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

Department of Medicinal Chemistry, Exelixis Inc., 4757 Nexus Centre Drive, San Diego, California 92121, USA. bflatt@exelixis.com

Journal of medicinal chemistry 2009 Feb 26

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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.

Citation

Brenton Flatt, 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. Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR). Journal of medicinal chemistry. 2009 Feb 26;52(4):904-7