Testing the Lipoxygenase Inhibitor BPN-27332 as Acute Phase Stroke Treatment in the SPAN Network

本项目的目标是评估一种新的12/15脂氧合酶（12/15-LOX）抑制剂， SPAN网络中缺血性卒中的临床前啮齿动物模型。为此，BPN-27332将在 在多个实验室的严格条件下与其他临床前卒中治疗进行比较。 12/15-LOX在啮齿类动物和人类的缺血性梗塞周围区域中均显示上调。它 导致神经元细胞死亡，以及削弱血脑屏障和水肿 阵其中编码12/15-LOX的基因已被敲除的Alox 15（-/-）小鼠在 短暂局灶性缺血模型。通过NIH蓝图神经疗法项目， BPN-27332，一种新型的高选择性12/15-LOX抑制剂。在短暂局灶性缺血的小鼠模型中， BPN-27332在急性期给药时可减少梗死面积。保护是长期的， 在实验性卒中后四周仍观察到行为益处，具有优异的ADME和PK/PD 特性.我们现在建议以设盲方式检测BPN-27332，与溶剂进行比较，但也与 其他治疗方式。在目标1中，化合物经过严格的质量控制措施，包括 通过HPLC和质谱法验证同一性和纯度以及体外功效测试。在目标2中， 将化合物运送至协调中心，分发至试验中心，BPN-27332将 在缺血性中风的啮齿动物模型中进行广泛测试。成功完成这些研究将准备 BPN-27332用于人类患者的临床试验，这将有望导致急需的新治疗 缺血性中风患者的最佳选择。

The goal of this project is to evaluate a novel inhibitor of the 12/15 lipoxygenase (12/15-LOX) enzyme in preclinical rodent models of ischemic stroke within the SPAN network. To this end, BPN-27332 will be tested in comparison with other preclinical stroke treatments under rigorous conditions in multiple laboratories. 12/15-LOX has been shown to be up-regulated in the ischemic peri-infarct area in both rodents and humans. It contributes to both neuronal cell death, as well as to weakening of the blood – brain barrier and edema formation. Alox15(-/-) mice in which the gene encoding 12/15-LOX has been knocked out, are protected in models of transient focal ischemia. Through the NIH Blueprint Neurotherapeutics Program we have developed BPN-27332, a novel and highly selective inhibitor of 12/15-LOX. In a mouse model of transient focal ischemia, BPN-27332 reduces infarct size when given in the acute phase. Protection is long lasting, with significant behavioral benefits still seen four weeks after the experimental stroke with excellent ADME and PK/PD properties. We now propose to test BPN-27332 in a blinded fashion in comparison with vehicle, but also with other treatment modalities. In Aim 1, the compound is subjected to rigorous quality control measures, including verification of identity and purity by HPLC and mass spectrometry and in vitro efficacy testing. In Aim 2, the compound will be shipped to the Coordinating Center for distribution to the testing sites, where BPN-27332 will be extensively tested in rodent models of ischemic stroke. Successful completion of these studies will ready BPN-27332 for clinical trials in human patients, which will hopefully lead to a much needed new treatment option for patients with ischemic strokes.