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A Selective ACAT-1 Inhibitor, K-604, Suppresses Fatty Streak Lesions in Fat-Fed Hamsters Without Affecting Plasma Cholesterol Levels

A Selective ACAT-1 Inhibitor, K-604, Suppresses Fatty Streak Lesions in Fat-Fed Hamsters Without Affecting Plasma Cholesterol Levels

Mami Ikenoya, Yasunobu Yoshinaka, Hideyuki Kobayashi, Katsumi Kawamine, Kimiyuki Shibuya, Fumiyasu Sato, Kimio Sawanobori, Takuya Watanabe, Akira Miyazaki

Atherosclerosis. 2007 Apr;191(2):290-7.

PMID: 16820149

Abstract:

Background:
Acyl-coenzyme A:cholesterol O-acyltransferase-1 (ACAT-1), a major ACAT isozyme in macrophages, plays an essential role in foam cell formation in atherosclerotic lesions. However, whether pharmacological inhibition of macrophage ACAT-1 causes exacerbation or suppression of atherosclerosis is controversial.
Methods and results:
We developed and characterized a novel ACAT inhibitor, K-604. The IC(50) values of K-604 for human ACAT-1 and ACAT-2 were 0.45 and 102.85 micromol/L, respectively, indicating that K-604 is 229-fold more selective for ACAT-1. Kinetic analysis indicated that the inhibition was competitive with respect to oleoyl-coenzyme A with a K(i) value of 0.378 micromol/L. Exposure of human monocyte-derived macrophages to K-604 inhibited cholesterol esterification with IC(50) of 68.0 nmol/L. Furthermore, cholesterol efflux from THP-1 macrophages to HDL(3) or apolipoprotein A-I was enhanced by K-604. Interestingly, administration of K-604 to F1B hamsters on a high-fat diet at a dose of >or=1mg/kg suppressed fatty streak lesions without affecting plasma cholesterol levels.
Conclusions:
K-604, a potent and selective inhibitor of ACAT-1, suppressed the development of atherosclerosis in an animal model without affecting plasma cholesterol levels, providing direct evidence that pharmacological inhibition of ACAT-1 in the arterial walls leads to suppression of atherosclerosis.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP217094321	K-604		217094-32-1	Price

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