Design and synthesis of piperazinylpyridine derivatives as novel 5-HT1A agonists/5-HT3 antagonists for the treatment of irritable bowel syndrome (IBS)

Chem Pharm Bull (Tokyo). 2009 Jan;57(1):34-42. doi: 10.1248/cpb.57.34.

Abstract

We have prepared a series of piperazinylpyridine derivatives for the treatment of irritable bowel syndrome (IBS). These compounds, which were designed by pharmacophore analysis, bind to both serotonin subtype 1A (5-HT1A) and subtype 3 (5-HT3) receptors. The nitrogen atom of the isoquinoline, a methoxy group and piperazine were essential to the pharmacophore for binding to these receptors. We also synthesized furo- and thienopyridine derivatives according to structure-activity relationship analyses. Compound 17c (TZB-20810) had high affinities to these receptors and exhibited 5-HT1A agonistic activity and 5-HT3 antagonistic activity concurrently, and is a promising drug for further development in the treatment of IBS.

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Guinea Pigs
  • Humans
  • Irritable Bowel Syndrome / drug therapy*
  • Molecular Structure
  • Piperazines* / chemical synthesis
  • Piperazines* / chemistry
  • Piperazines* / therapeutic use
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / therapeutic use*
  • Receptors, Serotonin, 5-HT3 / chemistry*
  • Serotonin Antagonists* / chemistry
  • Serotonin Antagonists* / therapeutic use
  • Serotonin Receptor Agonists* / chemistry
  • Serotonin Receptor Agonists* / therapeutic use

Substances

  • Piperazines
  • Pyridines
  • Receptors, Serotonin, 5-HT3
  • Serotonin Antagonists
  • Serotonin Receptor Agonists