Cyclic agonists and antagonists of c5a receptors and g protein-coupled receptors

Abstract

The present invention relates to novel cyclic or constrained acyclic compounds which modulate the activity of G protein-coupled receptors and are useful in the treatment of conditions mediated by G protein-coupled receptors, for example, inflammatory conditions.

1 - 32 . (canceled) 
     
     
         33 . A compound, which is an antagonist of a G protein-coupled receptor, which has no agonist activity, and which has a cyclic or constrained acyclic structure adapted to provide a framework defined by a polygon having:
 a first corner (I) comprising a critical amino side chain (A);   a second corner (II) comprising a critical amino side chain (B);   a third corner (III) comprising a critical amino side chain (C); and   a fourth corner (IV), comprising a critical amino side chain (D);   wherein:   corner (I) is connected to corners (II) and (IV); corner (II) is connected to corners (I) and (III); corner (III) is connected to corners (II) and (IV); and corner (IV) is connected to corners (I) and (III), and   a distance between corners (I) and (II) is 3.9±1 Å, a distance between corners (II) and (III) is 3.8±1 Å, a distance between corners (III) and (IV) is 5.8±1 Å, and a distance between corners (IV) and (I) is 4.4±1 Å;   each distance is between an C α  carbon of the amino acid or their analogue or derivative, and A, B, C and D are not necessarily on adjacent amino acids, or analogues or derivatives thereof;   A is any common or uncommon, basic, charged amino acid side chain which serves to position a positively charged group in the framework defined;   B is any common or uncommon, aromatic amino acid side chain which serves to position an aromatic side-chain in the framework defined;   C is any common or uncommon, hydrophobic amino acid side chain which serves to position any alkyl, aromatic or other group in the framework defined; and   D is any common or uncommon, aromatic amino acid which serves to position an aromatic side-chain in the framework defined, and has a structure:   
       
         
           
           
               
               
           
         
         wherein:
 Z is indole, indole methyl, benzyl, benzene, naphthyl, naphthyl methyl, or a derivative thereof; and 
 R 1  is H, an alkyl group, an aromatic group, an acyl group, or an aromatic-acyl group. 
 
       
     
     
         34 . The antagonist of  claim 33 , wherein the G protein-coupled receptor is a C5a receptor. 
     
     
         35 . The antagonist of  claim 33 , wherein A has any one side-chain: 
       
         
           
           
               
               
           
         
         or another mimetic of an arginine side chain; 
         wherein:
 X is NCN, NNO 2 , CHNO 2 , or NSO 2 NH 2 ; 
 n is an integer from 1 to 4; and 
 R′ is H, an alkyl, an aryl, CN, NH 2 , OH, —CO—CH 2 CH 3 , —CO—CH 3 , —CO—CH 2 CH 2 CH 3 , —CO—CH 2 Ph, or —CO-Ph; and 
 
         B is an indole, indole methyl, benzyl, phenyl, naphthyl, naphthyl methyl, cinnamyl group, or any other derivative of an aromatic group; and 
         C is D- or L-cyclohexylalanine (Cha), leucine, valine, isoleucine, phenylalanine, tryptophan, or methionine. 
       
     
     
         36 . The antagonist of  claim 35 , wherein R 1  is methyl, ethyl, propyl, or butyl. 
     
     
         37 . The antagonist of  claim 33 , which is a constrained acyclic compound comprising a type II β-turn. 
     
     
         38 . An antagonist of  claim 37 , wherein the type II β-turn comprises a γ-turn. 
     
     
         39 . The antagonist of  claim 33 , which is a cyclic peptide or peptide derivative. 
     
     
         40 . The antagonist of  claim 33 , having a formula of:
   Ac-phe-[lys-pro-(dCha)-trp-arg]; or     Ac-phe-[orn-pro-(dCha)-trp-argl.   
     
     
         41 . The antagonist of  claim 33 , wherein A is L-arginine. 
     
     
         42 . The antagonist of  claim 33 , which has antagonist activity against C5aR, has no agonist activity against C5a, and has a formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is H, alkyl, aryl, NH 2 , NHalkyl, N(alkyl) 2 , NHaryl, or NHacyl; 
 B is an alkyl, aryl, phenyl, benzyl, naphthyl, or indole group, or a side chain of a D- or L-amino acid selected from the group consisting of phenylalanine, homophenylalanine, tryptophan, homotryptophan, tyrosine, and homotyrosine; 
 C is a side chain of a D-, L-, or homo-amino acid selected from the group consisting of proline, alanine, leucine, valine, isoleucine, arginine, histidine, aspartate, glutamate, glutamine, asparagine, lysine, tyrosine, phenylalanine, cyclohexylalanine, norleucine, tryptophan, cysteine, and methionine; 
 D is a side chain of a D- or L-amino acid selected from the group consisting of cyclohexylalanine, homocyclohexylalanine, leucine, norleucine, homoleucine, homonorleucine, and tryptophan; 
 E is a side chain of a D- or L-amino acid selected from the group consisting of tryptophan and homotryptophan; 
 F is a side chain of a D- or L-amino acid selected from the group consisting of arginine, homoarginine, lysine, and homolysine; and 
 X 1  is —(CH 2 ) n NH—, (CH 2 ) n —S, —(CH 2 ) 2 O—, —(CH 2 ) 3 O—, (CH 2 ) 3 —, —(CH 2 ) 4 —, or —CH 2 COCHRNH—, wherein R is a side chain of any common or uncommon amino acid, and 
 n is an integer of from 1 to 4. 
 
     
     
         43 . The antagonist of  claim 42 , wherein F is a L-amino acid. 
     
     
         44 . The antagonist of  claim 43 , wherein F s L-arginine. 
     
     
         45 . The antagonist of  claim 42 , which is a compound selected from the group consisting of SEQ ID NOs: 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28. 
     
     
         46 . The antagonist of  claim 42 , wherein n is 2 or 3. 
     
     
         47 . A compound, which is an agonist of a G protein-coupled receptor, and has structure defined by a polygon having:
 a first corner (I) comprising a critical amino side chain (A);   a second corner (II) comprising a critical amino side chain (B);   a third corner (III) comprising a critical amino side chain (C); and   a fourth corner (IV), comprising a critical amino side chain (D);   wherein:   corner (I) is connected to corners (II) and (IV); corner (II) is connected to corners (I) and (III); corner (III) is connected to corners (II) and (IV); and corner (IV) is connected to corners (I) and (III), and   a distance between corners (I) and (II) is 3.9±1 Å, a distance between corners (II) and (III) is 3.8±1 Å, a distance between corners (III) and (IV) is 5.8±1 Å, and a distance between corners (IV) and (I) is 4.4±1 Å;   each distance is between an C α  carbon of the amino acid or their analogue or derivative, and A, B, C and D are not necessarily on adjacent amino acids, or analogues or derivatives thereof;   B is a non-aromatic amino acid; and   A is any common or uncommon, basic, charged amino acid side chain which serves to position a positively charged group in this position;   C is any common or uncommon, hydrophobic amino acid side chain which serves to position any alkyl, aromatic or other group in this position; and   D is any common or uncommon, aromatic amino acid which serve to position an aromatic side-chain in this position, and has the structure:   
       
         
           
           
               
               
           
         
         wherein:
 Z is indole, indole methyl, benzyl, benzene, naphthyl, naphthyl methyl, or a derivative thereof; and 
 R 1  is H or an alkyl, aromatic, acyl or aromatic-acyl group. 
 
       
     
     
         48 . The compound of  claim 47 , wherein B is a D- or L-form of alanine, leucine, valine, norleucine, glutamic acid, aspartic acid, methionine, cysteine, isoleucine, serine, or threonine. 
     
     
         49 . The compound of  claim 47 , having a structure IV: 
       
         
           
           
               
               
           
         
       
       wherein:
 E is any amino acid other than tryptophan and homotryptophan; and 
 F is a side chain of a D- or L-amino acid selected from the group consisting of arginine, homoarginine, lysine, and homolysine. 
 
     
     
         50 . The compound of  claim 47 , wherein the compound is an agonist of C5a. 
     
     
         51 . The compound of  claim 42 , having a structure: 
       
         
           
           
               
               
           
         
       
     
     
         52 . A composition, comprising:
 a compound of  claim 33 ; and   a pharmaceutically-acceptable carrier or excipient.   
     
     
         53 . A method for treating a pathological condition mediated by a G protein-coupled receptor, the method comprising:
 administering an effective amount of a compound of  claim 33 , to a mammal in need thereof.   
     
     
         54 . The method of  claim 53 , wherein the condition involves an overexpression or an underregulation of C5a. 
     
     
         55 . The method of  claim 53 , wherein the condition is selected from the group consisting of rheumatoid arthritis, adult respiratory distress syndrome (ARDS), systemic lupus erythematosus, tissue graft rejection, ischaemic heart disease, reperfusion injury, septic shock, psoriasis, gingivitis, atherosclerosis, Alzheimer's disease, multiple sclerosis, lung injury, and extracorporeal post-dialysis syndrome. 
     
     
         56 . A method for manufacturing a medicament, the method comprising:
 combining a compound of  claim 33  with a pharmaceutically-acceptable carrier or excipient, wherein the medicament treats a condition mediated by a G protein-coupled receptor.   
     
     
         57 . The method of  claim 56 , wherein the condition is mediated by C5a. 
     
     
         58 . The method of  claim 57 , wherein the condition involves an overexpression or an underregulation of C5a.