CL 277,082: a novel inhibitor of ACAT-catalyzed cholesterol esterification and cholesterol absorption.
CL 277,082 (I) was found to be a potent inhibitor of acyl CoA:cholesterol acyltransferase (ACAT, EC 2.3.1.26) in microsomes from a variety of tissues with IC50 values of 0.14 microM for intestinal mucosal microsomes, 0.74 microM for liver, and 1.18 microM for rat adrenal. I was also shown to inhibit ACAT in cultured smooth muscle cells (IC50 = 0.8 microM) and was found to be specific in inhibiting cholesterol esterification since it did not inhibit fatty acid incorporation into triglycerides or phospholipids. Also, other cholesterol esterifying enzymes such as lecithin:cholesterol acyltransferase (LCAT) and pancreatic cholesterol esterase were not inhibited by I, nor was esterification of retinol by acyl CoA:retinol acyltransferase (ARAT) from intestinal mucosal microsomes inhibited. I was a potent inhibitor of cholesterol absorption in cholesterol-fed rats by markedly inhibiting increases in liver and serum cholesterol concentration (ED50 = 5.2 mg/kg per day) while increasing the excretion of neutral 14C-labeled sterol in the feces.
Largis
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American Cyanamid Company, Medical Research Division, Pearl River, NY 10965.
Wang
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DeVries
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Schaffer
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D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002788:Cholesterol Esters / Q000096:biosynthesis; D002791:Cholesterol, Dietary / Q000378:metabolism*; D046508:Culture Techniques; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D000924:Anticholesteremic Agents; D002788:Cholesterol Esters; D002791:Cholesterol, Dietary; D010671:Phenylurea Compounds; C050492:CL 277082; D002785:Sterol O-Acyltransferase