Phosphaisocoumarins as a new class of potent inhibitors for pancreatic cholesterol esterase.

Abstract

Due to the importance of pancreatic cholesterol esterase (CEase) as a potential target in atherosclerosis and for the development of hypocholesterolemic agents, there are increasing interests in designing and synthesizing CEase inhibitors. In the present study, we prepared forty-five isocoumarin phosphorus analogues (i.e., phosphaisocoumarins) and investigated the inhibition of these compounds on the CEase. The results showed that some phosphaisocoumarins could act as potent inhibitors of CEase. The most potent inhibitors, compounds 9d, 10a and 12e give IC50 values of 4.8 microM, 2.3 microM and 1.9 microM, respectively. The inhibition mechanism and kinetic characterization studies indicate that they are reversible competitive inhibitors.

• Authors: Baojian Li, Binhua Zhou, Hailiang Lu, Lin Ma, Ai-Yun Peng
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 45 Issue 5 Pg. 1955-63 (May 2010) ISSN: 1768-3254 [Electronic] France
• PMID: 20149492 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2010. Published by Elsevier Masson SAS.

Chemical References

• Enzyme Inhibitors
• Isocoumarins
• Sterol Esterase

Topics

• Animals
• Drug Design
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Isocoumarins (chemical synthesis, chemistry, pharmacology)
• Kinetics
• Molecular Structure
• Pancreas (enzymology)
• Stereoisomerism
• Sterol Esterase (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Swine