Discovery of XL335 (WAY-362450), a Highly Potent, Selective, and Orally Active Agonist of the Farnesoid X Receptor (FXR)

• Published in: Journal of medicinal chemistry 2009-02, Vol.52 (4), p.904-907
• Main Authors: Flatt, Brenton, Martin, Richard, Wang, Tie-Lin, Mahaney, Paige, Murphy, Brett, Gu, Xiao-Hui, Foster, Paul, Li, Jiali, Pircher, Parinaz, Petrowski, Mary, Schulman, Ira, Westin, Stefan, Wrobel, Jay, Yan, Grace, Bischoff, Eric, Daige, Chris, Mohan, Raju
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Aorta, Thoracic - pathology; Atherosclerosis - drug therapy; Atherosclerosis - prevention & control; Azepines - pharmacokinetics; Azepines - pharmacology; Azepines - therapeutic use; Biological and medical sciences; Cholesterol - blood; Disease Models, Animal; DNA-Binding Proteins - agonists; Drug Discovery; General and cellular metabolism. Vitamins; Indoles - pharmacokinetics; Indoles - pharmacology; Indoles - therapeutic use; Medical sciences; Mice; Mice, Knockout; Pharmacology. Drug treatments; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, LDL - deficiency; Transcription Factors - agonists; Triglycerides - blood
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm8014124

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 (EC50 = 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.