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 use molecular modeling and kinetic studies to deduce structure-activity relationships for the development of selective inhibitors of CE, and (2) to use versatile schemes described in this proposal for the synthesis of haloenol lactones such as substituted 4-chloroisocoumarins as potential irreversible inhibitors of cholesterol esterase. 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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
2R15HL068598-02
Application #
6898103
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Rabadan-Diehl, Cristina
Project Start
2002-02-15
Project End
2009-03-31
Budget Start
2005-04-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$225,000
Indirect Cost
Name
University of New Mexico
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
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Heidrich, John E; Contos, Linda M; Hunsaker, Lucy A et al. (2004) Inhibition of pancreatic cholesterol esterase reduces cholesterol absorption in the hamster. BMC Pharmacol 4:5