title: Novel 4,1-benzoxazepine derivatives with potent squalene synthase inhibitory activities.
abstract: A series of (3,5-trans)-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine derivatives were synthesized and evaluated for squalene synthase inhibitory and cholesterol biosynthesis inhibitory activities. Through modification of substituents of the lead compounds 1a and 1b, it was found that 4,1-benzoxazepine-3-acetic acid derivatives with isobutyl and neopentyl groups at the 1-position, the chloro atom at the 7-position, and the chloro and methoxy groups at the 2'-position on the 5-phenyl ring, had potent squalene synthase inhibitory activity. Among such compounds, the 5-(2,3-dimethoxyphenyl) derivative 2t exhibited potent inhibition of cholesterol biosynthesis in HepG2 cells. As a result of optical resolution study of 2t, the absolute stereochemistry required for inhibitory activity was determined to be 3R,5S. In vivo study showed that the sodium salt of (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid 20 effectively reduced plasma cholesterol in marmosets.
authors.affiliation: Takeda Chemical Industries, Ltd. Pharmaceutical Research Division, 2-17-85, Juso-Honmachi, Yodogawa-ku, 532-8686, 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: Hiroshi
authors.initials: H
authors.lastname: Mabuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Banno
authors.forename: Ryu ichi
authors.initials: Ri
authors.lastname: Tozawa
authors.forename: Masahira
authors.initials: M
authors.lastname: Nakamura
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Itokawa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Yukimasa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002144:Callithrix; D006528:Carcinoma, Hepatocellular / Q000201:enzymology; D002784:Cholesterol / Q000097:blood; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000201:enzymology; D008297:Male; D010077:Oxazepines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C453003:4,1-benzoxazepine; D004791:Enzyme Inhibitors; D010077:Oxazepines; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase