Identification and hit-to-lead optimization of a novel class of CB1 antagonists

Jeffrey J Letourneau, Patrick Jokiel, John Olson, Christopher M Riviello, Koc-Kan Ho, Lihong McAleer, Jingchun Yang, Robert N Swanson, James Baker, Phillip Cowley, Darren Edwards, Nick Ward, Michael H J Ohlmeyer, Maria L Webb

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat.

Original languageEnglish
Pages (from-to)5449-5453
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Issue number18
Publication statusPublished - 15 Sep 2010


  • animals
  • benzimidazoles
  • humans
  • hypothermia
  • indoles
  • mice
  • microsomes, liver
  • obesity
  • rats
  • rats, wistar
  • receptor, Cannabinoid, CB1
  • solubility
  • structure-activity relationships


Dive into the research topics of 'Identification and hit-to-lead optimization of a novel class of CB1 antagonists'. Together they form a unique fingerprint.

Cite this