2. Academic Validation
  3. Discovery of potent, orally available vanilloid receptor-1 antagonists. Structure-activity relationship of N-aryl cinnamides

Discovery of potent, orally available vanilloid receptor-1 antagonists. Structure-activity relationship of N-aryl cinnamides

  • J Med Chem. 2005 Jan 13;48(1):71-90. doi: 10.1021/jm049485i.
Elizabeth M Doherty 1,  Christopher Fotsch,  Yunxin Bo,  Partha P Chakrabarti,  Ning Chen,  Narender Gavva,  Nianhe Han,  Michael G Kelly,  John Kincaid,  Lana Klionsky,  Qingyian Liu,  Vassil I Ognyanov,  Rami Tamir,  Xianghong Wang,  Jiawang Zhu,  Mark H Norman,  James J S Treanor
Affiliations

Affiliation

  • 1 Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. edoherty@amgen.com
PMID: 15634002 DOI: 10.1021/jm049485i
Abstract

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 (45)CA(2+) in TRPV1-expressing Chinese hamster ovary cells with IC(50) 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).

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