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
| Autor: | Komath Damodaran, Paul Beroza, Randy M. Wadkins, Christopher L. Morton, Janice L. Hyatt, Philip M. Potter, Kyoung Jin P. Yoon, Richard E. Lee, Mary K. Danks |
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| Rok vydání: | 2004 |
| Předmět: |
Diarrhea
Models Molecular Quantitative structure–activity relationship Quantitative Structure-Activity Relationship Pharmacology Irinotecan chemistry.chemical_compound medicine Animals Humans Enzyme Inhibitors Active metabolite Butyrylcholinesterase Sulfonamides Biological activity Acetylcholinesterase Antineoplastic Agents Phytogenic Intestines chemistry Biochemistry Toxicity Molecular Medicine Camptothecin Rabbits Glucuronide Carboxylic Ester Hydrolases medicine.drug |
| Zdroj: | Molecular pharmacology. 65(6) |
| ISSN: | 0026-895X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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