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

Vivreon Biosciences，LLC 卡罗尔峡谷路4940号套件110 San Diego，CA milton@vivreonbiosciences.com Vivreon Biosciences-NIA SBIR #PA-20 - 272：AG055205 项目摘要 Vivreon Biosciences很高兴申请NIA SBIR补充#PA-20 - 272，以解决药物化学问题 在我们目前资助的SBIR AG055205中，"用于以下目的的CRAC通道抑制剂的先导优化" 老年痴呆症的治疗补充资金是迫切需要去风险我们的计划之前， 到发展研究。Vivreon Biosciences正在开发一系列新型小分子Ca2+， 用于治疗阿尔茨海默病（AD）的通道抑制剂。我们的铅化合物系列达到 通过一种全新的机制-抑制Ca2+释放激活的Ca2+（CRAC）通道， 阻断小胶质细胞增生。Vivreon寻求NIA的资助，以弥合发现和开发之间的差距。我们将 进行化学和生物学实验，以确定和验证新的临床候选治疗药物。 成功完成该计划后，我们的临床候选人将成为第一个专门针对CRAC的人 AD神经保护通路，因此构成了对抗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，可渗透到中枢神经系统中 在中枢神经系统（CNS）完整性的欧文试验中显示无神经毒性， 并在阿尔茨海默病模型中显示出神经保护作用。铅系列抑制小胶质细胞增生， 以nM效力阻断CRAC通道活性;抑制M1样NF-κ B活性，同时增强M2样NF-κ B活性， 吞噬作用在推进开发之前，需要补充资金来降低我们计划的风险 问题研究几种有前途的化合物由于某些性质而阻碍了进一步的开发， 在选择开发化合物之前，需要进一步优化先导物以消除不利因素。

Vivreon Biosciences, LLC 4940 Carroll Canyon Rd. Suite 110 San Diego, CA 92121 milton@vivreonbiosciences.com Vivreon Biosciences – NIA SBIR # PA-20-272: AG055205 Project Summary Vivreon Biosciences is pleased to apply for NIA SBIR Supplement #PA-20-272 to address medicinal chemistry optimization issues in our currently funded SBIR AG055205, “Lead Optimization of CRAC Channel Inhibitors for the Treatment of Alzheimer's Disease”. Supplemental funding is urgently required to de-risk our program prior to advancing to development studies. Vivreon Biosciences 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 perform chemistry and biology experiments to identify and validate a new clinical candidate therapeutic drug. Upon successful completion of the program, our clinical 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 central nervous system (CNS) integrity, and demonstrates neuroprotection in models of Alzheimer’s disease. The lead series inhibits microgliosis by blocking CRAC channel activity with nM potency; suppressing M1-like NF-κB activity, while enhancing M2-like phagocytosis. Supplemental funding is required to de-risk our program prior to advancing to development studies. Several promising compounds are hampered from further development due to certain properties and further lead optimization is required to remove liabilities prior to selection of a development compound.