PHARMACOLOGICAL PROFILE OF A NOVEL SYNTHETIC INHIBITOR OF 3-HYDROXY-3-METHYLGLUTARYL-COENZYME-A REDUCTASE

Pharmacological properties of NK-104 ((+)-monocalcium rophenyl)-3-quin olyl]-3,5-dihydroxy-6-heptenoate}, CAS 147526-32-7), a novel synthetic inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductas e, were investigated. The kinetic study, using rat liver microsomal HM G-CoA reductase, revealed that NK-104 is a competitive inhibitor of HM G-CoA reductase with a K-i of 1.7 nmol/l. To examine the inhibitory ef fect on sterol synthesis in vivo, de novo synthesis of sterols from [C -14]acetate 3 h after oral administration of NK-104 was measured in ra ts. NK-104 showed marked inhibition in liver (ED50 0.13 mg/kg) and in ileum (ED50 0.20 mg/kg), but much weaker in the other tissues. The inh ibitory effect of NK-104 on liver sterol synthesis lasted over 6 h, wh ile that of pravastatin and simvastatin disappeared 6 h after administ ration of the drugs twice the ED(50)s. Due to induction of HMG-CoA red uctase, initial suppression of hepatic sterol synthesis by pravastatin and simvastatin was compensated, and the cumulative change in hepatic sterol synthesis during 12 h after drug administration was remarkably negative only with long-acting NK-104. Hypolipidemic effects of NK-10 4 (0.03, 0.1, 0.3 and 1 mg/kg p.o. for 2 weeks) were examined in beagl e dogs. NK-104 reduced plasma total cholesterol dose-dependently (13.1 , 18.5 and 20.2% at doses of 0,1, 0.3 and 1 mg/kg, respectively), and also plasma triglycerides by 0.1 mg/kg or more. Pravastatin (1 and 3 m g/kg) and simvastatin (3 mg/kg) lowered plasma total cholesterol (14.0 , 15.4 and 17.4%, respectively), but did not significantly affect plas ma triglyceride levels. These results indicate that NK-104 is a potent , liver-selective, long-acting HMG-CoA reductase inhibitor with a high cholesterol- and triglyceride-lowering potency.