Administration (p.o.) of SKP 450, 2-[2'-(1',3'-dioxolane)]-2-methyl-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro-2H-1 -benzopyran, a novel antihypertensive agent, to hypercholesterolemic Syrian hamsters led to a significant reduction in plasma lipids in a dose-dependent manner, i.e., a 10.8% to 29% reduction in low-density lipoprotein cholesterol at doses of 0.3 to 10 mg/kg of SKP-450. SKP-450 was found to specifically inhibit the hepatic microsomal lanosterol 14α-methyl demethylase (14α-DM) in a competitive manner (K(i):2.65 μM). Furthermore, a dose dependent decrease in the 14α-DM activity by SKP 450 parallelled the cholesterol synthetic rate in vitro in both the rat hepatic S10 fractions (supernatants at 10,000 g; IC50:20 μM) and Chinese hamster ovary cells (IC50:23 μM) However, this phenomenon was not seen in AR45 cells, which are deficient in 14α-DM, suggesting that 14α-DM is the major target for the inhibitory action of SKP-450 in regard to cholesterol biosynthesis.
Bibliographical noteFunding Information:
This work was supported in part by grants from the Korean Ministry of Science and Technology (G7-4464-4 to YKP) and KOSEF (9514-0401-00-12-3) through the Bioproducts Research Center at Yonsei University. We thank Dr. James M. Trzaskos, Dupont-Merck Pharmaceuticals Co. for kindly providing AR45 cells.
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