title: Synthesis and biological activity of novel 4,4-difluorobenzazepine derivatives as non-peptide antagonists of the arginine vasopressin V1A receptor.
abstract: To find potent and selective antagonists of the arginine vasopressin (AVP) V1A receptor, optimization studies of compounds structurally related to (Z)-N-{4'-[(4,4-difluoro-5-carbamoylmethylidene-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]phenyl}carboxamide were performed. The synthesis and pharmacological properties of these compounds are described. We first investigated the effect of the carboxamide moiety, and found that a 2-methylfuran-3-carbonyl group at this position increased V1A binding affinity and selectivity for the V1A receptor versus the V2 receptor. The amino group of the 5-carbamoylmethylidene moiety was also examined, and a 4-piperidinopiperidino group was found to be optimal at this position. The hemifumarate of compound 12l (YM218) was shown to exhibit potent binding affinity, V1A receptor selectivity, and in vivo antagonist activity.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 300-2698, Japan. yoshiaki.shimada@jp.astellas.com
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Shimada
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Taniguchi
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuhisa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Akane
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kawano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Takahiko
authors.initials: T
authors.lastname: Tobe
authors.forename: Akio
authors.initials: A
authors.lastname: Kakefuda
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Yatsu
authors.forename: Atsuo
authors.initials: A
authors.lastname: Tahara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tomura
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kusayama
authors.forename: Koh-ichi
authors.initials: K
authors.lastname: Wada
authors.forename: Junko
authors.initials: J
authors.lastname: Tsukada
authors.forename: Masaya
authors.initials: M
authors.lastname: Orita
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005461:Fluorine / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008297:Male; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D010455:Peptides; D005461:Fluorine