Melanin concentrating hormone receptor 1 (MCHR1) antagonists-Still a viable approach for obesity treatment?

Bioorg Med Chem Lett. 2012 Oct 1;22(19):6039-47. doi: 10.1016/j.bmcl.2012.08.025. Epub 2012 Aug 19.

Abstract

Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes investigated in efforts to overcome hERG liabilities while having orally active, potent and selective compounds with sufficient brain penetration. A chemometric comparison of ∼2000 diverse MCHR1 and ∼1000 diverse hERG ligands underline the structural similarities. A binding pocket analysis of a MCHR1 model and recent X-ray structures of GPCRs invoked in selectivity issues indicate a way to support future drug design.

MeSH terms

  • Anti-Obesity Agents / chemistry
  • Anti-Obesity Agents / pharmacology*
  • Anti-Obesity Agents / therapeutic use
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology*
  • Biphenyl Compounds / therapeutic use
  • Crystallography, X-Ray
  • Drug Design
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology*
  • Naphthalenes / therapeutic use
  • Obesity / drug therapy*
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Piperidines / therapeutic use
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Receptors, Somatostatin / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Anti-Obesity Agents
  • Biphenyl Compounds
  • Ether-A-Go-Go Potassium Channels
  • MCHR1 protein, human
  • Naphthalenes
  • Piperidines
  • Pyrimidines
  • Receptors, Somatostatin
  • SNAP7941
  • T-226296