Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity

J Med Chem. 2008 Jan 24;51(2):305-13. doi: 10.1021/jm0709034. Epub 2007 Dec 21.

Abstract

The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.

MeSH terms

  • Animals
  • Anti-Obesity Agents / chemical synthesis*
  • Anti-Obesity Agents / pharmacokinetics
  • Anti-Obesity Agents / pharmacology
  • Benzazepines / chemical synthesis*
  • Benzazepines / pharmacokinetics
  • Benzazepines / pharmacology
  • Cell Line
  • Eating / drug effects
  • Humans
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Male
  • Obesity / drug therapy*
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin 5-HT2 Receptor Agonists*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Weight Gain / drug effects

Substances

  • Anti-Obesity Agents
  • Benzazepines
  • Serotonin 5-HT2 Receptor Agonists
  • lorcaserin
  • Inositol 1,4,5-Trisphosphate