Wadkins_2004_Mol.Pharmacol_65_1336

Reference

Title : 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 - Wadkins_2004_Mol.Pharmacol_65_1336
Author(s) : Wadkins RM , Hyatt JL , Yoon KJ , Morton CL , Lee RE , Damodaran K , Beroza P , Danks MK , Potter PM
Ref : Molecular Pharmacology , 65 :1336 , 2004
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.

PubMedSearch : Wadkins_2004_Mol.Pharmacol_65_1336
PubMedID: 15155827

Related information

Citations formats

Wadkins RM, Hyatt JL, Yoon KJ, Morton CL, Lee RE, Damodaran K, Beroza P, Danks MK, Potter PM (2004)
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
Molecular Pharmacology 65 :1336

Wadkins RM, Hyatt JL, Yoon KJ, Morton CL, Lee RE, Damodaran K, Beroza P, Danks MK, Potter PM (2004)
Molecular Pharmacology 65 :1336