Cyclic peptides as g-protein coupled receptor antagonists

Abstract

The invention relates to novel cyclic compounds which have the ability to modulate the activity of G protein-coupled receptors. The compounds preferably act as antagonists. In preferred embodiments, the invention provides cyclic peptidic and peptidomimetic antagonists of C5a receptors, which are active against C5a receptors on polymorphonuclear leukocytes and macrophages. The compounds of the invention are both potent and selective, and are useful in the treatment of a variety of inflammatory conditions.

1 . A compound which is an antagonist of a C5a G protein-coupled receptor, which has no C5a agonist activity, and which is a cyclic peptide or peptidomimetic of the general formula: 
       
         
           
           
               
               
           
         
         wherein A is H, alkyl, aryl, NH-alkyl, N(alkyl) 2 , NH-aryl, NH-benzoyl, NHSO 3 , NHSO 2 -alkyl, NHSO 2 -aryl, OH, O-alkyl, or O-aryl; 
         B is an alkyl, aryl, benzyl, naphthyl or indole group, or is the side chain of L-phenylalanine or L-phenylglycine; 
         C is a side chain of glycine, alanine, leucine, valine, proline, hydroxyproline, or thioproline; 
         D is a side chain of D-leucine, D-homoleucine, D-cyclohexylalanine, D-homocyclohexylalanine, D-valine, D-norleucine, D-homo-norleucine, D-phenylalanine, D-tetrahydroisoquinoline, D-glutamine, D-glutamate, or D-tyrosine; 
         E is L-1-napthyl or L-3-benzothienyl alanine, or is a side chain of an amino acid selected from the group consisting of L-phenylalanine, L-tryptophan and L-homotryptophan; 
         F is a side chain of L-arginine, L-homoarginine, L-citrulline, or L-canavanine; 
         X is —(CH 2 ) n NH— or (CH 2 ) n —S—, where n is an integer of from 1 to 4; —(CH 2 ) 2 O—; —(CH 2 ) 3 O—; —(CH 2 ) 3 —; —(CH 2 ) 4 —; —CH 2 COCHRNH—; or —CH 2 —CHCOCHRNH—, and where R is a side chain of any common or uncommon amino acid, with the proviso that the compound is not AcF-[OPdChaWR] (compound 1). 
       
     
     
         2 - 18 . (canceled) 
     
     
         19 . The compound of  claim 1 , in which n is 2 or 3. 
     
     
         20 . The compound of  claim 1 , in which A is an aminomethyl group, or a substituted or unsubstituted sulphonamide group. 
     
     
         21 . The compound of  claim 20 , in which A is a substituted sulfonamide group and wherein the substituent on the substituted sulfonamide is an alkyl chain of 1 to 6 carbon atoms, or a phenyl or toluoyl group. 
     
     
         22 . The compound of  claim 21 , in which A is a substituted sulfonamide group, and wherein the substituent on the substituted sulfonamide is an alkyl chain of 1 to 4 carbon atoms. 
     
     
         23 . The compound of  claim 1 , in which the compound has antagonist activity against a C5a receptor, a vasopressin receptor or a neurokinin receptor. 
     
     
         24 . The compound of  claim 1 , in which the compound has antagonist activity at submicromolar concentrations. 
     
     
         25 . The compound of  claim 24 , in which the compound has a receptor affinity IC 50 <25 μM, and an antagonist potency IC 50 <1 μM. 
     
     
         26 . A compound selected from the group consisting of compounds 2, 10, 11 and 17. 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         27 . The compound of  claim 1  or  claim 26 , together with a pharmaceutically-acceptable carrier or excipient. 
     
     
         28 . The compound of  claim 1 , having the formula hydrocinnamate-[Orn-Pro-dCha-Trp-Arg]. 
     
     
         29 . A composition comprising the compound of  claim 1 , and a pharmaceutically-acceptable carrier or excipient. 
     
     
         30 . A method of treatment of a pathological condition mediated by a G protein-coupled receptor, comprising administering an effective amount of a compound according to  claim 1  to a mammal in need of such treatment. 
     
     
         31 . The method of  claim 30 , in which the condition mediated by a G protein-coupled receptor is a condition mediated by a C5a receptor. 
     
     
         32 . The method of  claim 31 , in which the condition involves overexpression or underregulation of C5a. 
     
     
         33 . The method of  claim 32 , in which the condition comprises rheumatoid arthritis, adult respiratory distress syndrome (ARDS), systemic lupus erythematosus, tissue graft rejection, ischemic heart disease, reperfusion injury, septic shock, gingivitis, fibrosis, atherosclerosis, multiple sclerosis, Alzheimer's disease, asthma, dementias, central nervous system disorders, lung injury, extracorporeal post-dialysis syndrome, or dermal inflammatory disorders. 
     
     
         34 . The method of  claim 33 , in which the condition is reperfusion injury. 
     
     
         35 . A method of treating reperfusion injury, comprising administering to a mammal in need of such treatment an effective amount of a compound according to  claim 1 .