Lead Optimization of CRAC Channel Inhibitors for the Treatment of Alzheimer's Disease

Vivreon Biosciences很高兴申请NIA SBIR征集#PA-16-091。威力龙 生物科学是一家创新的生命科学公司，正在开发一系列新颖的 用于治疗阿尔茨海默病(AD)的小分子、钙通道抑制剂。 我们的先导化合物系列通过一种全新的机制实现神经保护- 抑制钙释放激活的钙通道以阻断小胶质细胞。威力龙 寻求NIA资金，以弥合发现和开发之间的差距。我们会 通过药物化学优化我们前景看好的先导化合物系列。vt.在.的基础上 成功完成该计划，我们的临床前候选人将是第一个 针对阿尔茨海默病的神经保护的CRAC通路，因此包括一个 在对抗AD的战斗中的全新工具。 Vivreon发现了一种具有口服生物利用度的铅化合物系列，可穿透 非常有效地进入中枢神经系统(CNS)，在 中枢神经系统完整性的Irwin测试，并在小鼠模型中展示了神经保护作用 小胶质细胞增多症(实验性自身免疫性脑炎)。铅系列抑制了 NM抑制CRAC通道活性，抑制M1、NF-κB的小胶质细胞增多症 活性，同时保持M2吞噬功能。我们将在这些有利条件的基础上加以改进 通过药物化学引导优化性能，然后进行生物优化 放映。我们的销售线索提出了几种可能导致改进的修改方法 类似药物的特性，这些路线将被用来确定临床前候选 适合未来研究新药(IND)的分子。这个 候选人将使用适合AD的动物模型来确定(5XFAD，Blurton博士- 琼斯，加州大学欧文分校)。这项建议的最终目标是综合和 首个用于AD治疗的CRAC通道抑制剂的特征。

Vivreon Biosciences is pleased to apply for NIA SBIR Solicitation #PA-16-091. Vivreon Biosciences is an innovative life sciences company that is developing a series of novel small molecule, Ca2+ channel inhibitors for the treatment of Alzheimer’s disease (AD). Our lead compound series achieves neuroprotection by an entirely new mechanism – inhibition of Ca2+ release-activated Ca2+ (CRAC) channels to block microgliosis. Vivreon seeks NIA funding to bridge the gap between discovery and development. We will optimize our promising lead compound series through medicinal chemistry. Upon successful completion of the program, our preclinical candidate will be the first to specifically target the CRAC pathway for neuroprotection in AD, thus comprising an entirely new tool in the battle against AD. Vivreon has discovered a lead compound series with oral bioavailability that penetrates into the central nervous system (CNS) very efficiently, shows no neurotoxicity in the Irwin test of CNS integrity, and demonstrates neuroprotection in a mouse model of microgliosis (experimental autoimmune encephalitis). The lead series inhibits microgliosis by blocking CRAC channel activity with nM potency; suppressing M1 NF-κB activity, while preserving M2 phagocytosis. We will improve on these favorable properties through medicinal chemistry lead optimization followed by biological screening. Our lead presents several routes for modification that could lead to improved drug-like properties, and these routes will be pursued to identify a preclinical candidate molecule suitable for future Investigational New Drug (IND)-enabling studies. The candidate will be identified using an animal model suitable for AD (5XFAD, Dr. Blurton- Jones, University of California, Irvine). The final aim for this proposal is synthesis and characterization of the first CRAC channel inhibitor for AD therapy.