Pancreatic cholesterol esterase (CE) has a dual function in the absorption of dietary cholesterol. First, CE catalyzes the hydrolysis of cholesterol esters to liberate cholesterol for absorption; second, CE transports cholesterol from micelles to the surface of the enterocyte where absorption takes place. There is also evidence that CE functions within the enterocyte to re-esterify cholesterol in the pathway leading to the formation of chylomicrons. It is our hypothesis that inhibition of any of these functions of CE would provide a new approach to the treatment of hypercholesterolemia through limiting the bioavailability of dietary cholesterol. This proposal will focus on the development of irreversible inhibitors of CE for prevention of the hydrolysis of cholesterol ester. CE is a serine esterase with a catalytic mechanism that is similar to that of serine proteases. We propose to develop selective irreversible inhibitors of CE.
Our specific aims are: (1) to develop versatile schemes for the synthesis of haloenol lactones such as substituted 6-chloropyrones as potential irreversible inhibitors of cholesterol esterase, and (2) to use molecular modeling and kinetic studies to reduce structure-activity relationships for the development of selective inhibitors of CE. Our preliminary work demonstrates the versatility of the synthetic schemes that we have developed. Selectivity will be determined at the enzyme level by screening compounds for their rates of inactivation of CE compared with the proteases chymotrypsin, trypsin and elastase, all of which are serine proteases that function within the intestine.
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