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Improved, Selective, Human Intestinal Carboxylesterase Inhibitors Designed to Modulate 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (Irinotecan; CPT-11) Toxicity.

Improved, Selective, Human Intestinal Carboxylesterase Inhibitors Designed to Modulate 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (Irinotecan; CPT-11) Toxicity.

Authors :
Latorya D. Hicks
Janice L. Hyatt
Shana Stoddard
Lyudmila Tsurkan
Carol C. Edwards
Randy M. Wadkins
Philip M. Potter
Source :
Journal of Medicinal Chemistry. Jun2009, Vol. 52 Issue 12, p3742-3752. 11p.
Publication Year :
2009

Abstract

CPT-11 is an antitumor prodrug that is hydrolyzed by carboxylesterases (CE) to yield SN-38, a potent topoisomerase I poison. However, the dose limiting toxicity delays diarrhea that is thought to arise, in part, from activation of the prodrug by a human intestinal CE (hiCE). Therefore, we have sought to identify selective inhibitors of hiCE that may have utility in modulating drug toxicity. We have evaluated one such class of molecules (benzene sulfonamides) and developed QSAR models for inhibition of this protein. Using these predictive models, we have synthesized a panel of fluorene analogues that are selective for hiCE, demonstrating no cross reactivity to the human liver CE, hCE1, or toward human cholinesterases, and have Kivalues as low as 14 nM. These compounds prevented hiCE-mediated hydrolysis of the drug and the potency of enzyme inhibition correlated with the clogP of the molecules. These studies will allow the development and application of hiCE-specific inhibitors designed to selectively modulate drug hydrolysis in vivo. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00222623
Volume :
52
Issue :
12
Database :
Academic Search Index
Journal :
Journal of Medicinal Chemistry
Publication Type :
Academic Journal
Accession number :
42321852
Full Text :
https://doi.org/10.1021/jm9001296