Tetrahydro-naphthols as orally available TRPV1 inhibitors

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• 作者：Klaus Urbahns^a ; ^{Klaus.Urbahns@merckgroup.com} ; Takeshi Yura^a ; Jang B. Gupta^a ; Masaomi Tajimi^a ; Hiroshi Fujishima^a ; Tsutomu Masuda^a ; Noriyuki Yamamoto^a ; Yuka Ikegami^a ; Makiko Marumo^a ; Kayo Yasoshima^a ; Nagahiro Yoshida^a ; Toshiya Moriwaki^a ; David Madge^b ; Fiona Chan^b ; Muneto Mogi^a
• 关键词：Naphthols ; Urinary incontinence ; Oral bioavailability ; TRPV1 ; Vanilloid receptor antagonist
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 May, 2012
• 卷：22
• 期：10
• 页码：3408-3411
• 文件大小：2106 K

摘要

Starting from a naphthol-based lead series with low oral bioavailability, we have identified potent TRPV1 antagonists with oral bioavailability in rats. These compounds emerged from SAR studies aimed at replacing the lead鈥檚 phenol structure whilst maintaining potency. Compound rac-6a is an orally available TRPV1 antagonist with single-digit nanomolar activity. The enantiomers show a low eudismic ratio at the receptor level.