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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Abstract

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-methyl-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.

The synthesis and biological evaluation of 3a (S-4522) is described.

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References (13)

  • S.M. Grundy

    J. Am. Med. Assoc.

    (1986)
  • D.S. Thelle

    Drug Invest.

    (1990)
  • Scandinavian Simvastatin Survival Study Group

    Lancet

    (1994)
  • J. Shepherd et al.

    New Engl. J. Med.

    (1995)
  • A. Endo

    J. Antibiot.

    (1979)
    A.W. Alberts

    Drug Invest.

    (1990)
    A. Endo

    J. Med. Chem.

    (1985)
    H. Tamachi et al.

    J. Am. Med. Assoc.

    (1987)
    A.W. Alberts

    Am. J. Cardiol.

    (1988)
    P.J. Connolly et al.

    J. Med. Chem.

    (1993)
    S.M. Grundy

    New Engl. J. Med.

    (1988)
  • V.W. Rodwell et al.

    Adv. Enzymol.

    (1973)
    W.F. Hoffmann et al.

    J. Med. Chem.

    (1986)
There are more references available in the full text version of this article.

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Present address: Aburahi Laboratories, Shionogi & Co., Ltd. 1405, Gotanda, Koka-cho, Koka-gun, Shiga 520-34, Japan.

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