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N-4-t-Butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure-activity relationships in the A-region

Title: N-4-t-Butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure-activity relationships in the A-region

Authors: Kim Y.S.; Kil M.-J.; Kang S.-U.; Ryu H.; Kim M.S.; Cho Y.; Bhondwe R.S.; Thorat S.A.; Sun W.; Liu K.; Lee J.H.; Choi S.; Pearce L.V.; Pavlyukovets V.A.; Morgan M.A.; Tran R.; Lazar J.; Blumberg P.M.; Lee J.

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 (54S versus 54R). A docking study of 54S with our hTRPV1 homology model highlighted crucial hydrogen bonds between the ligand and the receptor contributing to its potency. © 2011 Elsevier Ltd. All rights reserved.