The discovery of diazepinone-based 5-HT3 receptor partial agonists

Bioorg Med Chem Lett. 2014 Jun 1;24(11):2578-81. doi: 10.1016/j.bmcl.2014.03.074. Epub 2014 Apr 2.

Abstract

Serotonin type 3 (5-HT3) receptor partial agonists have been targeted as potential new drugs for the symptomatic relief of irritable bowel syndrome (IBS). Multiple diazepinone-based compounds have been discovered, which exhibit nanomolar binding affinity for the h5-HT3A receptor and display a range of intrinsic activities (IA=7-87% of 5-HT Emax) in HEK cells heterologously expressing the h5-HT3A receptor. Favorable physicochemical properties and in vitro ADME profile coupled with oral activity in the murine von Bezold-Jarisch reflex model demonstrates the series has promise for producing low to moderate IA partial agonists suitable for an IBS indication.

Keywords: 5-HT(3) receptor partial agonist; Alosetron; Diazepinone; Irritable bowel syndrome (IBS); Ligand-gated ion channel; Ramosetron.

MeSH terms

  • Administration, Oral
  • Animals
  • Azepines / administration & dosage
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • HEK293 Cells
  • Humans
  • Irritable Bowel Syndrome / drug therapy*
  • Mice
  • Molecular Structure
  • Receptors, Serotonin, 5-HT3 / metabolism*
  • Structure-Activity Relationship

Substances

  • Azepines
  • Receptors, Serotonin, 5-HT3