K-604 is a potent and selective acyl-CoA:cholesterol acyltransferase 1 (ACAT-1) inhibitor. K-604 inhibits against acyl-coenzyme A (acyl-CoA):cholesterol O-acyltransferase-1 (ACAT1, SOAT1) activitiy in a selective (IC50 = 450 nM vs. 102.85 μ M against human ACAT1 and ACAT2, respectively) and acyl-CoA-competitive (Ki = 378 nM against oleoyl-coA) manner.
Acetyl-CoA acetyltransferase 1 (ACAT 1) is a protein coding gene that encodes a nitochondrially localized enzyme that catalyzes the reversible formation of acetoacetyl-CoA rom two molecules of acetyl-CoA. This enzyme plays an essential role in breaking down proteins and fats from diet. it helps process isoleucine, an amino acid that is a building block of many proteins. This enzyme is also involved in processing ketones, which are molecules that are produced when fats are broken down in the body.
K-604 dihydrochloride is a potent and selective acyl-CoA:cholesterol acyltransferase 1 (ACAT-1) inhibitor with an IC50 of 0.45±0.06 μM. K-604 efficiently inhibits cholesterol esterification in human macrophages with IC50 value of 68 nM. The plasma cholesterol levels in fat-fed hamsters are ~12-fold higher than those in chow-fed hamsters, which are significantly decreased by K-604 only at the highest dose tested (30 mg/kg) but not at lower doses (1-10 mg/kg). The fatty streak lesions stain with oil red O are markedly induced by the high-fat diet, which is significantly reduced by administration of K-604.[1]. Administration of K-604 to 8-week-old apoE-knockout mice for 12 weeks at a dose of 60 mg/kg/day significantly reduced macrophage-positive area and increased collagen-positive area in atherosclerotic plaques in the aorta without affecting plasma cholesterol levels or lesion areas, indicating direct plaque-modulating effects of K-604 on vascular walls independent of plasma cholesterol levels. Exposure of cultured human aortic smooth muscle cells to K-604 resulted in increased procollagen type 1 contents in the culture supernatant and increased procollagen type 1 mRNA levels[2].
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