2. Academic Validation
  3. Discovery of 3-aryl-4-isoxazolecarboxamides as TGR5 receptor agonists

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

Affiliation

  • 1 Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426-0989, USA. karen.a.evans@gsk.com
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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