AcylCoAcholesterol acyltransferase inhibitors

Since the accumulation of cholesteryl ester within the macrophages and SMC of the developing lesion are important for atherosclerosis progression, inhibitors of ACAT, which esterifies intracellular free cholesterol, may have antiatherogenic properties. Selective inhibitors of ACAT-2, which is only found within peripheral macrophages, may be particularly effective. The acyl sulfamic ester, avasimibe 38 (Figure 14) is a selective ACAT inhibitor that was orally effective as a lipid-lowering agent in multiple animal studies. Avasimibe (10 or 25 mgkg_ 1 day_ 1 p.o.) reduced both VLDLc and LDLc by up to 40% in miniature pigs. It was safe and well tolerated and, in phase II trials, daily oral dosing of avasimibe at 50-500 mg decreased VLDLc by up to 30%, but no clear dose response was observed. While avasimibe was the first ACAT inhibitor to reach clinical proof of concept, it has been discontinued. Research is however continuing on other orally active ACAT inhibitors.

Pactimibe 39 (Figure 14) is a dual ACAT1 and ACAT2 inhibitor that has progressed to Phase II testing. When given orally, 39 reduced the progression of atherosclerosis in animal models by preventing cholesteryl ester accumulation in macrophages. Development of 39 was recently halted when it failed to meet its primary endpoint in Phase II trials.83 SMP-797 is an ACAT inhibitor for hyperlipidemia in phase II testing. A related analog, SMP-500 40 (Figure 14), is a potent hepatic ACAT inhibitor (IC50 = 0.07-0.08 mM) that reduced serum cholesterol as well as serum cholesteryl ester levels in several animal models after oral dosing.84

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