Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR)

  • J Med Chem. 2009 Feb 26;52(4):904-7. doi: 10.1021/jm8014124.
Brenton Flatt  1 ,  Richard Martin ,  Tie-Lin Wang ,  Paige Mahaney ,  Brett Murphy ,  Xiao-Hui Gu ,  Paul Foster ,  Jiali Li ,  Parinaz Pircher ,  Mary Petrowski ,  Ira Schulman ,  Stefan Westin ,  Jay Wrobel ,  Grace Yan ,  Eric Bischoff ,  Chris Daige ,  Raju Mohan
Affiliations
  • 1. Department of Medicinal Chemistry, Exelixis Inc., 4757 Nexus Centre Drive, San Diego, California 92121, USA. [email protected]
PMID: 19159286 DOI: 10.1021/jm8014124
Abstract

Azepino[4,5-b]indoles have been identified as potent agonists of the farnesoid X receptor (FXR). In vitro and in vivo optimization has led to the discovery of 6m (XL335, WAY-362450) as a potent, selective, and orally bioavailable FXR Agonist (EC(50) = 4 nM, Eff = 149%). Oral administration of 6m to LDLR(-/-) mice results in lowering of Cholesterol and triglycerides. Chronic administration in an atherosclerosis model results in significant reduction in aortic arch lesions.

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