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.

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]-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.   
     
     
         127 . The method of  claim 109 , wherein the disease or disorder is an inflammatory bowel disease (IBD), and the peptide inhibitor is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         128 . The method of  claim 109 , wherein the disease or disorder is an inflammatory bowel disease (IBD), and the peptide inhibitor is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         129 . The method of  claim 109 , wherein the disease or disorder is an inflammatory bowel disease (IBD), and the peptide inhibitor is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         130 . The method of  claim 109 , wherein the disease or disorder is an inflammatory bowel disease (IBD), and the peptide inhibitor is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         131 . The method of  claim 109 , wherein the disease or disorder is an inflammatory bowel disease (IBD), and the peptide inhibitor is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         132 . The method of  claim 109 , wherein the disease or disorder is an inflammatory bowel disease (IBD), and the peptide inhibitor is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         133 . The method of  claim 109 , wherein the disease or disorder is an inflammatory bowel disease (IBD), and the peptide inhibitor is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         134 . The method of  claim 109 , wherein the disease or disorder is an inflammatory bowel disease (IBD), and the peptide inhibitor is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         135 . The method of  claim 109 , wherein the disease or disorder is an inflammatory bowel disease (IBD), and the peptide inhibitor is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         136 . The method of  claim 109 , wherein the subject is a mammal. 
     
     
         137 . The method of  claim 136 , wherein the mammal is a human.