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

Article abstract of DOI:10.1016/S0968-0896(96)00248-9

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.