Formulation and evaluation of a prostate cancer drug

花生四烯酸经12-脂氧合酶代谢生成12(s)-羟基二十碳四烯酸，具有丰富的生物活性，在肿瘤细胞存活、血管生成和转移过程中发挥重要作用。前列腺癌是美国最常见的肿瘤，也是男性死亡的第二大原因。人类前列腺癌细胞表达增加的血小板型12-脂氧合酶，这可能是一种生存因子并有助于其转移到骨。BMD 188是血小板型12-脂氧合酶抑制剂，在体外和体内均能有效诱导前列腺癌细胞凋亡，抑制血管生成。在几种前列腺癌动物模型中显示它是一种有效的抗癌剂。BMD188是一种疏水化合物，水溶性很小。在目前的应用中，我们建议开发新的MBD188配方，以提高生物利用度。将采用共溶剂和固体分散策略来提高BMD188的水溶性。制剂BMD188的口服生物利用度将在一项简短的药代动力学研究中进行测试。作为开展MBD188药代动力学研究的前提，本研究将建立MBD188的反相高效液相色谱定量分析方法。还将制定合成BMD188以研究5-10克批次的放大程序，以协助配方和初步药代动力学研究。BMD188中潜在杂质的两种化合物（BMD189和一种羟胺）的分析标准品也将使用先前开发的方案合成，用于BMD188的HPLC方法开发。

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.