t-Butyl Pyridine and Phenyl C-region Analogues of 2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as Potent TRPV1 Antagonists

Publication date: Available online 6 March 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Sunho Lee, Dong Wook Kang, HyungChul Ryu, Changhoon Kim, Jihyae Ann, Hobin Lee, Eunhye Kim, Sunhye Hong, Sun Choi, Peter M. Blumberg, Robert Frank-Foltyn, Gregor Bahrenberg, Hannelore Stockhausen, Thomas Christoph, Jeewoo Lee
A series of 2-substituted 6-t-butylpyridine and 4-t-butylphenyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis of structure activity relationships indicated that the pyridine derivatives generally exhibited a little better antagonism than did the corresponding phenyl surrogates for most of the series. Among the compounds, compound 7 showed excellent antagonism toward capsaicin activation with Ki = 0.1 nM and compound 60S demonstrated a strong antiallodynic effect with 83% MPE at 10 mg/kg in the neuropathic pain model. The docking study of 7S in our hTRPV1 homology model indicated that the interactions between the A/B-regions of 7S with Tyr511 and the interactions between the t-butyl and ethyl groups in the C-region of 7S with the two hydrophobic binding pockets of hTRPV1 contributed to the high potency.

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