title: Syntheses of (4,1-benzoxazepine-3-ylidene)acetic acid derivatives and their inhibition of squalene synthase.
abstract: The (3,5-trans)-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid derivatives 1 have been previously identified as potent squalene synthase inhibitors. A series of (4,1-benzoxazepin-3-ylidene)acetic acid derivatives were synthesized and evaluated for their inhibition of rat and human squalene synthase, and the (E)-isomers were found to exhibit potent inhibitory activity, with the same potency as 4,1-benzoxazepine-3-acetic acid derivatives. In contrast the (Z)-isomers did not exhibit significant inhibitory activity, and the active conformation of the 4,1-benzoxazepine-3-acetic acid derivatives was deduced from the folded conformation of the (E)-isomers.
authors.affiliation: Takeda Chemical Industries, Ltd., Pharmaceutical Research Division, Osaka, Japan. Miki_Takashi@takeda.co.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Miki
authors.forename: Masakuni
authors.initials: M
authors.lastname: Kori
authors.forename: Ryu-ichi
authors.initials: R
authors.lastname: Tozawa
authors.forename: Masahira
authors.initials: M
authors.lastname: Nakamura
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Yukimasa
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
chemical_list: C460563:(3,5)-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid; D001381:Azepines; D004791:Enzyme Inhibitors; D013186:Farnesyl-Diphosphate Farnesyltransferase