2-Alkyl/alkenyl substituted pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists.

Bioorganic & medicinal chemistry letters

PubMedID: 24948568

Ryu H, Seo S, Cho SH, Kim HS, Jung A, Kang DW, Son K, Cui M, Hong SH, Sharma PK, Choi S, Blumberg PM, Frank-Foltyn R, Bahrenberg G, Stockhausen H, Schiene K, Christoph T, Frormann S, Lee J. 2-Alkyl/alkenyl substituted pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists. Bioorg Med Chem Lett. 2014;.
A series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our hTRPV1 homology model provided insight into its specific binding mode.