1207988-19-9Relevant articles and documents
Improvement of physiochemical properties of the tetrahydroazepinoindole series of farnesoid X receptor (FXR) agonists: Beneficial modulation of lipids in primates
Lundquist IV, Joseph T.,Harnish, Douglas C.,Kim, Callain Y.,Mehlmann, John F.,Unwalla, Rayomand J.,Phipps, Kristin M.,Crawley, Matthew L.,Commons, Thomas,Green, Daniel M.,Xu, Weixin,Hum, Wah-Tung,Eta, Julius E.,Feingold, Irene,Patel, Vikram,Evans, Mark J.,Lai, Kehdih,Borges-Marcucci, Lisa,Mahaney, Paige E.,Wrobel, Jay E.
experimental part, p. 1774 - 1787 (2010/08/06)
In an effort to develop orally active farnesoid X receptor (FXR) agonists, a series of tetrahydroazepinoindoles with appended, solubilizing amine functionalities were synthesized. The crystal structure of the previously disclosed FXR agonist, 1 (FXR-450), aided in the design of compounds with tethered solubilizing functionalities designed to reach the solvent cavity around the hFXR receptor. These compounds were soluble in 0.5% methylcellulose/2% Tween-80 in water (MC/T) for oral administration. In vitro and in vivo optimization led to the identification, of 14dd and 14cc, which in a dosedependent fashion regulated low density lipoprotein, cholesterol (LDLc) in low density lipoprotein receptor knockout (LDLR-/-) mice. Compound 14cc was dosed in female rhesus monkeys for 4 weeks at 60 mg/kg daily in MC/T vehicle. After 7 days, triglyceride (TG) levels and very low density lipoprotein cholesterol (VLDLc) levels were significantly decreased and LDLc was decreased 63%. These data are the first to demonstrate the dramatic lowering of serum LDLc levels by a FXR agonist in primates and supports the potential utility of 14cc in treating dyslipidemia in humans beyond just TG lowering.
