Syntheses of fused heterocyclic compounds and their inhibitory activities for squalene synthase. |
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Authors: | Takashi Miki Masakuni Kori Akira Fujishima Hiroshi Mabuchi Ryu ichi Tozawa Masahira Nakamura Yasuo Sugiyama Hidefumi Yukimasa |
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Institution: | Takeda Chemical Industries, Ltd., Pharmaceutical Research Division, 2-17-85, Juso-Honmachi, Osaka 532-8686, Yodogawa-ku, Japan. Miki_Takashi@takeda.co.jp |
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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. |
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