Arzneimittelforschung 2008; 58(12): 666-672
DOI: 10.1055/s-0031-1296569
Editio Cantor Verlag Aulendorf (Germany)

Relationships between Lipophilicity and Biological Activities in a Series of Indoline-based Anti-oxidative Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitors

Kenji Takahashi
1   Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Kyoto, Japan
Kazuyoshi Kunishiro
1   Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Kyoto, Japan
Masayasu Kasai
1   Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Kyoto, Japan
Tomohiro Miike
1   Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Kyoto, Japan
Kazuyoshi Kurahashi
1   Pharmacology Division, Radioisotope Research Center, Kyoto University, Kyoto, Japan
Hiroaki Shirahase
1   Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Kyoto, Japan
› Author Affiliations
Further Information

Publication History

Publication Date:
19 December 2011 (online)


A novel series of 1-alkyl-7-amido-indo-line-based anti-oxidative acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors have been reported and are expected to lower plasma cholesterol levels due to the inhibition of intestinal and hepatic ACAT, and to inhibit cholesterol accumulation in macrophages due to the inhibition of low density lipoprotein (LDL) oxidation. In the present study, relationships between lipophilicity and biological activities were examined in 13 derivatives. Lipophilicity (logP) increased and water solubility decreased with dependence on the number of carbons in the 1-alkyl chain. Inhibitory activity against both in vitro intestinal ACAT and LDL oxidation positively correlated with logP; however, the optimum logP, at which the level of activity is maximal, differed between these two effects. Inhibitory activity against in vitro plasma oxidation was weakly dependent on logP. Plasma concentrations of the derivatives after oral administration at 10 mg/kg correlated negatively with logP and positively with water solubility. Hypocholesterolemic activity in rats fed a high-cholesterol diet, and the ratio of Cmax and IC50 values for ACAT inhibition, an index of effective plasma concentration, positively and highly correlated with logP, while ex vivo inhibitory activity against plasma oxidation in rats, and the ratio of Cmax and IC50 values for the inhibition of plasma oxidation negatively correlated with logP. In conclusion, in vitro ACAT inhibitory and anti-oxidative activity were differently dependent on logP, and intestinal absorption was inversely dependent on lipophilicity in indoline-based anti-oxidative ACAT inhibitors. The hypocholesterolemic effect positively correlated and the ex vivo anti-oxidative effect negatively correlated with lipophilicity. Optimum logP as a bioavailable dual inhibitor against in vivo ACAT and lipid peroxidation was estimated to be 3.8 (1-pentyl and 1-isopentyl derivatives) in the present series of derivatives.

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