Improvement of Physiochemical Properties of the Tetrahydroazepinoindole Series of Farnesoid X Receptor (FXR) Agonists: Beneficial Modulation of Lipids in Primates

• Published in: Journal of medicinal chemistry Vol. 53; no. 4; pp. 1774 - 1787
• Main Authors: Lundquist, 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.02.2010; Amer Chemical Soc
• Subjects: Animals; Azepines - chemical synthesis; Azepines - pharmacokinetics; Azepines - pharmacology; Biological and medical sciences; Biological Availability; Cell Line; Chemistry, Medicinal; Cholesterol, LDL - blood; Female; General and cellular metabolism. Vitamins; Humans; Hypolipidemic Agents - chemical synthesis; Hypolipidemic Agents - pharmacokinetics; Hypolipidemic Agents - pharmacology; Indoles - chemical synthesis; Indoles - pharmacokinetics; Indoles - pharmacology; Life Sciences & Biomedicine; Macaca mulatta; Male; Medical sciences; Mice; Mice, Knockout; Microsomes, Liver - metabolism; Models, Molecular; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, LDL - genetics; Science & Technology; Solubility; Structure-Activity Relationship; Triglycerides - blood; BILE-ACID; TRIGLYCERIDE; METABOLISM; LIGANDS; TRANSCRIPTION; CHENODEOXYCHOLIC ACID; IDENTIFICATION; EXPRESSION; NUCLEAR RECEPTOR; Farnesoid X receptor; Agonist; Nuclear receptor; Cholesterol LDL; Lipids; Morpholine derivatives; Triglyceride; In vitro; Dose activity relation; In vivo; Vertebrata; Mammalia; Animal; Modulation; Primates; Fluorine Organic compounds; Chemical synthesis; Antilipemic agent; Biological receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm901650u

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 dose-dependent 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.