New site-directed reversible inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase

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).