Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 50, Issue 23, Pages 5727-5734Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm0706867
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Funding
- NCI NIH HHS [P30 CA21765, CA9468, CA108775] Funding Source: Medline
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Carboxylesterases (CE) are ubiquitous enzymes responsible for the detoxification of xenobiotics, including numerous clinically used drugs. Therefore, the selective inhibition of these proteins may prove useful in modulating drug half-life and bioavailability. Recently, we identified 1,2-diones as potent inhibitors of CEs, although little selectivity was observed in the inhibition of either human liver CE (hCE1) or human intestinal CE (hiCE). In this paper, we have further examined the inhibitory properties of ethane-1,2-diones toward these proteins and determined that, when the carbonyl oxygen atoms are cis-coplanar, the compounds demonstrate specificity for hCE1 Conversely, when the dione oxygen atoms are not planar (or are transcoplanar), the compounds are more potent at hiCE inhibition. These properties have been validated in over 40 1,2-diones that demonstrate inhibitory activity toward at least one of these enzymes. Statistical analysis of the results confirms the correlation (P < 0.001) between the dione dihedral angle and the preferential inhibition of either hiCE or hCE1 Overall, the results presented here define the parameters necessary for small molecule inhibition of human CEs.
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