Antiatherosclerotic properties of EP2302, a novel squalene synthase inhibitor, in the cholesterol-fed rabbit.

EP2302 is a novel nitric oxide donor compound that inhibits squalene synthase. We hypothesized that EP2302 can reduce atherosclerosis in the cholesterol-fed rabbit atherosclerosis model. Animals were fed a high-cholesterol (HC) diet for 4 weeks.

EP2306 and EP2302, two novel squalene synthase inhibitors, stimulate endothelial nitric oxide synthase expression in cultured endothelial cells.

EP2306 and EP2302 are two novel squalene synthase inhibitors with hypolipidemic, antiatherosclerotic, and antioxidant properties. In the present study, the authors investigated their effect on the expression and activity of endothelial nitric oxide synthase (eNOS) in cultured bovine aortic endothelial (BAE) cells and calf pulmonary artery endothelial (CPAE) cells. eNOS concentration was determined by immunoassay and eNOS activity by measuring the conversion of [(3)H]arginine to [(3)H]citrulline.

EP2306 [2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol, hydrobromide], a novel squalene synthase inhibitor, reduces atherosclerosis in the cholesterol-fed rabbit.

EP2306 [2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol, hydrobromide] inhibits squalene synthase and lipid biosynthesis and possesses antioxidant properties. We hypothesized that EP2306 can effectively modify circulating lipids and reduce atherosclerosis in the cholesterol-fed rabbit. Animals were fed a high-cholesterol diet for 4 weeks followed by 4 (phase 1 and 2) or 12 weeks (phase 3) of drug treatment while on high-cholesterol diet.

Pharmacological characterization in vitro of EP2306 and EP2302, potent inhibitors of squalene synthase and lipid biosynthesis.

We investigated the effects of EP2306 and EP2302, two novel 2-biphenylmorpholine derivatives, on squalene synthase activity in rabbit and human liver microsomes, lipid biosynthesis, low-density lipoprotein (LDL) receptor expression and LDL protein uptake as well as apoB secretion in HepG2 cells. Both EP2306 and EP2302 inhibited squalene synthase activity dose-dependently. In rabbit liver microsomes, the IC50 values were 33 microM for EP2306 and 0.

The role of halogen substitution in classical cannabinoids: a CB1 pharmacophore model.

The presence of halogens within the classical cannabinoid structure leads to large variations in the compounds' potencies and affinities for the CB1 receptors. To explore the structure activity relationships within this class of analogs we have used a series of halogen-substituted (-)-Delta8-tetrahydrocannabinol analogs and compared their affinities for the CB1 cannabinoid receptor. Our results indicate that halogen substitution at the end-carbon of the side chain leads to an enhancement in affinity with the bulkier halogens (Br, I) producing the largest effects.