title: Development of potent serotonin-3 (5-HT3) receptor antagonists. II. Structrue-activity relationships of N-(1-benzyl-4-methylhexahydro-1H-1,4- diazepin-6-yl)carboxamides.
abstract: Our studies on 4-amino-5-chloro-2-ethoxybenzamides led to the discovery that the N-(1,4-dimethylhexahydro-1H-1,4-diazepin-6-yl)benzamide 9 and the 1-benzyl-4-methylhexahydro-1H-1,4-diazepine analogue 10 are potent serotonin-3 (5-HT3) receptor antagonists. Structure-activity relationship (SAR) studies on the influence of the aromatic nucleus of 9 and 10 upon inhibition of the von Bezold-Jarisch reflex in rats are described. Heteroaromatic rings such as pyrrole, thiophene, furan, pyridine, pyridazine, 1,2-benzisoxazole, indole, quinoline, and isoquinoline rings showed weak 5-HT3 receptor antagonistic activity. Within this series, use of the 1H-indazole ring as an aromatic moiety led to a substantial increase of the activity; the 1H-indazolylcarboxamides 54, 57, 97, and 102 showed potent 5-HT3 receptor antagonistic activity. The optimal compound identified via extensive SAR studies was N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indaz ole-3- carboxamide (54), whose effect was superior to that of the corresponding benzamide 10 and essentially equipotent to those of ondanbsetron (1) and granisetron (4).
authors.affiliation: Exploratory Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Harada
authors.forename: T
authors.initials: T
authors.lastname: Morie
authors.forename: Y
authors.initials: Y
authors.lastname: Hirokawa
authors.forename: H
authors.initials: H
authors.lastname: Terauchi
authors.forename: I
authors.initials: I
authors.lastname: Fujiwara
authors.forename: N
authors.initials: N
authors.lastname: Yoshida
authors.forename: S
authors.initials: S
authors.lastname: Kato
mesh_terms: D000818:Animals; D001919:Bradycardia / Q000139:chemically induced / Q000188:drug therapy; D017829:Granisetron / Q000494:pharmacology / Q000627:therapeutic use; D007275:Injections, Intravenous; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D017294:Ondansetron / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000188:drug therapy
chemical_list: D017829:Granisetron; D017294:Ondansetron; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists