Details

Autor(en) / Beteiligte

• 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

Titel

Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists

Ist Teil von

• Bioorganic & medicinal chemistry, 2015-11, Vol.23 (21), p.6844-6854

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2015

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• [Display omitted] A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 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 compounds 43 and 44S antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with Ki(CAP)=0.3nM. 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 of 44S in our hTRPV1 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.