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. 2007 Jul 15;17(14):3894-9.
doi: 10.1016/j.bmcl.2007.04.105. Epub 2007 May 3.

Alpha-methylation at benzylic fragment of N-aryl-N'-benzyl ureas provides TRPV1 antagonists with better pharmacokinetic properties and higher efficacy in inflammatory pain model

Arthur Gomtsyan  1 , Erol K Bayburt, Ryan Keddy, Sean C Turner, Tammie K Jinkerson, Stanley Didomenico, Richard J Perner, John R Koenig, Irene Drizin, Heath A McDonald, Carol S Surowy, Prisca Honore, Joe Mikusa, Kennan C Marsh, Jill M Wetter, Connie R Faltynek, Chih-Hung Lee
Affiliations

Alpha-methylation at benzylic fragment of N-aryl-N'-benzyl ureas provides TRPV1 antagonists with better pharmacokinetic properties and higher efficacy in inflammatory pain model

Arthur Gomtsyan et al. Bioorg Med Chem Lett. .

Abstract

SAR studies for N-aryl-N'-benzyl urea class of TRPV1 antagonists have been extended to cover alpha-benzyl alkylation. Alkylated compounds showed weaker in vitro potencies in blocking capsaicin activation of TRPV1 receptor, but possessed improved pharmacokinetic properties. Further structural manipulations that included replacement of isoquinoline core with indazole and isolation of single enantiomer led to TRPV1 antagonists like (R)-16a with superior pharmacokinetic properties and greater potency in animal model of inflammatory pain.

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