The main objective of the phase II investigation is the further in-depth evaluation of three newly synthesized phosphate or disulfide containing water-soluble prodrugs of Triapine TM and further evaluation of the parent drug itself. These include more extensive prodrug bioconversion studies both in vitro and in vivo along with in vivo efficacy evaluation of the TriapineTM prodrugs prepared in our phase I research. On the basis of the results obtained from these studies as well as from the information collected through phase I investigation, we intend to propose additional TriapineTM prodrugs for synthesis. The best TripineTM prodrug emerging from this investigation will then be evaluated against the parent drug. The best compound from this comparative study will be selected for development. Specifically, we are planning (1) to scale-up the synthesis of the two phosphate- and one disulfide-bearing TriapineTM prodrugs; (2) to synthesize a few selected new TriapineTM prodrugs; (3) to determine the water-solubility and the stability of the newly synthesized prodrugs; (4) to carry out an in vitro bioconversion study to determine the rate of activation of these prodrugs upon incubation either with alkaline phosphatase or with glutathione (GSH); (5) to investigate an in vivo bioconversion study of 3-AP prodrugs via IV route; (6) to perform analytical method development/validation; (7) to carry out in vivo efficacy evaluation of these prodrugs in various solid tumor models; (8) to perform metabolism and toxicology studies on the candidate selected for development.
Successful completion of Phase II study will provide additional water soluble prodrugs of 3-AP. Along with the parent 3-AP, these 3-AP prodrugs may possess desirable biological and pharmaceutical properties and will be useful antitumor agents against a variety of cancers.
