The use of prodrugs as a method for improving the ADME properties of a potential drug candidate are well documented. However, in some cases the liberation of a stoichiometric amount of the pro-moiety can lead to toxicity concerns. To overcome this potential pitfall a series of prodrugs based on a 6,6a-dihydrofuro[3,2-d]oxazol-5(3aH)-one motif were designed as 'traceless' prodrugs for caspase inhibitors.  In vivo hydrolysis of the lactone functional group is sufficient to liberate the active inhibitor in vivo and in vitro without producing any cleavage by-product. When dosed orally in rats an improvement in oral availability is observed. These results suggest such prodrugs may have the potential to be used to enhance the systemic exposure of peptidomimetic caspase inhibitors in indications where oral administration is desirable.

"Traceless" prodrugs for peptidomimetic caspase inhibitors

246th National Meeting (2013)

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