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

Abstract

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.

Key words

Acyl-CoA:cholesterol acyltransferase inhibitors - 1-Alkyl-7-amido-indoline derivatives, LDL oxidation, lipid peroxidation - lipophilicity, oral absorption, water solubility - Antioxidants

• References

• 1 Sliskovic DR, White AD. Therapeutic potential of ACAT inhibitors as lipid lowering and anti-atherosclerotic agents. Trends Pharmacol Sci. 1991; 12: 194-199
• 2 Heinonen TM. Acyl coenzyme A:cholesterol acyl transferase inhibition:potential atherosclerosis therapy or springboard for other discoveries?. Expert Opin Investig Drugs. 2002; 11: 1519-1527
• 3 Buhman KF, Accad M, Farese Jr RV. Mammalian acyl-CoA:cholesterol acyltransferases. Biochim Biophys Acta. 2000; 1529: 142-154
• 4 Rudel LL, Lee RG, Cockman TL. Acyl coenzyme A:cholesterol acyl transferase types 1 and 2:structure and function in atherosclerosis. Curr Opin Lipidol. 2001; 12: 121-127
• 5 Matsuda K. ACAT inhibitors as antiatherosclerotic agents: Compounds and mechanisms. Med Res Rev. 1994; 14: 271-305
• 6 Sliskovic DR, Picard JA, Krause BR. ACAT inhibitors: The search for a novel and effective treatment of hypercholesterolemia and atherosclerosis. Prog Med Chem. 2002; 39: 121-171
• 7 Homan R, Hamelehle KL. Influence of membrane partitioning on inhibitors of membrane-bound enzymes. J Pharm Sci. 2001; 90: 1859-1867
• 8 Harris WS, Dujovne CA, von Bergmann K, Neal J, Akester J, Windsor SL et al. Effects of the ACAT inhibitor CL 277,082 on cholesterol metabolism in humans. Clin Pharmacol Ther. 1990; 48: 189-194
• 9 Kita T, Nagano Y, Yokode M, Ishii K, Kume N, Ooshima A et al. Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbit, an animal model for familial hypercholesterolemia. Proc Natl Acad Sci USA. 1987; 84: 5928-5931
• 10 Pratico D, Tangirala RK, Rader DJ, Rokach J, FitzGerald GA. Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice. Nat Med. 1998; 4: 1189-1192
• 11 Kamiya S, Shirahase H, Yoshimi A, Nakamura S, Kanda M, Matsui H et al. Bioavailable acyl-CoA:cholesterol acyltransferase inhibitor with anti-peroxidative activity: synthesis and biological activity of novel indolinyl amide and urea derivatives. Chem Pharm Bull (Tokyo). 2000; 48: 817-827
• 12 Field FJ, Mathur SN. beta-sitosterol: esterification by intestinal acylcoenzyme A: cholesterol acyltransferase (ACAT) and its effect on cholesterol esterification. J Lipid Res. 1983; 24: 409-417
• 13 Heider JG, Pickens CE, Kelly LA. Role of acyl CoA:cholesterol acyltransferase in cholesterol absorption and its inhibition by 57-118 in the rabbit. J Lipid Res. 1983; 24: 1127-1134
• 14 Breugnot C, Iliou JP, Privat S, Robin F, Vilaine JP, Lenaers A. In vitro and ex vivo inhibition of the modification of low-density lipoprotein by indapamide. J Cardiovasc Pharmacol. 1992; 20: 340-347
• 15 Kamiya S, Shirahase H, Nakamura S, Kanda M, Matsui H, Yoshimi A et al. A novel series of thromboxane A₂ synthetase inhibitors with free radical scavenging and anti-peroxidative activities. Chem Pharm Bull (Tokyo). 2001; 49: 563-571
• 16 Nakamura S, Kamiya S, Shirahase H, Kanda M, Yoshimi A, Tarumi T et al. Hypolipidemic and antioxidant activity of the novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor KY-455 in rabbits and hamsters. Arzneimittel-Forschung (Drug Research). 2004; 54: 102-108