2-(Halogenated Phenyl) acetamides and propanamides as potent TRPV1 antagonists

A series consisting of 117 2-(halogenated phenyl) acetamide and propanamide analogs were investigated as TRPV1 antagonists. The structure-activity analysis targeting their three pharmacophoric regions indicated that halogenated phenyl A-region analogs exhibited a broad functional profile ranging from agonism to antagonism. Among the compounds, antagonists 28 and 92 exhibited potent antagonism toward capsaicin for hTRPV1 with Ki [CAP] = 2.6 and 6.9 nM, respectively. Further, antagonist 92 displayed promising analgesic activity in vivo in both phases of the formalin mouse pain model. A molecular modeling study of 92 indicated that the two fluoro groups in the A-region made hydrophobic interactions with the receptor.

Automated summary

The series of 117 2-(halogenated phenyl) acetamide and propanamide analogs were investigated as TRPV1 antagonists, with halogenated phenyl A-region analogs showing a broad functional profile. Antagonists 28 and 92 exhibited potent antagonism against capsaicin for hTRPV1, with antagonist 92 displaying promising analgesic activity in vivo. Molecular modeling of compound 92 suggested that the two fluoro groups in the A-region interacted hydrophobically with the receptor.