DEVELOPMENT OF PRODRUGS POSSESSING A NITRIC OXIDE DONOR DIAZEN-1-IUM-1,2-DIOLATE MOIETY USING IN VITRO/IN SILICO PREDICTIONS

摘要

The present invention provides a method of using a physiologically-based pharmacokinetic model to select a prodrug molecule (NO-X) comprising a therapeutic agent X (e.g. nonsteroidal anti- inflammatory drug, (NSAID) ) an d an appropriate nitric oxide donor NO. The NSAID can be a non- selective or selective cyclooxygenase inhibitor or other biocompatible compound comprisin g a carboxyl group. The pharmacokinetic model uses in vitro and/or in silico data to estimate an optimal set of parameters that can predict whether a particular NO-X candidate is capable of producing desirable therapeutic effects, e.g. enhanced antiif lammatory activity, reduced intestinal, cardia c and renal toxicity. Accordingly, the present invention can greatly enhance proper selection of an appropriate candidate for drug development, thereby minimizing development time and conserving costs.