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

Vivreon Biosciences - NIA SBIR # PA-16-091 项目摘要 Vivreon Biosciences很高兴申请NIA SBIR征集#PA-16-091。比夫雷翁 Biosciences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Ca 2+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Ca 2+释放激活的Ca 2+（CRAC）通道以阻断小胶质细胞增生。比夫雷翁 寻求NIA的资金，以弥合发现和发展之间的差距。我们将 通过药物化学优化我们有前途的先导化合物系列。后 成功完成该计划，我们的临床前候选人将是第一个 特异性靶向CRAC通路用于AD中的神经保护，因此包含 这是对抗AD的全新工具。 Vivreon发现了一种具有口服生物利用度的先导化合物系列， 非常有效地进入中枢神经系统（CNS）， 欧文测试的CNS完整性，并证明在小鼠模型中的神经保护作用， 小神经胶质增生（实验性自身免疫性脑炎）。铅系列抑制 通过以nM效力阻断CRAC通道活性来抑制小胶质细胞增生;抑制M1 NF-κB 活性，同时保留M2吞噬作用。我们将改善这些有利的 通过药物化学导致优化， 筛选我们的领导提出了几条修改路线，可以改善 药物样的性质，这些途径将被追求，以确定一个临床前的候选人 分子适合于未来的研究性新药（IND）使能研究。的 将使用适用于AD的动物模型（5XFAD，Dr. Blurton- Jones，加州大学欧文分校）。本提案的最终目的是综合和 用于AD治疗的第一种CRAC通道抑制剂的表征。

Vivreon Biosciences – NIA SBIR # PA-16-091 Project Summary 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.