Synthesis and Antiobesity Properties of 6-(4-Chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (BMS-814580): A Highly Efficacious Melanin Concentrating Hormone Receptor 1 (MCHR1) Inhibitor

J Med Chem. 2016 Oct 13;59(19):8848-8858. doi: 10.1021/acs.jmedchem.6b00676. Epub 2016 Sep 15.

Abstract

The potent MCHR1 in vitro and in vivo antagonist activity of a series of cyclic tertiary alcohols derived from compound 2b is described. Subsequent pharmacokinetic and pharmacodynamic studies identified BMS-814580 (compound 10) as a highly efficacious antiobesity agent with a relatively clean in vitro and in vivo safety profile.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Obesity Agents / chemistry*
  • Anti-Obesity Agents / pharmacokinetics
  • Anti-Obesity Agents / pharmacology
  • Anti-Obesity Agents / therapeutic use*
  • Dogs
  • Halogenation
  • Humans
  • Macaca fascicularis
  • Male
  • Mice
  • Obesity / drug therapy*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Rats
  • Receptors, Somatostatin / antagonists & inhibitors*
  • Receptors, Somatostatin / metabolism
  • Structure-Activity Relationship

Substances

  • Anti-Obesity Agents
  • MCHR1 protein, human
  • Pyrimidines
  • Receptors, Somatostatin
  • thieno(2,3-d)pyrimidine