Syntheses of fused heterocyclic compounds and their inhibitory activities for squalene synthase.
A variety of fused heterocyclic compounds (2-11) were synthesized as a modification of the lead compound 1a and evaluated for their inhibition of squalene synthase. 4,1-Benzothiazepine derivative 2, 1,4-benzodiazepine derivative 6, 1,3-benzodiazepine derivative 7, 1-benzazepine derivative 9, and 4,1-benzoxazocine derivative 10 potently inhibited squalene synthase activity, whereas the 4,1-benzoxazepine derivatives 1 was the most potent inhibitor. 4,1-Benzothiazepine S-oxide derivative 4, 1,4-benzodiazepine derivative 5, 1,3,4-benzotriazepine derivative 8, and 1,2,3,4-tetrahydroquinoline derivative 11 were found to be weakly active. Comparison of the X-ray structures of these compounds (1a, 2, 4, 5, 7 and 10) suggests that orientation of the 5- (or 6)-phenyl group is important for activity.
Miki
Takashi
T
Takeda Chemical Industries, Ltd., Pharmaceutical Research Division, 2-17-85, Juso-Honmachi, Osaka 532-8686, Yodogawa-ku, Japan. Miki_Takashi@takeda.co.jp
Kori
Masakuni
M
Fujishima
Akira
A
Mabuchi
Hiroshi
H
Tozawa
Ryu ichi
Ri
Nakamura
Masahira
M
Sugiyama
Yasuo
Y
Yukimasa
Hidefumi
H
D000818:Animals; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000201:enzymology; D008297:Male; D015394:Molecular Structure; D010077:Oxazepines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D010077:Oxazepines; D013186:Farnesyl-Diphosphate Farnesyltransferase