Pharmacological profile of a novel synthetic inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
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.
Aoki
T
T
Tokyo Research Laboratories, Kowa Company, Ltd., Tokyo, Japan.
Nishimura
H
H
Nakagawa
S
S
Kojima
J
J
Suzuki
H
H
Tamaki
T
T
Wada
Y
Y
Yokoo
N
N
Sato
F
F
Kimata
H
H
Kitahara
M
M
Toyoda
K
K
Sakashita
M
M
Saito
Y
Y
D000818:Animals; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007700:Kinetics; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D017035:Pravastatin / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin; D013261:Sterols / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D008055:Lipids; D011804:Quinolines; D013261:Sterols; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin; C108475:pitavastatin