIF was prepared by dissolving 1 mg Pancreatin (MP Biomedicals) in 10 mL SIF media concentrate (PROSENSE).

[0771 ] Peptide compounds were first dissolved at 1 mM stock concentration in 0.01 HCI (+/- 10% of DMSO) and were than diluted further with water to a stock concentration of 20 pM. Final peptide concentration in the incubation was 1 pM.

[0772] To 76 pL of the Pepsin-SGF buffer, 4 pL of the 20 pM peptide stock solution was added and incubated at 37°C. At each timepoint (0, 60, 120 and 240 minutes) the reaction was quenched with addition of 80 pL Ethanol (0,1 % HCOOH). The samples were centrifuged for 20 minutes and an aliquot of the supernatant 100 pL were transferred to a LoBind-MTP plate and analyzed by LCMS/MS. The peak area response was calculated at each time point for each test compound. As internal reference, the peak area response of the same test compound at TO was calculated. The percentage remaining at each timepoint was calculated based on the peak area response ratio of the test compound at TO. Time 0 was set to 100%, and all later timepoints were calculated relative to time 0.

[0773] Peptide compounds were first dissolved at 1 mM stock concentration in 0.01 HCI (+/- 10% of DMSO) and were than diluted further with water to a stock concentration of 20 pM. Final peptide concentration in the incubation was 1 pM.

[0774] To 76 pL of the Pepsin-SGF buffer, 4 pL of the 20 pM peptide stock solution was added and incubated at 37°C. At each timepoint (0, 60, 120 and 240 minutes) the reaction was quenched with addition of 80 pL Ethanol (0,1 % HCOOH). The samples were centrifuged for 20 minutes and an aliquot of the supernatant 100 pL were transferred to a LoBind-MTP plate and analyzed by LCMS/MS. The peak area response was calculated at each time point for each test compound. As internal reference, the peak area response of the same test compound at TO was calculated. The percentage remaining at each timepoint was calculated based on the peak area response ratio of the test compound at TO. Time 0 was set to 100%, and all later timepoints were calculated relative to time 0.

Table 7: Protease stability in simulated gastric fluids (FaSSGF) and simulated intestinal fluids (FaSSIF) expressed as remaining percentage of peptide compound.

[0775] n.a.: not available.

Example 8: Assay for specific human IL-23R inhibitors [0776] Antagonism of compounds for human interleukn-23 receptor inhibitors, was determined by an ELISA assay.

[0777] A 384-well plate was coated with 50 pl/well of human IL23 at a final concentration of 1 pg/ml and incubated overnight at 4°C. The wells were washed 3 times with 80 pl wash buffer and blocked with 80 pl blocking buffer for 60 minutes at room temperature and washed again. 20 pl of serially diluted test peptides was added to each well and subsequently 20 pl of recombinant human IL-23R-Fc chimera at final concentration of 0.1 pg/ml. The plate was incubated for 60 minutes at room temperature. After the wells were washed, bound IL23R-Fc was detected with goat anti-hu- IgG 1 -HRP antibody. Signals were visualized with QUANTABLU fluorogenic peroxidase substrate.

[0778] For selectivity of the IL23R inhibitor peptides binding to human IL12RB1 , recombinant human IL-12RB1 -Fc was used for the ELISA assay.

[0779] For selectivity of the IL23R inhibitor peptides binding to mouse IL23R, recombinant mouse IL-23R-Fc chimera was used, and bound mouse IL23R-FC was detected with goat anti-mouse-lgG1 -HRP antibody.

[0780] Results are presented in Table 8 below.

Table 8: IC50 values of inhibition of IL-23 binding to IL-23R as measured by ELISA

Example 9: Inhibition of IL-23 induced STAT3 signaling in HEKBIue™ IL-23 cells

[0781] HEK-Blue™ IL-23 cells (INVIVOGEN) are designed for the detection of bioactive human (hlL-23) and murine IL-23 (mlL-23) by monitoring the activation of the STAT3 pathway. Binding of IL-23 to its receptor on the surface of HEK-Blue™ IL-23 cells triggers a signaling cascade leading to the activation of STAT3 and the subsequent production of secreted embryonic alkaline phosphatase (SEAP). This can be readily assessed using QUANTI-Blue™ Solution, a SEAP detection reagent.

[0782] HEK-Blue™ IL-23 cells were cultured as described by INVIVOGEN.

[0783] On the first day of assay 10 pL of the HEK-BLUE IL23 cell suspension (final concentration: 10,000 cells/well) and 10 pl of serially diluted peptides solutions were dispensed into a 384-well assay plate. After pre-incubation of the reaction mixtures at 37°C/ 5% CO2/ 95% humidity for 60 minutes, 10 pl of the humanlL23 cytokine (final concentration: 0.25 ng/ml) was added to each well for the STAT3 signaling activation. The plate was incubated overnight at 37°C/ 5% CO2/ 95% humidity.

[0784] On the second day 20 pl per well of QUANTI-BLUE detection solution (prepared according to the manufacture instruction) was dispensed into a new 384-well plate and followed by the transfer of 5 pl supernatant of the overnight incubated cell/sample mixtures. After incubation of 45min at room temperature signals were measured with PHERASTAR (BMG) at OD 620-655 nm. [0785] Dose response data were fitted with XLfit.

Table 9: IC50 values of inhibition of IL-23 induced pSTAT3 as measured by SEAP reporter of phosphorylation of STAT3

[REFERENCES]

Atherton E. and R. C. Sheppard, Solid Phase Peptide Synthesis. A Practical Approach, Oxford-IRL Press, New York, 1989

Bis RL, Mallela KM. Antimicrobial preservatives induce aggregation of interferon alpha-2a: the order in which preservatives induce protein aggregation is independent of the protein. Int J Pharm. 2014 Sep 10;472(1-2):356-61. doi: 10.1016/j.ijpharm.2O14.06.044. Epub 2014 Jun 27. PMID: 24974985; PMCID: PMC4268133.

Brayden DJ, Mrsny RJ. Oral peptide delivery: prioritizing the leading technologies. Ther Deliv. 201 1 Dec;2(12):1567-73. doi: 10.4155/tde.11 .114. PMID: 22833982.

David B. Troy, Paul Beringer. Remington: The Science and Practice of Pharmacy Lippincott Williams & Wilkins, 2006 - 2393 pages

Kamerzell TJ, Esfandiary R, Joshi SB, Middaugh CR, Volkin DB. Protein-excipient interactions: mechanisms and biophysical characterization applied to protein formulation development. Adv Drug Deliv Rev. 201 1 Oct;63(13):11 18-59. doi:

10.1016/j.addr.2O11.07.006. Epub 201 1 Jul 29. PMID: 21855584.

King DS, Fields CG, Fields GB. A cleavage method which minimizes side reactions following Fmoc solid phase peptide synthesis. Int J Pept Protein Res. 1990 Sep;36(3):255- 66. doi: 10.11 11/J.1399-3011 ,1990.tb00976.x. PMID: 2279849.

Rowe, Raymond C. et al. “Handbook of Pharmaceutical Excipients.” (1994).

Siri Ram Chhabra, Bhupinder Hothi, David J. Evans, Peter D. White, Barrie W. Bycroft, Weng C. Chan, An appraisal of new variants of Dde amine protecting group for solid phase peptide synthesis, Tetrahedron Letters, Volume 39, Issue 12, 1998, Pages 1603-1606, ISSN 0040-4039, https://doi.Org/10.1016/S0040-4039(97) 10828-0.

Sayago C, Gonzalez Valcarcel IC, Qian Y, Lee J, Alsina-Fernandez J, Fite NC, Carrillo JJ, Zhang FF, Chalmers MJ, Dodge JA, Broughton H, Espada A. Deciphering Binding Interactions of IL-23R with HDX-MS: Mapping Protein and Macrocyclic Dodecapeptide Ligands. ACS Med Chem Lett. 2018 Aug 1 ;9(9):912-916. doi: 10.1021/acsmedchemlett.8b00255. PMID: 30258540; PMCID: PMC6142055.

Stewart John Morrow and Young Janis Dillaha. Solid phase peptide synthesis. Pierce Chemical Co., Rockford, III. et ©1984

Theodora W. Greene Ph.D.,, Peter G. M. Wuts Ph.D., Protective Groups in Organic Synthesis, Third Edition. Copyright © 1999 by John Wiley & Sons, Inc. Print ISBN:9780471 160199 (Online ISBN:9780471220572 |DOI:10.1002/0471220574 Tuvia S, Pelled D, Marom K, Salama P, Levin-Arama M, Karmeli I, Idelson GH, Landau I, Mamluk R. A novel suspension formulation enhances intestinal absorption of macromolecules via transient and reversible transport mechanisms. Pharm Res. 2014 Aug;31 (8):2010-21. doi: 10.1007/s11095-014-1303-9. Epub 2014 Feb 21. PMID: 24558008; PMCID: PMC4153969.

US 2013-029907 A1

WO 2016/011208 A1

WO 2017/011820 A2

WO 2018/089693 A2 WO 2018/022937 A1

WO 2018/136646 A1

WO 2022/109328 A1

WO 2013/063468 A1

WO 2015/179438 A1

Claims

[CLAIMS]

1. A peptide compound of formula (I):

X1 (§1 )(#1 )-X2(#1 )(@2)-X3-X4-X5-X6-X7-X8-X9(§1 )(@2)-X10-X1 1 -X12-X13-R1 (I), wherein

XI is absent or is a Butyl moiety and when X1 is a Butyl moiety, then (§1 ) represent an alkyl bond between X1 and X9 and (#1 ) represents an alkyl bond between X1 and X2, or when X1 is absent, then (@2) represents an amide bond between X2 and X9,

X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dad, Dae, Dec, Dod, Dpa, Kme, Kme(aAc), Lys(aAc), Nmapt, Nmha and Oca;

X3 is an amino acid residue selected among a residue of Nak, Trp, Wdm, Wim, Wme, Wcl and Wfl;

X4 is an amino acid residue selected among a residue of Aib, Gin, Glu, lie, Iva, Leu, Lys, Lys(Ac), Mie, Mly, Mva, Phe, Thr, Trp and Vai;

X5 is an amino acid residue selected among a residue of Aib, Mkdm, Mie, and Thp;

X6 is an amino acid residue selected among a residue of Trp, Tyr, Yae, Yde and Yme;

X7 is an amino acid residue selected among a residue of Nak, Nal and Trp;

X8 is an amino acid residue selected among a residue of Aib, Cba, Cit, Gin, Leu, Lys,

Lys(Ac), Mie, Mly, D-Mkdm, Mkdm, Thp, D-Trp and D-Tza;

X9 is an amino acid residue selected among a residue of Asp, Glu, Kme, Lys and Orn;

X10 is an amino acid residue selected among a residue of Ala, Asn, Gly and Ser;

XI I is an amino acid residue selected among a residue of Ala, Asn, Bal, Gly, Hol, Hph, His, lie, Iva, Leu, Mhis, Pal, Pyal, PyEA, Vai, and their corresponding D-forms;

X12 is absent or is an amino acid residue selected among a residue of Bal, Dnmy, lie, Lys, Mep, Mhis and Sar;

X13 is absent or is a residue of Lys; and,

R1 is absent or is selected among -NH₂, -OH and -N(C2H₅)2; or a salt or a solvate thereof.

2. The peptide compound according to claim 1 , wherein

X1 is a Butyl moiety, and X9 is a residue of Kme, or

X1 is absent, X2 is an amino acid residue selected among a residue of Dad, Dae, Dec, Dod, Dpa and Oca, and X9 is an amino acid residue selected among a residue Kme, Lys, and Orn, or

X1 is absent, X2 is an amino acid residue selected among a residue of Dec, Dod, Dpa and Oca, and X9 is an amino acid residue selected among a residue of Kme and Lys, or

X1 is absent, X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Kme, Kme(aAc), Lys(aAc), Nmapt and Nmha, and X9 is an amino acid residue selected among a residue of Asp and Glu, or

XI is absent, X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea and Aud, and X9 is a residue of Glu.

3. The peptide compound according to claim 1 , wherein

X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dec, Dod, Dpa, Kme, Kme(aAc), Nmapt, Nmha and Oca;

X3 is an amino acid residue selected among a residue of Trp, Wdm, Wim, and Wme;

X4 is an amino acid residue selected among a residue of Gin, Leu and Lys(Ac);

X5 is an amino acid residue selected among a residue of Aib and Thp;

X6 is a residue of Yde;

X7 is a residue of Nal;

X8 is an amino acid residue selected among a residue of Aib, Mkdm and Thp;

X9 is an amino acid residue selected among a residue of Glu, Kme and Lys;

X10 is an amino acid residue selected among a residue of Asn, Gly and Ser;

XI I is an amino acid residue selected among a residue of Pal and PyEA;

X12 is absent or is a residue of Sar;

X13 is absent; and,

R1 is absent or is -NH2.

4. The peptide compound according to claim 3, wherein

X10 represents Asn; or,

X10 represents an amino acid residue selected among a residue of Gly and Ser and X12 represents Sar; and

R1 represents NH2, or

R1 represents NH₂ and when X1 is a butyl moiety, X2 represents an amino acid residue selected among a residue of Kme, Nmapt and Nmha; or when X1 is absent, X2 represents an amino acid residue selected among Add, Ade, Aoa, Atd, Atea, Aud, Dec, Dod and Oca.

5. The peptide compound according to claim 1 or 2, wherein

X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dec, Dod, Dpa, Kme, Kme(aAc), Nmapt, Nmha and Oca;

X3 is an amino acid residue selected among a residue of Trp, Wim and Wme;

X4 is an amino acid residue selected among a residue of Gin, Leu and Lys(Ac);

X5 is an amino acid residue selected among a residue of Aib and Thp;

X6 is a residue of Yde;

X7 is a residue of Nal;

X8 is an amino acid residue selected among a residue of Aib, Mkdm and Thp;

X9 is an amino acid residue selected among a residue of Glu, Kme and Lys;

X10 is an amino acid residue selected among a residue of Asn, Gly and Ser;

X11 is an amino acid residue selected among a residue of Pal and PyEA;

X12 is absent or is a residue of Sar;

X13 is absent;

R1 is absent or is -NH2, wherein when X2 is a residue of Nmapt, X1 1 is a residue of PyEA, and X4 is a residue of Gin, then X10 is not a residue of Gly, or when X2 is a residue of Nmapt, X11 is a residue of PyEA, and X10 is a residue of Gly, then X4 is not a residue of Gin, or when X2 is a residue of Nmha and X11 is a residue of PyEA, then X4 is not a residue of Lys (Ac).

6. The peptide compound according to claim 1 or 3, wherein

X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dec, Dod, Dpa, Kme, Kme(aAc), Nmapt, Nmha and Oca;

X3 is an amino acid residue selected among a residue of Trp, Wim and Wme;

X4 is an amino acid residue selected among a residue of Gin, Leu and Lys(Ac);

X5 is an amino acid residue selected among a residue of Aib and Thp;

X6 is a residue of Yde;

X7 is a residue of Nal;

X8 is an amino acid residue selected among a residue of Aib, Mkdm and Thp; X9 is an amino acid residue selected among a residue of Glu, Kme and Lys;

X10 is an amino acid residue selected among a residue of Asn, Gly and Ser;

X11 is an amino acid residue selected among a residue of Pal and PyEA;

X12 is absent or is a residue of Sar;

X13 is absent; and

R1 is absent or is -NH2; wherein when X2 is a residue of Nmapt, X1 1 is a residue of PyEA, and X4 is a residue of Gin, then X10 is not a residue of Gly, or when X2 is a residue of Nmapt, X1 1 is a residue of PyEA, and X4 is a residue of Lys(Ac), then X10 is not a residue of Ser, or when X2 is a residue of Nmapt, X11 is a residue of PyEA, and X10 is a residue of Gly, then X4 is not a residue of Gin, or when X2 is a residue of Nmha, then X11 is not a residue of PyEA.

7. The peptide compound according to claim 1 or 3, wherein

X2 is an amino acid residue selected among a residue of Add, Ade, Ahd, Aoa, Atd, Atea, Aud, Dec, Dod, Kme, Kme(aAc), Nmapt, Nmha and Oca;

X3 is an amino acid residue selected among a residue of Trp, Wim and Wme;

X4 is an amino acid residue selected among a residue of Gin, Leu and Lys(Ac);

X5 is an amino acid residue selected among a residue of Aib and Thp;

X6 is a residue of Yde;

X7 is a residue of Nal;

X8 is an amino acid residue selected among a residue of Aib, Mkdm and Thp;

X9 is an amino acid residue selected among a residue of Glu, Kme and Lys;

X10 is an amino acid residue selected among a residue of Asn, Gly and Ser;

X11 is an amino acid residue selected among a residue of Pal and PyEA;

X12 is absent or is a residue of Sar;

X13 is absent; and

R1 is absent or is -NH2; wherein when X2 is a residue of Nmapt, then X11 is not PyEA, or when X2 is a residue of Nmapt and X1 1 is a residue of PyEA, then X3 is a residue of

Wim, X4 is a residue of Gin and X10 is a residue of Ser, or when X2 is a residue of Nmha, then X11 is not a residue of PyEA, or when X2 is a residue of Aoa or Dec, then X4 is not a residue of Leu.

8. The peptide compound according to claim 1 or 3, wherein

X2 is an amino acid residue selected among a residue of Add, Ade, Aoa, Atd, Atea, Aud, Dec, Dod, Kme, Kme(aAc), Nmapt, Nmha and Oca;

X3 is an amino acid residue selected among a residue of Trp, Wim and Wme;

X4 is an amino acid residue selected among a residue of Gin, Leu and Lys(Ac);

X5 is an amino acid residue selected among a residue of Aib and Thp;

X6 is a residue of Yde;

X7 is a residue of Nal;

X8 is an amino acid residue selected among a residue of Aib, Mkdm and Thp;

X9 is an amino acid residue selected among a residue of Glu, Kme and Lys;

X10 is an amino acid residue selected among a residue of Asn, Gly and Ser;

X11 is a residue of Pal;

X12 is a residue of Sar;

X13 is absent; and

R1 is -NH₂; wherein, when X2 is a residue of Nmapt and X3 is a residue of Wme, then X8 is not a residue of a residue of Mkdm, or when X2 is a residue of Aoa, then X4 is not a residue of a residue of Leu.

9. The peptide compound according to anyone of claims 1 to 8, wherein the peptide compound is represented by SEQ ID NO: 1 to 50, or a salt or a solvate thereof.

10. The peptide compound according to claim 9, wherein the peptide compound is represented by a sequence selected among:

SEQ ID NO: 1 -22, 24, 26-48 and 50, or a salt or a solvate thereof; or

SEQ ID NO: 1 -21 , 24, 26-36, 38-48 and 50, or a salt or a solvate thereof; or

SEQ ID NO: 1 -8, 10-14, 16, 18-21 , 24, 26-36, 39-47 and 50, or a salt or a solvate thereof; or

SEQ ID NO: 1 -2, 4-8, 10-14, 16, 18-21 , 24, 26-35, 39-44, 46-47 and 50, or a salt or a solvate thereof; or

SEQ ID NO: 1 -2, 4-5, 7-8, 10-14, 16, 18-21 , 26, 28-29, 31 -35, 39-40, 43-44, 46-47 and 50, or a salt or a solvate thereof; or

SEQ ID NO: 1 -2, 4-5, 7-8, 10-14, 16, 18-21 , 31 -35, 39, 44, 46-47 and 50, or a salt or a solvate thereof; or SEQ ID NO: 4, 1 1 , 16, 18, 19 and 50, or a salt or a solvate thereof.

11. The peptide compound according to any one of claims 1 to 10, wherein said peptide compound inhibits the IL-23-induced STAT3 phosphorylation with an IC50 of about 50 nM or less, or of about 25 nM or less, or of about 15 nM or less, or of about 10 nM or less, or of about 5 nM or less, or of about 3 nM or less, or of about 2 nM or less, or of about 1 nM or less.

12. The peptide compound according to any one of claims 1 to 11 , wherein said peptide compound has a protease stability measured as a percentage of remaining of said peptide compound in simulated intestinal fluids at 60 min, 37°C, of at least 50%.

13. The peptide compound according to any one of claims 1 to 12, for use for treating and/or preventing an autoimmune or an inflammatory disease in a subject in need thereof.

14. The peptide compound for use according to claim 13, wherein the autoimmune or inflammatory disease is selected among inflammatory bowel disease, such as Crohn’s disease and ulcerative colitis, psoriasis, psoriatic arthritis and hidradenitis suppurativa.

15. A pharmaceutical composition comprising at least one peptide compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or a solvate thereof, and at least one pharmaceutically acceptable excipient.

16. A method for treating and/or preventing an autoimmune or an inflammatory disease, the method comprising at least a step of administering to said subject a peptide compound according to any one of claims 1 to 12.

17. Use of a peptide compound according to any one of claims 1 to 12, for the manufacture of a medicament for treating and/or preventing an autoimmune or an inflammatory disease in a subject in need thereof.