Chemical and Pharmaceutical Bulletin p. 817 - 827 (2000)
Update date:2022-09-26
Topics:
Kamiya, Shoji
Shirahase, Hiroaki
Yoshimi, Akihisa
Nakamura, Shohei
Kanda, Mamoru
Matsui, Hiroshi
Kasai, Masayasu
Takahashi, Kenji
Kurahashi, Kazuyoshi
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,b-Dimethyl-1-octylindolin-7- yl)-2,2-dimethylpropanamide 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.
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