2. Academic Validation
  3. (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1h-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic acid (BMS-644950): a rationally designed orally efficacious 3-hydroxy-3-methylglutaryl coenzyme-a reductase inhibitor with reduced myotoxicity potential

(3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1h-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic acid (BMS-644950): a rationally designed orally efficacious 3-hydroxy-3-methylglutaryl coenzyme-a reductase inhibitor with reduced myotoxicity potential

  • J Med Chem. 2008 May 8;51(9):2722-33. doi: 10.1021/jm800001n.
Saleem Ahmad 1,  Cort S Madsen,  Philip D Stein,  Evan Janovitz,  Christine Huang,  Khehyong Ngu,  Sharon Bisaha,  Lawrence J Kennedy,  Bang-Chi Chen,  Rulin Zhao,  Doree Sitkoff,  Hossain Monshizadegan,  Xiaohong Yin,  Carol S Ryan,  Rongan Zhang,  Mary Giancarli,  Eileen Bird,  Ming Chang,  Xing Chen,  Robert Setters,  Debra Search,  Shaobin Zhuang,  Van Nguyen-Tran,  Carolyn A Cuff,  Thomas Harrity,  Celia J Darienzo,  Tong Li,  Richard A Reeves,  Michael A Blanar,  Joel C Barrish,  Robert Zahler,  Jeffrey A Robl
Affiliations

Affiliation

  • 1 Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, USA. saleem.ahmad@bms.com
PMID: 18412317 DOI: 10.1021/jm800001n
Abstract

3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to Other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.

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