Hyatt_2007_J.Med.Chem_50_1876

Reference

Title : Selective inhibition of carboxylesterases by isatins, indole-2,3-diones - Hyatt_2007_J.Med.Chem_50_1876
Author(s) : Hyatt JL , Moak T , Hatfield MJ , Tsurkan L , Edwards CC , Wierdl M , Danks MK , Wadkins RM , Potter PM
Ref : Journal of Medicinal Chemistry , 50 :1876 , 2007
Abstract :

Carboxylesterases (CE) are ubiquitous enzymes thought to be responsible for the metabolism and detoxification of xenobiotics. Numerous clinically used drugs including Demerol, lidocaine, capecitabine, and CPT-11 are hydrolyzed by these enzymes. Hence, the identification and application of selective CE inhibitors may prove useful in modulating the metabolism of esterified drugs in vivo. Having recently identified benzil (diphenylethane-1,2-dione) as a potent selective inhibitor of CEs, we sought to evaluate the inhibitory activity of related 1,2-diones toward these enzymes. Biochemical assays and kinetic studies demonstrated that isatins (indole-2,3-diones), containing hydrophobic groups attached at a variety of positions within these molecules, could act as potent, specific CE inhibitors. Interestingly, the inhibitory potency of the isatin compounds was related to their hydrophobicity, such that compounds with clogP values of <1.25 were ineffective at enzyme inhibition. Conversely, analogs demonstrating clogP values>5 routinely yielded Ki values in the nM range. Furthermore, excellent 3D QSAR correlates were obtained for two human CEs, hCE1 and hiCE. While the isatin analogues were generally less effective at CE inhibition than the benzils, the former may represent valid lead compounds for the development of inhibitors for use in modulating drug metabolism in vivo.

PubMedSearch : Hyatt_2007_J.Med.Chem_50_1876
PubMedID: 17378546

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Citations formats

Hyatt JL, Moak T, Hatfield MJ, Tsurkan L, Edwards CC, Wierdl M, Danks MK, Wadkins RM, Potter PM (2007)
Selective inhibition of carboxylesterases by isatins, indole-2,3-diones
Journal of Medicinal Chemistry 50 :1876

Hyatt JL, Moak T, Hatfield MJ, Tsurkan L, Edwards CC, Wierdl M, Danks MK, Wadkins RM, Potter PM (2007)
Journal of Medicinal Chemistry 50 :1876