Recognition of the exposure of phosphatidylserine (PS) on the outer surface of plasma membrane has been implicated in the phagocytosis of aged͞apoptotic cells. Because oxidized low-density lipoprotein (OxLDL) has been reported to block the phagocytosis, here we examined whether lectin-

No abstract

Delta-5 desaturase (D5D), encoded by fatty acid desaturase 1 (Fads1), is the rate-limiting enzyme for the conversion from dihomo-g-linolenic acid (DGLA) to arachidonic acid (AA) in the v-6 polyunsaturated fatty acid pathway. Several AA-derived eicosanoids (e.g., prostaglandins, thromboxanes, and leukotrienes) and DGLA-derived eicosanoids are reported to promote and/or prevent atherosclerosis progression through, at least in part, its proinflammatory or anti-inflammatory effects. To elucidate the effects of D5D inhibition by a D5D inhibitor on atherosclerosis, we generated a potent, orally available and selective D5D inhibitor, 2-(2,2,3,3,3-Pentafluoropropoxy)-3-[4-(2,2,2-trifluoroethoxy) phenyl]-5,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-4,6-dione, compound-326, and examined its effects on Western-diet fed ApoE knockout (KO) mice. Oral administration of compound-326 (3-10 mg/kg per day for 15 weeks) significantly inhibited the progression of atherosclerotic lesions in the aorta without affecting plasma total cholesterol and triglyceride levels. Compound-326 significantly decreased AA levels, while it increased DGLA levels in the liver and the blood accompanied by decreases in AA-derived eicosanoid production and increases in DGLA-derived eicosanoid production from the blood cells. We conclude that compound-326 prevents the progression of atherosclerosis in Western-diet fed ApoE KO mice by modulating a profile of eicosanoid production, suggesting that D5D inhibitors can be a novel remedy for preventing atherosclerosis and subsequent cardiovascular events. SIGNIFICANCE STATEMENT This study shows a D5D-specific and orally available potent inhibitor provided the first evidence to support the concept that D5D inhibitors will be a novel remedy for preventing the progression of atherosclerosis.

Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular enzyme that catalyzes cholesterol esterification. ACAT inhibitors are expected to be potent therapeutic agents for the treatment of atherosclerosis. A series of potent ACAT inhibitors based on an (4-phenylcoumarin)acetanilide scaffold was identified. Evaluation of the structure-activity relationships of a substituent on this scaffold, with an emphasis on improving the pharmacokinetic profile led to the discovery of 2-[7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (23), which exhibited potent ACAT inhibitory activity (IC50=12 nM) and good pharmacokinetic profile in mice. Compound 23 also showed regressive effects on atherosclerotic plaques in apolipoprotein (apo)E knock out (KO) mice at a dose of 0.3 mg/kg per os (p.o.).