INHIBITORS OF HMG-COA REDUCTASE - BIOLOGICAL EFFECTS OF A 6-[2-[2-(4-FLUORO-3-METHYLPHENYL)-4-SUBSTITUTED CYCLOHEX-1-EN-1-YL]ETHENYL]-4-HYDROXY-3,4,5,6-TETRAHYDRO-2H-PYRAN-2-ONE

We report on a series of potent inhibitors of HMG-CoA reductase (HMGR) that were designed to examine the biological consequences that result from molecular changes in RG 12561. The introduction of functional groups on the cyclohexene nucleus of RG 12561 and the resulting inhibitor-enzyme interaction...

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Bibliographic Details
Published inEuropean journal of medicinal chemistry Vol. 27; no. 7; pp. 735 - 742
Main Authors REGAN, BRUNO, JG, GUSTAFSON, K, AMIN, D, NEUENSCHWANDER, K, PERRONE, M
Format Journal Article
LanguageEnglish
Published PARIS Elsevier 01.10.1992
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
SELECTIVE-INHIBITION
COENZYME-A REDUCTASE
HMG-COA REDUCTASE INHIBITORS
COMPETITIVE INHIBITOR
HYPERCHOLESTEROLEMIA
CORONARY HEART-DISEASE
CHOLESTEROL BIOSYNTHESIS
TISSUE SELECTIVITY
PRAVASTATIN
RG 12561
SIMVASTATIN
DERIVATIVES
CHOLESTEROL-BIOSYNTHESIS
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Summary:We report on a series of potent inhibitors of HMG-CoA reductase (HMGR) that were designed to examine the biological consequences that result from molecular changes in RG 12561. The introduction of functional groups on the cyclohexene nucleus of RG 12561 and the resulting inhibitor-enzyme interactions at remote binding sites of HMGR are discussed. Cellular membrane permeability may also contribute to potency. The HMGR inhibitory activity was measured utilizing solubilized enzyme. The compounds were evaluated as inhibitors of sterol biosynthesis in vitro using liver slices and in vivo after oral administration to the rat.
ISSN:0223-5234
1768-3254
DOI:10.1016/0223-5234(92)90095-I