Claims for Patent: 12,552,836

Summary for Patent: 12,552,836

Title:	Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases
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.
Inventor(s):	Ashok Bhandari, Brian Troy Frederick, David Clifford Sullivan
Assignee:	Protagonist Therapeutics Inc
Application Number:	US17/549,579
Patent Claims:	1. A peptide inhibitor or pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor comprises the amino acid sequence of Formula (II): X4-X5-X6-X7-X8-X9-X10-X11 (II) wherein X4 is Pen; X5 is Asn, or Gln; X6 is Thr; X7 is Trp substituted with alkyl; X8 is Gln, alpha-Me-Lys, alpha-MeLys(Ac), or Lys(Ac); X9 is Pen; X10 is Phe substituted with 2-aminoethoxy, or 2-acetylaminoethoxy; and X11 is 2-Nal, or 1-Nal; wherein the peptide inhibitor is cyclized via a bond between X4 and X9, and wherein the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor. 2. The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein X5 is Asn. 3. The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein X8 is Gln or Lys(Ac). 4. The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein X8 is alpha-Me-Lys, or alpha-MeLys(Ac). 5. The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein X10 is Phe[4-(2-aminoethoxy)]. 6. The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein X7 is Trp substituted with methyl, ethyl, n-propyl, or isopropyl. 7. The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein X11 is 2-Nal. 8. The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein the peptide inhibitor comprises the structure of Formula (Z): R1—X—R2 (Z) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a bond, hydrogen, Ac, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12aryl-C1-6alkyl, a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing; X is the amino acid sequence of Formula (II) and R2 is OH or NH2. 9. The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1, further comprising a conjugated chemical substituent selected from a lipophilic substituent or a polymeric moiety. 10. The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 9, wherein the conjugated chemical substituent is Ac, Palm, gamaGlu-Palm, isoGlu-Palm, PEG with a molecular weight of 400 Da to 40,000 Da, PEG2-Ac, PEG4-isoGlu-Palm, (PEG)5-Palm, succinic acid, glutaric acid, pyroglutaric acid, benzoic acid, IVA, octanoic acid, 1,4 diaminobutane, isobutyl, or biotin. 11. The peptide inhibitor of claim 1, wherein the peptide inhibitor is selected from the group consisting of: (SEQ ID NO: 242) Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N- [BA]-NH2; (SEQ ID NO: 245) Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N- [(D)Leu]-NH2; (SEQ ID NO: 248) Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N-H- NH2; (SEQ ID NO: 249) Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N- [Cit]-NH2; (SEQ ID NO: 251) Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N- [(D)Val]-NH2; (SEQ ID NO: 252) Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N- [(D)Lys]-NH2; (SEQ ID NO: 258) Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N- [(D)Phe]-NH2; (SEQ ID NO: 284) Ac-[Pen]-N-T-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N- [(D)Leu]-NH2; and (SEQ ID NO: 285) Ac-[Pen]-N-T-[W(7-n-Pr)]-[Lys(Ac)]-[Pen]-Phe[4- (2-aminoethoxy)]-[2-Nal]-[[α-MeLys]-[Lys(Ac)]-N- [(D)Leu]-NH2; or a pharmaceutically acceptable salt or solvate thereof; wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond. 12. The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein the bond between X4 and X9 is a disulfide bond. 13. The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein X7 is Trp substituted with alkyl at 4-, 6-, or 7-position. 14. The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein X7 is W(1-Me), W(4-Me), W(6-Me), W(6-Et), W(7-Me), W(7-Et), W(7-n-Pr), or W(7-i-Pr). 15. The peptide inhibitor of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein: X4 is Pen; X5 is Asn; X6 is Thr; X7 is Trp substituted with alkyl; X8 is Gln, or Lys(Ac); X9 is Pen; X10 is Phe[4-(2-aminoethoxy)]; and X11 is 2-Nal; wherein the peptide inhibitor is cyclized via a bond between X4 and X9, and wherein the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor. 16. The peptide inhibitor of claim 15, or pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is: Ac-[Pen]-NT-[W(7-Me)]-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]—NN—NH2 (SEQ ID NO: 6); Ac-[Pen]-N-T-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]—N—[(D)Leu]-NH2 (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]-NH2 (SEQ ID NO: 285); wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond. 17. The peptide inhibitor of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is: Ac-[Pen]-NT-[W(7-Me)]-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]—NN—NH2 (SEQ ID NO: 6), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond. 18. The peptide inhibitor of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is: Ac-[Pen]-N-T-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]—N—[(D)Leu]-NH2 (SEQ ID NO: 284), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond. 19. The peptide inhibitor of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is: Ac-[Pen]-N-T-[W(7-n-Pr)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]—N—[(D)Leu]-NH2 (SEQ ID NO: 285), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond. 20. A pharmaceutical composition comprising the peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1, and a pharmaceutically acceptble carrier, excipient, or diluent. 21. The pharmaceutical composition of claim 20, further comprising an enteric coating.