Details

Autor(en) / Beteiligte

• Doherty, Elizabeth M
• Fotsch, Christopher
• Bo, Yunxin
• Chakrabarti, Partha P
• Chen, Ning
• Gavva, Narender
• Han, Nianhe
• Kelly, Michael G
• Kincaid, John
• Klionsky, Lana
• Liu, Qingyian
• Ognyanov, Vassil I
• Tamir, Rami
• Wang, Xianghong
• Zhu, Jiawang
• Norman, Mark H
• Treanor, James J. S

Titel

Discovery of Potent, Orally Available Vanilloid Receptor-1 Antagonists. Structure−Activity Relationship of N-Aryl Cinnamides

Ist Teil von

• Journal of medicinal chemistry, 2005-01, Vol.48 (1), p.71-90

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2005

Quelle

MEDLINE

Beschreibungen/Notizen

• The vanilloid receptor-1 (TRPV1 or VR1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role in regulating the function of sensory nerves. A growing body of evidence demonstrates the therapeutic potential of TRPV1 modulators, particularly in the management of pain. As a result of our screening efforts, we identified (E)-3-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide (1), an antagonist that blocks the capsaicin-induced and pH-induced uptake of 45Ca2+ in TRPV1-expressing Chinese hamster ovary cells with IC50 values of 17 ± 5 and 150 ± 80 nM, respectively. In this report, we describe the synthesis and structure−activity relationship of a series of N-aryl cinnamides, the most potent of which (49a and 49b) exhibit good oral bioavailability in rats (F oral = 39% and 17%, respectively).