2-(4-Methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure-activity relationships in the B and C-regions.

Abstract On the basis of the previous lead N -4- t -butylbenzyl 2-(3-fluoro-4-methylsulfonylaminophenyl) propanamide ( 3 ) as a potent TRPV1 antagonist, structure–activity relationships for the B (propanamide part) and C-region (4- t -butylbenzyl part) have been investigated for rTRPV1 in CHO cells. The B-region was modified with dimethyl, cyclopropyl and reverse amides and then the C-region was replaced with 4-substituted phenyl, aryl alkyl and diaryl alkyl derivatives. Among them, compound 50 showed high binding affinity with K i  = 21.5 nM, which was twofold more potent than 3 and compound 54 exhibited potent antagonism with K i(ant)  = 8.0 nM comparable to 3 .