title: Syntheses of fused heterocyclic compounds and their inhibitory activities for squalene synthase.
abstract: 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.
authors.affiliation: Takeda Chemical Industries, Ltd., Pharmaceutical Research Division, 2-17-85, Juso-Honmachi, Osaka 532-8686, Yodogawa-ku, 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: Akira
authors.initials: A
authors.lastname: Fujishima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mabuchi
authors.forename: Ryu ichi
authors.initials: Ri
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; 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
chemical_list: D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D010077:Oxazepines; D013186:Farnesyl-Diphosphate Farnesyltransferase