title: Studies on acyl-CoA: cholesterol acyltransferase (ACAT) inhibitory effects and enzyme selectivity of F-1394, a pantotheic acid derivative.
abstract: (1s,2s)-2-[3-(2,2-Dimethylpropyl)-3-nonylureido]aminocyclohe xane-1-yl 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionate (F-1394), a pantotheic acid derivative, is a newly synthesized inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT). In the present study, we investigated the inhibitory effects of F-1394 on the activities of ACAT. F-1394 reduced the ACAT activities in rat liver microsomes, homogenate of rabbit small intestinal mucosa and lysate of J774 macrophages with IC50 values of 6.4 nM, 10.7 nM and 32 nM, respectively. The kinetic studies showed that F-1394 exerted competitive-type inhibition, and the Ki values in liver and small intestinal ACAT were 4.0 nM and 9.9 nM, respectively. The inhibitory effects of F-1394 on the activity of ACAT were more potent than that of other ACAT inhibitors or hypolipidemic agents. The study on enzyme selectivity indicated that F-1394 did not affect 3-hydroxy-3-methylglutaryl CoA reductase, acyl-CoA synthetase and cholesterol esterase. F-1394 weakly inhibited the activity of lecithine:cholesterol acyltransferase (LCAT) originating from rat plasma. The inhibitory potency of F-1394 for the activity of liver microsomal ACAT was 4,690-fold stronger than that for the activity of LCAT. These findings indicate that F-1394 is a potent and selective inhibitor of ACAT, and its inhibition manner is the competitive type.
authors.affiliation: Pharmaceuticals Research Laboratories, Fujirebio Inc., Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Kusunoki
authors.forename: K
authors.initials: K
authors.lastname: Aragane
authors.forename: T
authors.initials: T
authors.lastname: Yamaura
authors.forename: H
authors.initials: H
authors.lastname: Ohnishi
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors; D003510:Cyclohexanes / Q000494:pharmacology*; D004146:Dioxanes / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
chemical_list: D000924:Anticholesteremic Agents; D003510:Cyclohexanes; D004146:Dioxanes; C094918:F 1394; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002785:Sterol O-Acyltransferase; D003066:Coenzyme A Ligases