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Arzneimittelforschung. 1997 Aug;47(8):904-9.

Pharmacological profile of a novel synthetic inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

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Tokyo Research Laboratories, Kowa Company, Ltd., Tokyo, Japan.


Pharmacological properties of NK-104 ((+)-monocalcium bis┬┐(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl++ +]-3,5-dihydroxy-6- heptenoate┬┐, CAS 147526-32-7), a novel synthetic inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, were investigated. The kinetic study, using rat liver microsomal HMG-CoA reductase, revealed that NK-104 is a competitive inhibitor of HMG-CoA reductase with a Ki of 1.7 nmol/l. To examine the inhibitory effect on sterol synthesis in vivo, de novo synthesis of sterols from [14C]acetate 3 h after oral administration of NK-104 was measured in rats. 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 inhibitory effect of NK-104 on liver sterol synthesis lasted over 6 h, while that of pravastatin and simvastatin disappeared 6 h after administration of the drugs twice the ED50s. Due to induction of HMG-CoA reductase, 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-104 (0.03, 0.1, 0.3 and 1 mg/kg p.o. for 2 weeks) were examined in beagle 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 mg/kg) and simvastatin (3 mg/kg) lowered plasma total cholesterol (14.0, 15.4 and 17.4%, respectively), but did not significantly affect plasma 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.

[Indexed for MEDLINE]

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