Biochemical basis for a cholesterol-lowering activity of 2-[2'-(1',3'-dioxolane)]-2-methyl-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro-2H-1 -benzopyran (SKP-450), a novel antihypertensive agent

Eun Young Lee; Dong Min Lim; Sung Eun Yoo; Dae Kee Kim; Young Ki Paik

doi:10.1016/S0006-2952(98)00321-9

Biochemical basis for a cholesterol-lowering activity of 2-[2'-(1',3'-dioxolane)]-2-methyl-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro-2H-1 -benzopyran (SKP-450), a novel antihypertensive agent

Eun Young Lee, Dong Min Lim, Sung Eun Yoo, Dae Kee Kim, Young Ki Paik

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	579-582
Number of pages	4
Journal	Biochemical Pharmacology
Volume	57
Issue number	5
DOIs	https://doi.org/10.1016/S0006-2952(98)00321-9
State	Published - 1 Mar 1999

Bibliographical note

Funding 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.

Keywords

Antihypertension
AR45 cells
Cardioprotection
Cholesterol-lowering
Lanosterol 14α-methyl demethylase
SKP-450

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10.1016/S0006-2952(98)00321-9

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@article{e467b1938f5543eba45ef4acfd964ca9,

title = "Biochemical basis for a cholesterol-lowering activity of 2-[2'-(1',3'-dioxolane)]-2-methyl-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro-2H-1 -benzopyran (SKP-450), a novel antihypertensive agent",

abstract = "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.",

keywords = "Antihypertension, AR45 cells, Cardioprotection, Cholesterol-lowering, Lanosterol 14α-methyl demethylase, SKP-450",

author = "Lee, {Eun Young} and Lim, {Dong Min} and Yoo, {Sung Eun} and Kim, {Dae Kee} and Paik, {Young Ki}",

note = "Funding 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.",

year = "1999",

month = mar,

day = "1",

doi = "10.1016/S0006-2952(98)00321-9",

language = "English",

volume = "57",

pages = "579--582",

journal = "Biochemical Pharmacology",

issn = "0006-2952",

publisher = "Elsevier Inc.",

number = "5",

}

Biochemical basis for a cholesterol-lowering activity of 2-[2'-(1',3'-dioxolane)]-2-methyl-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro-2H-1 -benzopyran (SKP-450), a novel antihypertensive agent. / Lee, Eun Young; Lim, Dong Min; Yoo, Sung Eun et al.
In: Biochemical Pharmacology, Vol. 57, No. 5, 01.03.1999, p. 579-582.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Biochemical basis for a cholesterol-lowering activity of 2-[2'-(1',3'-dioxolane)]-2-methyl-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro-2H-1 -benzopyran (SKP-450), a novel antihypertensive agent

AU - Lee, Eun Young

AU - Lim, Dong Min

AU - Yoo, Sung Eun

AU - Kim, Dae Kee

AU - Paik, Young Ki

N1 - Funding 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.

PY - 1999/3/1

Y1 - 1999/3/1

N2 - 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.

AB - 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.

KW - Antihypertension

KW - AR45 cells

KW - Cardioprotection

KW - Cholesterol-lowering

KW - Lanosterol 14α-methyl demethylase

KW - SKP-450

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U2 - 10.1016/S0006-2952(98)00321-9

DO - 10.1016/S0006-2952(98)00321-9

M3 - Article

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AN - SCOPUS:0033104227

SN - 0006-2952

VL - 57

SP - 579

EP - 582

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

IS - 5

ER -

Biochemical basis for a cholesterol-lowering activity of 2-[2'-(1',3'-dioxolane)]-2-methyl-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro-2H-1 -benzopyran (SKP-450), a novel antihypertensive agent

Abstract

Bibliographical note

Keywords

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