Discovery of novel selective inhibitors of human intestinal carboxylesterase for the amelioration of irinotecan-induced diarrhea: synthesis, quantitative structure-activity relationship analysis, and biological activity.

Abstract

The dose-limiting toxicity of the highly effective anticancer agent 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (irinotecan; CPT-11) is delayed diarrhea. This is thought to be caused by either bacteria-mediated hydrolysis of the glucuronide conjugate of the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) or direct conversion of CPT-11 to SN-38 by carboxylesterases (CE) in the small intestine. After drug administration, a very high level of CPT-11 is present in the bile; this is deposited into the duodenum, the region of the gut with the highest levels of CE activity. Hence, it is likely that direct conversion of the drug to SN-38 is partially responsible for the diarrhea associated with this agent. In an attempt to ameliorate this toxicity, we have applied Target-Related Affinity Profiling to identify novel CE inhibitors that are selective inhibitors of the human intestinal enzyme (hiCE). Seven inhibitors, all sulfonamide derivatives, demonstrated greater than 200-fold selectivity for hiCE compared with the human liver CE hCE1, and none was an inhibitor of human acetylcholinesterase or butyrylcholinesterase. Quantitative structure-activity relationship (QSAR) analysis demonstrated excellent correlations with the predicted versus experimental Ki values (r2 = 0.944) for hiCE. Additionally, design and synthesis of a tetrafluorine-substituted sulfonamide analog, which QSAR indicated would demonstrate improved inhibition of hiCE, validated the computer predictive analyses. These and other phenyl-substituted sulfonamides compounds are regarded as lead compounds for the development of effective, selective CE inhibitors for clinical applications.

• Authors: Randy M Wadkins, Janice L Hyatt, Kyoung Jin P Yoon, Christopher L Morton, Richard E Lee, Komath Damodaran, Paul Beroza, Mary K Danks, Philip M Potter
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 65 Issue 6 Pg. 1336-43 (Jun 2004) ISSN: 0026-895X [Print] United States
• PMID: 15155827 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents, Phytogenic
• Enzyme Inhibitors
• Sulfonamides
• Irinotecan
• Carboxylic Ester Hydrolases
• Camptothecin

Topics

• Animals
• Antineoplastic Agents, Phytogenic (adverse effects, metabolism)
• Camptothecin (adverse effects, analogs & derivatives, metabolism)
• Carboxylic Ester Hydrolases (antagonists & inhibitors)
• Diarrhea (chemically induced, drug therapy)
• Enzyme Inhibitors (chemistry, therapeutic use)
• Humans
• Intestines (enzymology)
• Irinotecan
• Models, Molecular
• Quantitative Structure-Activity Relationship
• Rabbits
• Sulfonamides (chemical synthesis, chemistry, therapeutic use)