title: New site-directed reversible inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase.
abstract: 1. CoA-thioether analogues of 3-hydroxy-3-methylglutaryl-CoA containing an additional methyl group at positions 2, 6(methyl at C3) or 4 of the acyl residue were prepared. To probe for hydrophobic interaction, their inhibitory properties were determined with 3-hydroxy-3-methylglutaryl-CoA reductase purified from baker's yeast. The CoA-thioethers were purely competitive inhibitors whose affinity to the reductase was near to that of the physiological substrate. 2. CoA-sulfoxides derived from the CoA-thioethers displayed affinities to the reductase superior to that of the physiological substrate (Km = 7 microM). Depending on the degree of recognition of diastereomers by the enzyme, the inhibitor constants of the two best inhibitors vary from Ki = 200 nM and Ki = 80 nM (diastereomeric mixtures) to 25 nM and 20 nM, respectively (if only one diastereomer would interact with the enzyme).
authors.affiliation: Institut für Physiologische Chemie, Technischen Universität München, Federal Republic of Germany.
authors.forename: B
authors.initials: B
authors.lastname: Sixt
authors.forename: H
authors.initials: H
authors.lastname: Eggerer
mesh_terms: D003065:Coenzyme A / Q000378:metabolism; D006868:Hydrolysis; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D013379:Substrate Specificity; D013440:Sulfides / Q000378:metabolism; D013454:Sulfoxides / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013440:Sulfides; D013454:Sulfoxides; D006903:Hydroxymethylglutaryl CoA Reductases; D003065:Coenzyme A