Part I: Structure-activity relationship of human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl)propyl thiourea template. Part II: α-Substituted 2-(3-Fluoro-4-methylsulfonamidophenyl)acetamides as Potent TRPV1 Antagonists.

Abstract

PART II: α-Substituted 2-(3-Fluoro-4-methylsulfonamidophenyl)-acetamides as Potent TRPV1 Antagonists. The transient receptor potential vanilloid 1 channel (TRPV1) has emerged as a very promising therapeutic target, reflecting its central role in nociception and its involvement in a range of diseases. Capsaicin and resiniferatoxin provided early structural leads for understanding the vanilloid pharmacophore, and it was soon recognized that appropriately modified derivatives were able to achieve antagonism. Of particular importance, hyperthermia represents a common side effect of TRPV1 antagonists and the pattern of antagonistic activities for different agonists has been suggested to be related to the ability of an antagonist to cause hyperthermia. Further, different antagonists are differentially affected by the signaling pathways that regulate TRPV1. The availability of novel antagonists will be critical for optimizing such characteristics.

The structure of capsaicin (CAP) has been divided into three pharmacophoric regions. Correspondingly, the antagonistic template was subdivided into the same three pharmacophoric regions, namely the A-region (3-fluoro-4-methylsulfon amidophenyl), the B-region (propanamide), and the C-region ((6-trifluoromethyl-pyridin-3-yl)methyl). In order to gain better positioning of the C-region with the receptor through α-substitution in the B-region, with consequent enhancement of activity, we have extensively investigated the structure activity relationships of α-substituted acetamide derivatives for hTRPV1 antagonism. We describe incorporation of various alkyl, dialkyl and aryl groups at the α-position in the B-region, with 4-methylpiperidinyl and cyclohexylthio groups at the 2-position in the pyridine C-region, and we have evaluated their antagonism of CAP stimulation of hTRPV1 expressed in CHO cells.