2. Academic Validation
  3. 1-Sulfonyl-4-acylpiperazines as selective cannabinoid-1 receptor (CB1R) inverse agonists for the treatment of obesity

1-Sulfonyl-4-acylpiperazines as selective cannabinoid-1 receptor (CB1R) inverse agonists for the treatment of obesity

  • J Med Chem. 2009 Apr 23;52(8):2550-8. doi: 10.1021/jm900063x.
Petr Vachal 1,  Joan M Fletcher,  Tung M Fong,  Cathy C R-R Huang,  Julie Lao,  Jing C Xiao,  Chun-Pyn Shen,  Alison M Strack,  Lauren Shearman,  Sloan Stribling,  Richard Z Chen,  Andrea Frassetto,  Xinchun Tong,  Junying Wang,  Richard G Ball,  Nancy N Tsou,  Gerard J Hickey,  Donald F Thompson,  Terry D Faidley,  Susan Nicolich,  Joana Achanfuo-Yeboah,  Donald F Hora,  Jeffrey J Hale,  William K Hagmann
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. [email protected]
PMID: 19320488 DOI: 10.1021/jm900063x
Abstract

A novel series of 1-sulfonyl-4-acylpiperazines as selective cannabinoid-1 receptor (CB1R) inverse agonists was discovered through high throughput screening (HTS) and medicinal chemistry lead optimization. Potency and in vivo properties were systematically optimized to afford orally bioavailable, highly efficacious, and selective CB1R inverse agonists that caused food intake suppression and body weight reduction in diet-induced obese rats and dogs. It was found that the receptor binding assay predicted in vivo efficacy better than functional antagonist/inverse agonist activities. This observation expedited the structure-activity relationship (SAR) analysis and may have implications beyond the series of compounds presented herein.

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