Substituted aryl pyrimidines as potent and soluble TRPV1 antagonists

  • Bioorg Med Chem Lett. 2008 Sep 15;18(18):5118-22. doi: 10.1016/j.bmcl.2008.07.112.
Markian M Stec  1 ,  Yunxin Bo ,  Partha P Chakrabarti ,  Lillian Liao ,  Mqhele Ncube ,  Nuria Tamayo ,  Rami Tamir ,  Narender R Gavva ,  James J S Treanor ,  Mark H Norman
Affiliations
  • 1. Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. [email protected]
PMID: 18722118 DOI: 10.1016/j.bmcl.2008.07.112
Abstract

Clinical candidate AMG 517 (1) is a potent antagonist toward multiple modes of activation of TRPV1; however, it suffers from poor solubility. Analogs with various substituents at the R region of 3 were prepared to improve the solubility while maintaining the potent TRPV1 activity of 1. Compounds were identified that maintained potency, had good pharmacokinetic properties, and improved solubility relative to 1.