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Carboxylesterases are responsible for the metabolism of a whole host of different drugs. This includes anticancer agents such as capecitabine and CPT-11, the narcotics heroin and cocaine, as well as popular drugs such as Demerol, Lunesta, Tamiflu, etc. Since carboxylesterases can activate and inactivate these compounds, potentially, selective inhibition of these enzymes could be used to modulate drug toxicity and/or half-life. With this goal in mind, we have screened for and identified selective inhibitors of these proteins. This includes a panel of benzene sulfonamides that are specific for the human intestinal carboxylesterase, and a series of ethane-1,2-diones that are generic inhibitors for this class of enzymes. Using these reagents, we have determined the mechanism of substrate hydrolysis by carboxylesterases, developed potent nM inhibitors of these proteins and we are currently synthesizing second generation compounds that have improved biological properties. These inhibitors modulate CPT-11 toxicity in cell culture models, and they are currently being evaluated for their ability to ameliorate the delayed diarrhea that is associated with drug treatment. If successful, we envisage that these compounds may have clinical utility in reducing the toxicity that occurs following CPT-11 treatment.