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2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent transient receptor potential vanilloid 1 (TRPV1) antagonists: Structure-activity relationships of 2-amino derivatives in the N-(6-trifluoromethylpyridin-3- ylmethyl) C-region

Title
2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent transient receptor potential vanilloid 1 (TRPV1) antagonists: Structure-activity relationships of 2-amino derivatives in the N-(6-trifluoromethylpyridin-3- ylmethyl) C-region
Authors
Kim M.S.Ryu H.Kang D.W.Cho S.-H.Seo S.Park Y.S.Kim M.-Y.Kwak E.J.Kim Y.S.Bhondwe R.S.Kim H.S.Park S.-G.Son K.Choi S.Deandrea-Lazarus I.A.Pearce L.V.Blumberg P.M.Frank R.Bahrenberg G.Stockhausen H.Kogel B.Y.Schiene K.Christoph T.Lee J.
Ewha Authors
최선
SCOPUS Author ID
최선scopus
Issue Date
2012
Journal Title
Journal of Medicinal Chemistry
ISSN
0022-2623JCR Link
Citation
vol. 55, no. 19, pp. 8392 - 8408
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
A series of N-(2-amino-6-trifluoromethylpyridin-3-ylmethyl)-2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides were designed combining previously identified pharmacophoric elements and evaluated as hTRPV1 antagonists. The SAR analysis indicated that specific hydrophobic interactions of the 2-amino substituents in the C-region of the ligand were critical for high hTRPV1 binding potency. In particular, compound 49S was an excellent TRPV1 antagonist (K i(CAP) = 0.2 nM; IC50(pH) = 6.3 nM) and was thus approximately 100- and 20-fold more potent, respectively, than the parent compounds 2 and 3 for capsaicin antagonism. Furthermore, it demonstrated strong analgesic activity in the rat neuropathic model superior to 2 with almost no side effects. Compound 49S antagonized capsaicin induced hypothermia in mice but showed TRPV1-related hyperthermia. The basis for the high potency of 49S compared to 2 is suggested by docking analysis with our hTRPV1 homology model in which the 4-methylpiperidinyl group in the C-region of 49S made additional hydrophobic interactions with the hydrophobic region. © 2012 American Chemical Society.
DOI
10.1021/jm300780p
Appears in Collections:
약학대학 > 약학과 > Journal papers
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