Bioavailable acyl-CoA: Cholesterol acyltransferase inhibitor with anti-peroxidative activity: Synthesis and biological activity of novel indolinyl amide and urea derivatives

We synthesized a series of indoline derivatives with an amide or urea moiet y and examined their inhibitory effects on acyl-CoA: cholesterol acyltransf erase (ACAT) activity, lipid-peroxidation and serum cholesterol levels in e xperimental animals. Among the derivatives synthesized, a series of N-(1-al kyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamides potently inhibited r abbit intestinal ACAT activity and lipid-peroxidation of rat brain homogena te. The effect on ACAT activity was related to the length of the alkyl chai n at the 1-position of indoline, N-(4,6-Dimethyl-1-octylindolin-7-yl)-2,2-d imethylpropanamide hydrochloride (55) showed inhibitory effects on intestin al and hepatic ACAT activity slightly weaker than those of YM-750, and an i nhibitory effect on low density lipoprotein (LDL)-peroxidation similar to t hat of probucol, Compound 55 also reduced serum cholesterol at 10 mg/kg/d i n hyperlipidemic rats and 20 mg/kg/d in normolipidemic hamsters, The plasma concentration of 55 reached 716 ng/ml in dogs (10 mg/kg, p.o.), which is a n effective concentration against hepatic ACAT activity and LDL-peroxidatio n, In conclusion, compound 55 is a novel bioavailable ACAT inhibitor with a nti-peroxidative activity and is thus a promising anti-atherosclerotic and anti-hyperlipidemic drug. Indoline proved to be a useful pharmacophore for molecular design of new anti-peroxidative drugs.