RT Journal Article
SR Electronic
T1 Analysis of Mammalian Carboxylesterase Inhibition by Trifluoromethylketone-Containing Compounds
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 713
OP 723
DO 10.1124/mol.105.021683
VO 71
IS 3
A1 Randy M. Wadkins
A1 Janice L. Hyatt
A1 Carol C. Edwards
A1 Lyudmila Tsurkan
A1 Matthew R. Redinbo
A1 Craig E. Wheelock
A1 Paul D. Jones
A1 Bruce D. Hammock
A1 Philip M. Potter
YR 2007
UL http://molpharm.aspetjournals.org/content/71/3/713.abstract
AB Carboxylesterases (CE) are ubiquitous enzymes that hydrolyze numerous ester-containing xenobiotics, including complex molecules, such as the anticancer drugs irinotecan (CPT-11) and capecitabine and the pyrethroid insecticides. Because of the role of CEs in the metabolism of many exogenous and endogenous ester-containing compounds, a number of studies have examined the inhibition of this class of enzymes. Trifluoromethylketone-containing (TFK) compounds have been identified as potent CE inhibitors. In this article, we present inhibition constants for 21 compounds, including a series of sulfanyl, sulfinyl, and sulfonyl TFKs with three mammalian CEs, as well as human acetyl- and butyrylcholinesterase. To examine the nature of the slow tight-binding inhibitor/enzyme interaction, assays were performed using either a 5-min or a 24-h preincubation period. Results showed that the length of the preincubation interval significantly affects the inhibition constants on a structurally dependent basis. The TFK-containing compounds were generally potent inhibitors of mammalian CEs, with Ki values as low as 0.3 nM observed. In most cases, thioether-containing compounds were more potent inhibitors then their sulfinyl or sulfonyl analogs. QSAR analyses demonstrated excellent observed versus predicted values correlations (r2 ranging from 0.908–0.948), with cross-correlation coefficients (q2) of ∼0.9. In addition, pseudoreceptor models for the TKF analogs were very similar to structures and models previously obtained using benzil- or sulfonamide-based CE inhibitors. These studies indicate that more potent, selective CE inhibitors, containing long alkyl or aromatic groups attached to the thioether chemotype in TFKs, can be developed for use in in vivo enzyme inhibition. The American Society for Pharmacology and Experimental Therapeutics