Synthesis and SAR study of pyrrolo[3,4-b]pyridin-7(6H)-one derivatives as melanin concentrating hormone receptor 1 (MCH-R1) antagonists

Bioorg Med Chem Lett. 2013 Mar 15;23(6):1736-9. doi: 10.1016/j.bmcl.2013.01.053. Epub 2013 Jan 24.

Abstract

The discovery and optimization of novel pyrrolo[3,4-b]pyridin-7(6H)-one MCH-R1 antagonists are described. A systematic SAR study probing the effects of aryl-, benzyl- and arylthio-substituents at the 2-position of the pyrrolo[3,4-b]pyridin-7(6H)-ones led to identification of the 2-[(4-fluorophenyl)thio] derivative 7b as a highly potent MCH-R1 antagonist. This compound also has favorable pharmacokinetic properties along with a high metabolic stability and a minimal impact on CYP isoforms and hERG.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Obesity Agents / chemical synthesis*
  • Anti-Obesity Agents / pharmacokinetics
  • Anti-Obesity Agents / therapeutic use
  • Half-Life
  • Humans
  • Obesity / drug therapy
  • Protein Binding
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacokinetics
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacokinetics
  • Pyrroles / chemistry*
  • Pyrroles / metabolism
  • Pyrroles / pharmacokinetics
  • Pyrrolidinones / chemical synthesis*
  • Pyrrolidinones / chemistry
  • Pyrrolidinones / pharmacokinetics
  • Rats
  • Receptors, Pituitary Hormone / antagonists & inhibitors*
  • Receptors, Pituitary Hormone / metabolism
  • Structure-Activity Relationship

Substances

  • Anti-Obesity Agents
  • Pyridines
  • Pyrimidines
  • Pyrroles
  • Pyrrolidinones
  • Receptors, Pituitary Hormone
  • melanin-concentrating hormone receptor
  • pyrrolopyrimidine