Synthesis and biological activity of methanesulfonamide pyrimidine- and N-methanesulfonyl pyrrole-substituted 3,5-dihydroxy-6-heptenoates, a novel series of HMG-CoA reductase inhibitors
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Watanabe, M
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机构:SHIONOGI & CO LTD, SHIONOGI RES LABS, FUKUSHIMA KU, OSAKA 553, JAPAN
Watanabe, M
Koike, H
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机构:SHIONOGI & CO LTD, SHIONOGI RES LABS, FUKUSHIMA KU, OSAKA 553, JAPAN
Koike, H
Ishiba, T
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机构:SHIONOGI & CO LTD, SHIONOGI RES LABS, FUKUSHIMA KU, OSAKA 553, JAPAN
Ishiba, T
Okada, T
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Okada, T
Seo, S
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Seo, S
Hirai, K
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Hirai, K
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[1] SHIONOGI & CO LTD, SHIONOGI RES LABS, FUKUSHIMA KU, OSAKA 553, JAPAN
[2] SHIONOGI & CO LTD, MFG DIV, CHEM PROC DEV DEPT, AMAGASAKI, HYOGO 660, JAPAN
A novel series of methanesulfonamide pyrimidine- and N-methanesulfonyl pyrrole-substituted 3,5-dihydroxy-6-heptenoates were synthesized and evaluated for their ability to inhibit the enzyme HMG-CoA reductase in vitro. Monocalcium bis(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulfonylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoate (3a,S-4522) was selected as a candidate for further evaluation. Compound 3a was approximately four times more potent than lovastatin sodium salt (in inhibiting HMG-CoA reductase in vitro (IC50 = 11 nM). Compound 3a was shown to be the most potent cholesterol biosynthesis inhibitor in this series (IC50 = 1.12 nM) in rat isolated hepatocytes; its inhibitory activity was approximately 100 times more potent than pravastatin. (C) 1997, Elsevier Science Ltd.