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.