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.
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-he ptenoate (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.
Watanabe
M
M
Shionogi Research Laboratories, Shionogi and Company, Ltd., Osaka, Japan.
Koike
H
H
Ishiba
T
T
Okada
T
T
Seo
S
S
Hirai
K
K
D000818:Animals; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; C105918:S 4522; D013449:Sulfonamides