Synthesis of novel bicyclo[4.1.0]heptane and bicyclo[3.1.0]hexane derivatives as melanin-concentrating hormone receptor R1 antagonists

Bioorg Med Chem Lett. 2007 Sep 1;17(17):4845-50. doi: 10.1016/j.bmcl.2007.06.048. Epub 2007 Jun 17.

Abstract

To address the hERG liability of MCHR1 antagonists such as 1 and 2, new analogs such as 4 and 5 that incorporated a polar heteroaryl group were designed and synthesized. Biological evaluation confirmed that these new analogs retained MCH R1 activity with greatly attenuated hERG liabilities as indicated in the Rb efflux assay.

MeSH terms

  • Animals
  • Chemistry, Pharmaceutical / methods*
  • Drug Design
  • Drug Evaluation, Preclinical
  • Fishes
  • Heptanes / chemistry*
  • Hexanes / chemistry*
  • Humans
  • Kinetics
  • Mice
  • Models, Chemical
  • Molecular Structure
  • Obesity / drug therapy
  • Receptors, Somatostatin / antagonists & inhibitors*

Substances

  • Heptanes
  • Hexanes
  • MCHR1 protein, human
  • Receptors, Somatostatin