title: New 5-HT3 (serotonin-3) receptor antagonists. V. Synthesis and structure-activity relationships of pyrrolo[2,1-c][1,4]benzoxazine-6-carboxamides.
abstract: This paper describes the discovery of structurally novel heterocyclic carboxamides which are highly potent 5-HT3 (serotonin-3) receptor antagonists. Pyrrolo[2,1-c][1,4]benzoxazine-6-carboxamides (12 and 20) were found to possess potent 5-HT3 receptor antagonist activity on the von Bezold-Jarisch reflex in anesthetized rats. Structure-activity studies showed that compounds with small and lipophilic substituents such as chloro and methyl at the 8-position of the aromatic ring portion retained high potency, whereas those with bulky substituents showed essentially no activity. A dimethyl group at the 4-position slightly decreased the potency. 1-Azabicyclo[2.2.2]octan-3-amine as the amine part afforded the most potent activity. From this series, 20a was found to be the most potent 5-HT3 receptor antagonist, being 40-fold more potent than ondansetron (1).
authors.affiliation: New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kato
authors.forename: S
authors.initials: S
authors.lastname: Nishino
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.forename: H
authors.initials: H
authors.lastname: Yamakuni
authors.forename: H
authors.initials: H
authors.lastname: Takasugi
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D010078:Oxazines; D011758:Pyrroles; D012702:Serotonin Antagonists