Synthesis and pharmacological validation of a novel series of non-steroidal FXR agonists

✍ Scribed by Ulrich Abel; Thomas Schlüter; Andreas Schulz; Eva Hambruch; Christoph Steeneck; Martin Hornberger; Thomas Hoffmann; Sanja Perović-Ottstadt; Olaf Kinzel; Michael Burnet; Ulrich Deuschle; Claus Kremoser

• Publisher: Elsevier Science
• Year: 2010
• Tongue: English
• Weight: 707 KB
• Volume: 20
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.06.084

✦ Synopsis

To overcome the known liabilities of GW4064 a series of analogs were synthesized where the stilbene double bond is replaced by an oxymethylene or amino-methylene linker connecting a terminal benzoic acid with a substituted heteroaryl in the middle ring position. As a result we discovered compounds with increased potency in vitro that cause dose-dependent reduction of plasma triglycerides and cholesterol in db/db mice down to 2 x 1 mg/kg/day upon oral administration.