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

1. 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-MeLeu, alpha-MeLys, 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 is 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; and

R 2 is OH or NH 2 ;

wherein the peptide inhibitor or pharmaceutically acceptable salt or solvate thereof comprises a disulfide bond between two Pen residues;

and

wherein the peptide inhibitor or pharmaceutically acceptable salt thereof inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor.

2. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 ,

wherein X7 is Trp substituted with alkyl, and the substitution is at a 1-, 2-, or 7-position.

3. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 2 , wherein X7 is Trp substituted with 1-Me, 2-Me, or 7-Me.

4. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 2 , wherein X8 is Gln, alpha-Me-Lys, alpha-MeLys(Ac), or Glu.

5. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 2 , wherein X8 is Gln.

6. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 2 , wherein X8 is Gln, Cit, alpha-MeLys, alpha-MeLeu, Aib, or Lys(Ac).

7. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 2 , wherein X8 is Lys(Ac).

8. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 2 , wherein X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], or Phe(4-CONH 2 ).

9. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 2 , wherein X10 is Phe[4-(2-aminoethoxy)], or Phe[4-(2-acetylaminoethoxy)].

10. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 2 , wherein X11 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy.

11. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 2 , wherein X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal.

12. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 2 , wherein X11 is 2-Nal or 1-Nal.

13. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 2 , wherein X11 is 2-Nal.

14. The peptide inhibitor or pharmaceutically acceptable salt thereof claim 1 , wherein R 1 is Ac.

15. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor is:

(SEQ ID NO: 201)

Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-

aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-N-[bA]-

NH 2 ;

(SEQ ID NO: 227)

Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-

aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-N-[bA]-

NH 2 ;

(SEQ ID NO: 242)

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-

aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-

NH 2 ;

(SEQ ID NO: 245)

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-

aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-

[(D)Leu]-NH 2 ;

(SEQ ID NO: 249)

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-

aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Cit]-

NH 2 ;

(SEQ ID NO: 252)

Ac-[Pen]-N--T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-

aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-

[(D)Lys]-NH 2 ;

(SEQ ID NO: 267)

Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-

aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-

NH 2 ;

or

(SEQ ID NO: 284)

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 , or

(SEQ ID NO: 285)

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 .

16. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor is:

17. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor is:

18. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor is:

19. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor is:

20. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor is

21. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor is:

22. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor is:

23. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor is:

24. A pharmaceutical composition comprising the peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , and a pharmaceutically acceptable carrier, excipient, or diluent.

25. The pharmaceutical composition of claim 24 , wherein the peptide inhibitor is:

(SEQ ID NO: 201)

Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-

aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-N-[bA]-

NH 2 ;

(SEQ ID NO: 227)

Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-

aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-N-[bA]-

NH 2 ;

(SEQ ID NO: 242)

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-

aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bA]-

NH 2 ;

(SEQ ID NO: 245)

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-

aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-

[(D)Leu]-NH 2 ;

(SEQ ID NO: 249)

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-

aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-

[Cit]-NH 2 ;

(SEQ ID NO: 252)

Ac-[Pen]-N--T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-

aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-

[(D)Lys]-NH 2 ;

(SEQ ID NO: 267)

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: 284)

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 ;

or

(Seq. ID. No. 285)

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 .

26. The pharmaceutical composition of claim 24 , wherein the peptide inhibitor is: