Formulation and evaluation of a prostate cancer drug

花生四烯酸经12-脂氧合酶代谢形成12（S）-羟基二十碳四烯酸，其表现出深刻的生物活性并在肿瘤细胞存活、血管生成和转移中起重要作用。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。 人前列腺癌细胞表达增加的血小板型12-脂氧合酶，其可作为存活因子并协助其转移到骨。BMD 188是血小板型12-脂氧合酶的抑制剂，其在体外和体内均有效诱导前列腺癌细胞凋亡以及抑制血管生成。在几种前列腺癌动物模型中，它被证明是一种有效的抗癌剂。BMD 188是一种疏水性化合物，水溶性很低。在本申请中，我们提出开发MBD 188的新制剂以提高生物利用度。共溶剂和固体分散策略将用于使BMD 188更易溶于水。将在简化的药代动力学研究中测试配制的BMD 188的口服生物利用度。作为药代动力学研究的先决条件，将开发MBD 188的定量反相HPLC方法。还将开发用于合成BMD 188以研究5-10 g批次的规模扩大程序，以协助制剂和初步药代动力学研究。两种化合物（BMD 189和一种羟胺）的分析标准品（BMD 188中的潜在杂质）也将使用早期开发的方案合成，用于BMD 188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.