title: Design and synthesis of piperazinylpyridine derivatives as novel 5-HT1A agonists/5-HT3 antagonists for the treatment of irritable bowel syndrome (IBS).
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.
authors.affiliation: Synthetic Research Department, ASKA Pharmaceutical Co., Ltd, Japan. asagarasu-a@aska-pharma.co.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Asagarasu
authors.forename: Teruaki
authors.initials: T
authors.lastname: Matsui
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hayashi
authors.forename: Satoru
authors.initials: S
authors.lastname: Tamaoki
authors.forename: Yukinao
authors.initials: Y
authors.lastname: Yamauchi
authors.forename: Michitaka
authors.initials: M
authors.lastname: Sato
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006168:Guinea Pigs; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry*; D012702:Serotonin Antagonists / Q000737:chemistry / Q000627:therapeutic use; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D010879:Piperazines; D011725:Pyridines; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists