Alpha-AminoCycloLactam Ligands for G-Protein Coupled Receptors, and Methods of Using Same

Abstract

The invention relates to the generation of a library of compounds enriched in agonist and antagonists for members of the G-protein coupled class of receptors (GPCRs). The library contains compounds of general formula (II) wherein: y is any integer from 1 to 8; X is —CO—R 1 or —SO 2 —R 1 ; each R 1 is independently selected from an alkyl, haloalkyl, alkenyl, alkynyl, alkylaminoalkyl, alkylaminodialkyl, or charged alkylaminotrialkyl, radical of 1 to 20 carbon atoms; or each R 1 is independently selected from oxyalkyl, aminoalkyl, aminodialkyl, or charged aminotrialkyl radical; and wherein the R 1 radical has a “key” carbon next to the carbonyl of the carbon amide or the sulfonyl group of the sulfonamide which is di-substituted with the same or different groups selected from: alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl and alkylamino radicals.

1 . A compound of general formula (II) 
       
         
           
           
               
               
           
         
         wherein: 
         y is any integer from 1 to 8; 
         X is —CO—R 1  or —SO 2 —R 1 ; 
         each R 1  is independently selected from an alkyl, haloalkyl, alkenyl, alkynyl, alkylaminoalkyl, alkylaminodialkyl, or charged alkylaminotrialkyl, radical of 1 to 20 carbon atoms; 
         or each R 1  is independently selected from oxyalkyl, aminoalkyl, aminodialkyl, or charged aminotrialkyl radical; and 
         wherein the R 1  radical has a “key” carbon next to the carbonyl of the carbon amide or the sulfonyl group of the sulfonamide which is di-substituted with the same or different groups selected from: alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl and alkylamino radicals. 
       
     
     
         2 . A pharmaceutical composition comprising, as active ingredient, a compound of general formula (II), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient and/or carrier: 
       
         
           
           
               
               
           
         
         wherein: 
         y is any integer from 1 to 8; 
         X is —CO—R 1  or —SO 2 —R 1 ; 
         each R 1  is independently selected from an alkyl, haloalkyl, alkenyl, alkynyl, alkylaminoalkyl, alkylaminodialkyl, or charged alkylaminotrialkyl, radical of 1 to 20 carbon atoms; 
         or each R 1  is independently selected from oxyalkyl, aminoalkyl, aminodialkyl, or charged aminotrialkyl radical; and 
         wherein the R 1  radical has a “key” carbon next to the carbonyl of the carbon amide or the sulfonyl group of the sulfonamide which is di-substituted with the same or different groups selected from: alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl and alkylamino radicals. 
       
     
     
         3 . A method for the treatment, amelioration or prophylaxis of the symptoms of disease or condition selected from the group consisting of hypertension, atherosclerosis, asthma, obesity, neurodegenerative disorders, autoimmune disorders and psychopathic disorders comprising the step of administrating an effective amount of a compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
         y is any integer from 1 to 8; 
         X is —CO—R 1  or SO 2 —R 1 ; 
         each R 1  is independently selected from an alkyl, haloalkyl, alkenyl, alkynyl, alkylaminoalkyl, alkylaminodialkyl, or charged alkylaminotrialkyl, radical of 1 to 20 carbon atoms; 
         or each R 1  is independently selected from oxyalkyl, aminoalkyl, aminodialkyl, or charged aminotrialkyl radical; and 
         wherein the R 1  radical has a “key” carbon next to the carbonyl of the carbon amide or the sulfonyl group of the sulfonamide which is di-substituted with the same or different groups selected from: alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl and alkylamino radicals. 
       
     
     
         4 . A library composed of, or enriched in, library elements which are compounds according to  claim 1 . 
     
     
         5 . A method of screening in an assay, a library according to  claim 4 , to identify agent(s) which modulate signalling through GPCRs. 
     
     
         6 . The method according to  claim 5 , wherein the agent(s) identified are antagonists at one or more GPCRs. 
     
     
         7 . The method according to  claim 5 , wherein the agent(s) identified are agonists at one or more GPCRs. 
     
     
         8 . The method according to  claim 5 , wherein the GPCR is selected from the group consisting of adrenalin receptors, endothelin receptors, chemokine receptors, EDG receptors, VIP/PECAP receptors, dopamine receptors, serotonin receptors, purine receptors, metabotropic glutamate receptors, acetyl choline receptors, C5a receptors, fMLP receptors, glucagon or GLP receptors, NPY receptors, MSH receptors, glycoprotein hormone receptors, protease activated receptors (PARs), somatostatin receptors, angiotensin receptors, cholecystokinin receptors, and melatonin receptors.