Design and synthesis of N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5- methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine [Muraglitazar/BMS-298585], a novel peroxisome proliferator-activated receptor alpha/gamma dual agonist with efficacious glucose and lipid-lowering activities

  • J Med Chem. 2005 Mar 24;48(6):2248-50. doi: 10.1021/jm0496436.
Pratik V Devasthale  1 ,  Sean Chen ,  Yoon Jeon ,  Fucheng Qu ,  Chunning Shao ,  Wei Wang ,  Hao Zhang ,  Michael Cap ,  Dennis Farrelly ,  Rajasree Golla ,  Gary Grover ,  Thomas Harrity ,  Zhengping Ma ,  Lisa Moore ,  Jimmy Ren ,  Ramakrishna Seethala ,  Lin Cheng ,  Paul Sleph ,  Wei Sun ,  Aaron Tieman ,  John R Wetterau ,  Arthur Doweyko ,  Gamini Chandrasena ,  Shu Y Chang ,  W Griffith Humphreys ,  Vito G Sasseville ,  Scott A Biller ,  Denis E Ryono ,  Fred Selan ,  Narayanan Hariharan ,  Peter T W Cheng
Affiliations
  • 1. Metabolic Diseases Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-5400, USA. [email protected]
PMID: 15771468 DOI: 10.1021/jm0496436
Abstract

Muraglitazar/BMS-298585 (2) has been identified as a non-thiazolidinedione PPAR alpha/gamma dual agonist that shows potent activity in vitro at human PPARalpha (EC(50) = 320 nM) and PPARgamma(EC(50) = 110 nM). Compound 2 shows excellent efficacy for lowering glucose, Insulin, triglycerides, and free fatty acids in genetically obese, severely diabetic db/db mice and has a favorable ADME profile. Compound 2 is currently in clinical development for the treatment of type 2 diabetes and dyslipidemia.