Design, synthesis, and structure-activity relationships of indole-3-heterocycles as agonists of the CB1 receptor

Bioorg Med Chem Lett. 2011 Jan 1;21(1):506-9. doi: 10.1016/j.bmcl.2010.10.093. Epub 2010 Oct 25.

Abstract

Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead 1, a bioisostere approach replacing a piperazine amide was undertaken. This was found to be a good strategy for improving stability both in vitro and in vivo. This led to the discovery of 24, which had an increased duration of action in the mouse tail flick test in comparison to the lead 1.

MeSH terms

  • Animals
  • Drug Design
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry*
  • Heterocyclic Compounds / pharmacokinetics
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Indoles / pharmacokinetics
  • Mice
  • Microsomes / metabolism
  • Models, Molecular
  • Receptor, Cannabinoid, CB1 / agonists*
  • Receptor, Cannabinoid, CB1 / metabolism
  • Structure-Activity Relationship
  • Thiadiazoles / chemical synthesis
  • Thiadiazoles / chemistry*
  • Thiadiazoles / pharmacokinetics

Substances

  • Heterocyclic Compounds
  • Indoles
  • Receptor, Cannabinoid, CB1
  • Thiadiazoles