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

Patent metadata

Field	Value
Publication number	US-12552836-B2
Application number	US-202117549579-A
Country	US
Kind code	B2
Filing date	Dec 13, 2021
Priority date	Jul 12, 2018
Publication date	Feb 17, 2026
Grant date	Feb 17, 2026

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

What is claimed is:

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):
R 1 —X—R 2   (Z)
or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 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 R 2 is OH or NH 2 .

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]-NH 2 ;

(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]-NH 2 ;

(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-

NH 2 ;

(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]-NH 2 ;

(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]-NH 2 ;

(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]-NH 2 ;

(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]-NH 2 ;

(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]-NH 2 ; 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]-NH 2 ;

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.

Assignees

• Protagonist Therapeutics Inc

Inventors

• Bhandari Ashok
• Frederick Brian Troy
• Sullivan David Clifford

Classifications

• A61K38/00

  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

• C07K7/02

  Linear peptides containing at least one abnormal peptide link · CPC title

• C07K7/56 Primary

  the cyclisation not occurring through 2,4-diamino-butanoic acid · CPC title

• C07K7/08 Primary

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