Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists. Issue 21 (1st November 2015)

• Record Type: Journal Article
• Authors: Ann, Jihyae; Jung, Aeran; Kim, Mi-Yeon; Kim, Hyuk-Min; Ryu, HyungChul; Kim, Sunjoo; Kang, Dong Wook; Hong, Sunhye; Cui, Minghua; Choi, Sun; Blumberg, Peter M.; Frank-Foltyn, Robert; Bahrenberg, Gregor; Stockhausen, Hannelore; Christoph, Thomas; Lee, Jeewoo
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 21(2015)
• Page Start: 6844
• Page End: 6854
• Publication Date: 2015-11-01
• Subjects: Vanilloid receptor 1 -- TRPV1 antagonists -- Analgesic; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.10.001
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for h TRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds43 and44 S antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with K i(CAP) = 0.3 nM. These two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of action, and they demonstrated promising analgesic activities in a neuropathic pain model without hyperthermia. The docking study of44 S in our h TRPV1 homology model indicated that its binding mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped configuration in the C-region.