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

Patent metadata

Field	Value
Publication number	US-2022041658-A1
Application number	US-202117314396-A
Country	US
Kind code	A1
Filing date	May 7, 2021
Priority date	Jul 10, 2019
Publication date	Feb 10, 2022
Grant date	—

Abstract

The present invention provides novel peptide inhibitors of the interleukin-23 receptor, and related compositions and methods of using these peptide inhibitors to treat or prevent a variety of diseases and disorders, including inflammatory bowel diseases.

First claim

1 - 108 . (canceled)

109 . A method of treating an interleukin-23 (IL-23) receptor mediated disease or disorder in a subject in need thereof, comprising administering to the subject a peptide inhibitor according to Formula (Z′):
R 1 —X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-R 2   (Z′)

or a pharmaceutically acceptable salt thereof, wherein
X4 is Pen;
X5 is Asn;
X6 is Thr;
X7 is Trp substituted with alkyl;
X8 is Gln, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp;
X9 is Pen;
X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy;
X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy;
X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexylAla, Lys, or Aib;
X13 is Aib, Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Lys, pegylated Lys, b-homoGlu, or Lys(Y2-Ac), wherein Y2 is an amino acid;

X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Ala, (D)Ala, beta-Ala, His, Thr, n-Leu, Gln, Ser, (D)Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac);
X15 Leu, (D)Leu, beta-Ala, Cit, or (D)Lys;
R 1 is hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12aryl-C1-C6alkyl, or a C1-C20 alkanoyl;
R 2 is OH or NH 2 ;
wherein the peptide inhibitor or pharmaceutically acceptable salt thereof comprises a disulfide bond between two Pen residues;
wherein the peptide inhibitor or pharmaceutically acceptable salt thereof inhibits the binding of an IL-23 to an IL-23 receptor; and
wherein the disease or disorder is an inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, Celiac disease (nontropicalSprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich Syndrome, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, or graft versus host disease.

110 . The method of claim 109 , wherein the peptide inhibitor is:
Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 201); Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 227); Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 242); Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 (SEQ ID NO: 245); Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Cit]-NH 2 (SEQ ID NO: 249); Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-NH 2 (SEQ ID NO: 252); Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 267); Ac-[Pen]-N-T-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 (SEQ ID NO: 284); or Ac-[Pen]-N-T-[W(7-n-Pr)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 (SEQ ID NO: 285); or a pharmaceutically acceptable salt thereof.

111 . The method of claim 109 , wherein the peptide inhibitor is:

or a pharmaceutically acceptable salt thereof.

112 . The method of claim 109 , wherein the peptide inhibitor is:

or a pharmaceutically acceptable salt thereof.

113 . The method of claim 109 , wherein the peptide inhibitor is:

or a pharmaceutically acceptable salt thereof.

114 . The method of claim 109 , wherein the peptide inhibitor is:

or a pharmaceutically acceptable salt thereof.

115 . The method of claim 109 , wherein the peptide inhibitor is:

or a pharmaceutically acceptable salt thereof.

116 . The method of claim 109 , wherein the peptide inhibitor is:

or a pharmaceutically acceptable salt thereof.

117 . The method of claim 109 , wherein the peptide inhibitor is:

or a pharmaceutically acceptable salt thereof.

118 . The method of claim 109 , wherein the peptide inhibitor is:

or a pharmaceutically acceptable salt thereof.

119 . The method of claim 109 , wherein the peptide inhibitor is:

or a pharmaceutically acceptable salt thereof.

120 . The method of claim 109 , wherein the peptide inhibitor or pharmaceutically acceptable salt is administered to the subject orally.

121 . The method of claim 109 , wherein the disease or disorder is an inflammatory bowel disease (IBD).

122 . The method of claim 121 , wherein the IBD is ulcerative colitis.

123 . The method of claim 121 , wherein the IBD is Crohn's disease.

124 . The method of claim 109 , wherein the disease or disorder is psoriasis.

125 . The method of claim 109 , wherein the disease or disorder is psoriatic arthritis.

126 . The method of claim 109 , wherein the disease or disorder is an inflammatory bowel disease (IBD), and the peptide inhibitor is:
Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 201); Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 227); Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-NH 2 (SEQ ID NO: 242); Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 (SEQ ID NO: 245); Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-P

Assignees

• Protagonist Therapeutics Inc

Inventors

• Bhandari Ashok
• Frederick Brian Troy
• Sullivan David Clifford

Classifications

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title

• A61K38/00 Primary

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61P1/14

  Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents · CPC title

• C07K7/08 Primary

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• C07K14/54

  Interleukins [IL] · CPC title