title: Novel potassium channel activators: synthesis and structure-activity relationship studies of 3,4-dihydro-2H-1,4-benzoxazine derivatives.
abstract: Strong potassium channel-activating effects were found among a series of novel 4-substituted 3,4-dihydro-2H-1,4-benzoxazine derivatives. The key step in preparation was the nucleophilic substitution of 3,4-dihydro-2H-1,4-benzoxazine (3) with activated halogenopyridines, such as halogenopyridine N-oxides (15a--c) and the borane adduct (15d) of 4-bromopyridine. Structure-activity relationship studies identified 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)pyridin e-1-oxide (16a: YM934) as the optimal compound. This compound (16a) showed a more potent oral antihypertensive effect than cromakalim in conscious spontaneously hypertensive rats.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: R
authors.initials: R
authors.lastname: Tsuzuki
authors.forename: A
authors.initials: A
authors.lastname: Matsuhisa
authors.forename: K
authors.initials: K
authors.lastname: Takayama
authors.forename: T
authors.initials: T
authors.lastname: Yoden
authors.forename: W
authors.initials: W
authors.lastname: Uchida
authors.forename: M
authors.initials: M
authors.lastname: Asano
authors.forename: S
authors.initials: S
authors.lastname: Fujita
authors.forename: I
authors.initials: I
authors.lastname: Yanagisawa
authors.forename: T
authors.initials: T
authors.lastname: Fujikura
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship
chemical_list: D000959:Antihypertensive Agents; D010078:Oxazines; D015221:Potassium Channels