Discovery of benzhydrylpiperazine derivatives as CB1 receptor inverse agonists via privileged structure-based approach

Eur J Med Chem. 2010 Mar;45(3):1133-9. doi: 10.1016/j.ejmech.2009.12.018. Epub 2009 Dec 16.


The present study describes the identification via privileged structure-based approach of the benzhydrylpiperazine moiety as a potential scaffold to develop novel CB(1) receptor modulators. Efficient structural optimization of the initial four hit compounds led to a high quality lead series, represented by compound 6c. Compound 6c is a highly potent and selective CB(1) receptor inverse agonist that is able to reduce body weight in diet-induced obese Sprague-Dawley rats. The preparation of privileged structure-based library, the progression from hit to lead, the structure-activity relationships in the lead series and in vitro and in vivo activity of compound 6c are discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Benzhydryl Compounds / chemical synthesis*
  • Benzhydryl Compounds / chemistry
  • CHO Cells
  • Cells, Cultured
  • Cricetinae
  • Cricetulus
  • Inhibitory Concentration 50
  • Male
  • Molecular Structure
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 / agonists*
  • Receptor, Cannabinoid, CB1 / genetics
  • Recombinant Proteins / genetics
  • Structure-Activity Relationship


  • Benzhydryl Compounds
  • Piperazines
  • Receptor, Cannabinoid, CB1
  • Recombinant Proteins