title: Novel 5-HT3 antagonists. Isoquinolinones and 3-aryl-2-pyridones.
abstract: Synthesis and pharmacological evaluation of a series of 1,2-dihydro-1-[(5-methyl-1-imidazol-4-yl)methyl]-2-oxopyridine 5-HT3 antagonists are described. The key pharmacophoric elements were defined as a basic nitrogen, a linking group capable of hydrogen bonding interactions, and an aromatic moiety. 1,2-Dihydro-2-oxopyridine moiety could be a good linking group because of its nicely planar structure. The steric limitations of the aromatic moiety were investigated by X-ray analysis and computer analysis and shown to be optimal when the aromatic moiety was constrained within an arched planar system, which could be successfully replaced by 3-(2-thienyl)-2-oxopyridine function or 6-amino-7-chloro-1-isoquinolinone function without any loss of the activity. Among the synthesized compounds, 42 showed the most potent activity in the inhibition of Bezold-Jarisch reflex in rats. Compounds 44a and 64 were orally active in the protection against cisplatin-induced emesis in dogs or ferrets. Structure-activity relationships are discussed.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Matsui
authors.forename: T
authors.initials: T
authors.lastname: Sugiura
authors.forename: H
authors.initials: H
authors.lastname: Nakai
authors.forename: S
authors.initials: S
authors.lastname: Iguchi
authors.forename: S
authors.initials: S
authors.lastname: Shigeoka
authors.forename: H
authors.initials: H
authors.lastname: Takada
authors.forename: Y
authors.initials: Y
authors.lastname: Odagaki
authors.forename: Y
authors.initials: Y
authors.lastname: Nagao
authors.forename: Y
authors.initials: Y
authors.lastname: Ushio
authors.forename: K
authors.initials: K
authors.lastname: Ohmoto
mesh_terms: D000818:Animals; D004285:Dogs; D005289:Ferrets; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D007546:Isoquinolines; D011728:Pyridones; D012702:Serotonin Antagonists