Formulation and evaluation of a prostate cancer drug

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Metabolism of arichidonic acid by 12-lipoxygenase results in the formation of 12(s)-hydroxy eicosatetraenoic acid, which exhibits profound biological activity and plays an important role in tumor cell survival, angiogenesis, and metastases. Prostate cancer is the most commonly diagnosed neoplasm and second leading cause of male death in the United States. Human prostate cancer cells express increased platelet-type 12- lipoxygenase, which may serve as a survival factor and assist in their metastasis to bone. BMD 188 is an inhibitor of platelet- type 12-lipoxygenase that is effective in inducing in inducing apoptosis of prostate cancer cells as well as inhibiting angiogenesis both in vitro and in vivo. It was shown to be an effective anti-cancer agent in several animal models of prostate cancer. BMD188 is a hydrophobic compound with little water solubility. In the present application, we propose to develop new formulations of MBD188 for increased bioavailability. Co- solvent and solid dispersion strategies will be applied to make BMD188 more water soluble. The oral bioavailability of the formulated BMD188 will be tested in an abbreviated pharmacokinetics study. As a prerequisite to the pharmacokinetics study, a quantitative reverse phase HPLC method will be developed for MBD188. Scale-up procedures for the synthesis of BMD188 to research 5-10 g batches will also be developed to assist the formulation and preliminary pharmacokinetic studies. Analytical standards of two compounds (BMD189 and a hydroxylamine), which are potential impurities in BMD188 will also be synthesized using protocols developed earlier for their use in the HPLC method development for BMD188.