US 2021/0261622 A1 · 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.

A monocyclic peptide inhibitor of an interleukin-23 receptor;

or a pharmaceutically acceptable salt thereof;
wherein the monocyclic peptide inhibitor of the interleukin-23 receptor comprises an amino acid sequence of Formula (I):
X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16 (I)
wherein;
X3 is absent or any amino acid;
X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide);
X5 is Cit, Glu, Gly, substituted Gly, Leu, lie, beta-Ala, Ala, Lys, Asn, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gin, or Asp;
X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val;
X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
X8 is Gin, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, substituted Phe, Tyr, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, Lys(b-Ala), Lys(Gly), Lys(Benzyl, Ac), Lys(butyl, Ac), Lys(isobutyl,Ac), Lys(propyl,Ac), or Trp;
X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide);
X10 is Tyr, or substituted Tyr, unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy;
X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy;
X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Acvc, alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexylAla, Lys, or Aib;
X13 is any amino acid;
X14 is any amino acid;
and
i) X15 is any amino acid other than His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, or 4Pal;
X16 is Sarc, aMeLeu, (D)NMeTyr, His, (D)Thr, bAla, Pro, or (D)Pro;
and
provided that the monocyclic peptide inhibitor is other than:
Ac-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NNPG-NH2;
Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-NN-[Sarc]-NH2;
Ac-[(D) Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2;
or
Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys (Ac)]-N-[Aib]-[bA]-NH2;
or
ii) X15 is His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, 4Pal, 4TriazolAla, or 5Pyal;
and X16 is absent, (D)aMeTyr, (D)NMeTyr or any amino acid other than THP, substituted or unsubstituted Phe, substituted or unsubstituted (D)Phe, substituted or unsubstituted His, substituted or unsubstituted (D)His, substituted or unsubstituted Trp, substituted or unsubstituted 2-Nal, or N-substituted Asp;
and
provided that the monocyclic peptide inhibitor is other than:
Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N—H—NH2;
wherein;
2Pal is 2-pyridyl substituted alanine;
3Pal is 3-pyridyl substituted alanine;
4Pal is 4-pyridyl substituted alanine;
5Pyal is 5-pyrimidine substituted alanine;
wherein
X4 and X9 form a disulfide bond or a thioether bond;
and
wherein the peptide inhibitor of the interleukin-23 receptor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor.

38 more elements

Facts

Application

17/149,509Filed 14 Jan 2021

Priority

15 Jan 2020

Published

26 Aug 2021

Term ends

Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07K 7/08
Linear peptides containing only normal peptide links: having 12 to 20 amino acids
C07K 7/64
Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof: cyclic peptides containing only normal peptide links
C07K 14/7155
For cytokines; for lymphokines; for interferons: for interleukins [IL]
A61K 38/00
Medicinal preparations containing peptides

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

Life of this patent

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

Life of this patent

Abstract

Claims62