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

Vivreon生物科学有限责任公司 卡罗尔峡谷路4940号110号套房 加州圣地亚哥，邮编92121 邮箱：milton@vivreonbiosciences.com Vivreon生物科学-NIA SBIR#PA-20-272：AG055205 项目摘要 Vivreon生物科学公司高兴地申请NIA SBIR补编#PA-20-272，以解决药物化学问题 我们目前资助的SBIR AG055205中的优化问题，“CRAC通道抑制剂的领先优化 阿尔茨海默病的治疗“。迫切需要补充资金来降低我们的计划之前的风险 向发展研究进军。Vivreon生物科学公司正在开发一系列新型小分子钙离子 治疗阿尔茨海默病(AD)的通道抑制剂。我们的铅化合物系列实现了 一种全新的神经保护机制--抑制钙释放激活的钙通道 阻塞性小胶质细胞增多症。Vivreon寻求NIA资金，以弥合发现和开发之间的差距。我们会 进行化学和生物实验，以确定和验证新的临床候选治疗药物。 在成功完成该计划后，我们的临床候选人将成为第一个专门针对CRAC的 阿尔茨海默病的神经保护途径，从而构成了对抗阿尔茨海默病的一个全新的工具。 Vivreon发现了一系列具有口服生物利用度的铅化合物，可以渗透到中枢神经系统 中枢神经系统(CNS)非常有效，在中枢神经系统(CNS)完整性的欧文测试中没有神经毒性， 并在阿尔茨海默病模型中展示了神经保护。铅系列通过以下途径抑制小胶质细胞增生 抑制类M1的NF-κB活性，同时增强类M2的活性 吞噬作用。在推进开发之前，需要补充资金来降低我们的计划的风险 学习。一些有希望的化合物由于某些性质和 在选择开发化合物之前，需要进一步优化铅以消除负债。

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.