Novel 4,1-benzoxazepine derivatives with potent squalene synthase inhibitory activities.
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.
Miki
Takashi
T
Takeda Chemical Industries, Ltd. Pharmaceutical Research Division, 2-17-85, Juso-Honmachi, Yodogawa-ku, 532-8686, Osaka, Japan. Miki_Takashi@takeda.co.jp
Kori
Masakuni
M
Mabuchi
Hiroshi
H
Banno
Hiroshi
H
Tozawa
Ryu ichi
Ri
Nakamura
Masahira
M
Itokawa
Shigekazu
S
Sugiyama
Yasuo
Y
Yukimasa
Hidefumi
H
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
C453003:4,1-benzoxazepine; D004791:Enzyme Inhibitors; D010077:Oxazepines; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase