Metabolism of arachidonic 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 metastasis. 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. BMD188 is an inhibitor of platelet-type 12-lipoxygenase that is effective 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 anticancer agent in several animal models of prostate cancer. BMD1 88 is a hydrophobic compound with little water solubility. In the present application, we proposed to develop new formulations of BMD188 in Phase I, for increased bioavailability. Based on the success of abbreviated pharmacokinetic studies performed in Phase I, the co-solvent and/or solid dispersion strategies will be modified to achieve >30% oral bioavailability of BMD188 in a complete pharmacokinetic study in rats. The HPLC method developed in Phase I will be validated and modified appropriately to study the stability of BMD188 in formulations, using standard procedures. A complete stability study will be performed on the BMD188 formulations. Based on the degradation products identified in the stability study, analytical standards will be synthesized for use in the long term stability study of BMD188. Formulations that show >30% oral bioavailability will be tested in three animal models of prostate cancer, viz. SCID-hu bone model for metastasis, Matrigel implantation model for angiogenesis, and SCID orthotopic model for primary tumor growth. Finally, BMD188 synthesis will scaled-up to >50 g batches and the process will be standardized for an eventual GMP production as a goal.
Thesaurus Terms: antineoplastic, arachidonate, drug design /synthesis /production, drug screening /evaluation, enzyme inhibitor, lipoxygenase, pharmacokinetics, prostate neoplasm hydroxylamine, oral administration high performance liquid chromatography, male
