title: Bioavailable acyl-CoA: cholesterol acyltransferase inhibitor with anti-peroxidative activity: synthesis and biological activity of novel indolinyl amide and urea derivatives.
abstract: We synthesized a series of indoline derivatives with an amide or urea moiety and examined their inhibitory effects on acyl-CoA:cholesterol acyltransferase (ACAT) activity, lipid-peroxidation and serum cholesterol levels in experimental animals. Among the derivatives synthesized, a series of N-(1-alkyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamides++ + potently inhibited rabbit intestinal ACAT activity and lipid-peroxidation of rat brain homogenate. The effect on ACAT activity was related to the length of the alkyl chain at the 1-position of indoline. N-(4,6-Dimethyl-1-octylindolindolin-7-yl)-2,2-dimethylpropanami de hydrochloride (55) showed inhibitory effects on intestinal and hepatic ACAT activity slightly weaker than those of YM-750, and an inhibitory effect on low density lipoprotein (LDL)-peroxidation similar to that of probucol. Compound 55 also reduced serum cholesterol at 10 mg/kg/d in 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 an effective concentration against hepatic ACAT activity and LDL-peroxidation. In conclusion, compound 55 is a novel bioavailable ACAT inhibitor with anti-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.
authors.affiliation: Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kamiya
authors.forename: H
authors.initials: H
authors.lastname: Shirahase
authors.forename: A
authors.initials: A
authors.lastname: Yoshimi
authors.forename: S
authors.initials: S
authors.lastname: Nakamura
authors.forename: M
authors.initials: M
authors.lastname: Kanda
authors.forename: H
authors.initials: H
authors.lastname: Matsui
authors.forename: M
authors.initials: M
authors.lastname: Kasai
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Kurahashi
mesh_terms: D000588:Amines / Q000737:chemistry*; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D006224:Cricetinae; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013055:Spectrophotometry, Infrared; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D014508:Urea / Q000737:chemistry*
chemical_list: D000588:Amines; D004791:Enzyme Inhibitors; D014508:Urea; D002784:Cholesterol; D002785:Sterol O-Acyltransferase