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型的12/15脂氧合酶(12/15-LOX)酶抑制剂 SPAN网络内缺血性卒中的临床前啮齿动物模型。为此，将在以下地点测试BPN-27332 在多个实验室的严酷条件下与其他临床前卒中治疗方法进行比较。 12/15-LOX已被证明在啮齿动物和人类的脑梗塞周围缺血区表达上调。它 导致神经细胞死亡，以及血脑屏障的减弱和水肿 队形。编码12/15-LOX基因被敲除的ALOX15(-/-)小鼠在 短暂性局灶性脑缺血模型。通过NIH蓝图神经治疗计划，我们开发了 BPN-27332，一种新型的高选择性的12/15-LOX抑制剂。在短暂性局灶性脑缺血的小鼠模型中， 在急性期给药时，bpn-27332可缩小梗塞面积。保护是长期的，具有重要的意义 ADME和PK/PD良好的实验性卒中后四周仍可看到行为益处 属性。我们现在建议以盲目的方式测试BPN-27332，与车辆进行比较，但也与 其他治疗方式。在目标1中，该化合物受到严格的质量控制措施，包括 用高效液相色谱、质谱仪和体外药效试验进行鉴定和纯度鉴定。在目标2中， 化合物将运往协调中心，然后分发到测试地点，在那里，BPN-27332将 在缺血性中风的啮齿动物模型上进行广泛测试。成功完成这些研究将做好准备。 Bpn-27332用于人类患者的临床试验，有望带来亟需的新疗法 缺血性中风患者的选择。

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.