N-4-t-Butylbenzyl 2-(4-Methylsulfonylaminophenyl) Propanamide TRPV1 Antagonists : Structure Activity Relationships in the A-region

Abstract Structure–activity relationships for the A-region in a series of N -4- t -butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamides as TRPV1 antagonists have been investigated. Among them, the 3-fluoro analogue 54 showed high binding affinity and potent antagonism for both rTRPV1 and hTRPV1 in CHO cells. Its stereospecific activity was demonstrated with marked selectivity for the ( S )-configuration ( 54 S versus 54 R ). A docking study of 54 S with our hTRPV1 homology model highlighted crucial hydrogen bonds between the ligand and the receptor contributing to its potency.