Discovery of 3-aryl-4-isoxazolecarboxamides as TGR5 receptor agonists

  • J Med Chem. 2009 Dec 24;52(24):7962-5. doi: 10.1021/jm901434t.
Karen A Evans  1 ,  Brian W Budzik ,  Sean A Ross ,  David D Wisnoski ,  Jian Jin ,  Ralph A Rivero ,  Mythily Vimal ,  George R Szewczyk ,  Channa Jayawickreme ,  David L Moncol ,  Thomas J Rimele ,  Susan L Armour ,  Susan P Weaver ,  Robert J Griffin ,  Sarva M Tadepalli ,  Michael R Jeune ,  Todd W Shearer ,  Zibin B Chen ,  Lihong Chen ,  Donald L Anderson ,  J David Becherer ,  Maite De Los Frailes ,  Francisco Javier Colilla
Affiliations
  • 1. Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426-0989, USA. [email protected]
PMID: 19902954 DOI: 10.1021/jm901434t
Abstract

A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent small molecule agonists of the human TGR5 G-protein coupled receptor is described. Subsequent optimization resulted in the rapid identification of potent exemplars 6 and 7 which demonstrated improved GLP-1 secretion in vivo via an intracolonic dose coadministered with glucose challenge in a canine model. These novel TGR5 receptor agonists are potentially useful therapeutics for metabolic disorders such as type II diabetes and its associated complications.

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