Development of Dual GABAA and alpah7 Nicotinic Receptor Modulators for AD

描述（由申请人提供）：各种药物发现工作的重点是创造能够增加尼古丁胆碱能神经传递的分子，以增强痴呆症患者的认知。除烟碱系统外，含有a5亚基的GABAA受体（GABAA a5受体）可调节海马神经传递。在学习和记忆动物模型中，选择性抑制海马GABAA a5受体功能可增强认知，提示抑制GABAA a5可能也是一种可行的治疗策略。与a7 nachr一样，据报道，在轻度AD等情况下，GABAA a5受体的下降相对较少。此外，a7 nAChRs或GABAA a5受体的选择性调节剂的测试在认知和记忆的临床研究中显示出积极的结果。重要的是，这表明两个辅助学习和记忆的治疗靶点在阿尔茨海默病大脑中被保留并发挥作用，并且可以同时靶向。我们已经确定了a7 nAChRs和GABAA a5受体的双变构调节剂，命名为522-054，在我们之前的R21基金（AG028800）的资助下合成。拟议的工作将支持备用化合物优化、初始药物安全性评估、化学放大、药物配方、毒理学研究以及将522-054作为初始主要临床前开发候选药物向FDA提交IND申请。我们将评估522-054和当前提案中合成的备用化合物：与其他已知受体类型的交叉反应性，与hERG K+通道（心脏QT间期延长的预测因子）的相互作用，与药物代谢P450细胞色素酶的相互作用，血浆蛋白和p糖蛋白转运体结合。这些研究将有助于预测和消除可能有潜在药物安全问题的候选化合物。当从这些药物安全性研究中出现一个主要候选药物时，我们将确定一条化学路线，提供最简单和最具成本效益的合成方法。这条优化的路线将用于生产GLP材料，用于正式的毒理学研究。还将为毒理学研究设计适当的配方，以最大限度地暴露于试验物种（狗，啮齿动物等）的药物水平。毒理学研究将确定暴露于药物是否会引起重大毒理学事件及其最大耐受剂量。拟议研究的成功完成将最终向FDA提交IND申请，以启动首个用于治疗AD认知缺陷的尼古丁和GABAA受体双变构调节剂的I期临床研究。

DESCRIPTION (provided by applicant): A variety of drug discovery efforts are focused on creation of molecules that will increase nicotinic cholinergic neurotransmission to augment cognition in the dementias. In addition to the nicotinic system, GABAA receptors containing the a5 subunit (GABAA a5 receptors) can modulate hippocampal neurotransmission. Selective inhibition of GABAA a5 receptor function in the hippocampus enhances cognition in animal models of learning and memory, suggesting that inhibition of GABAA a5 may also be a viable therapeutic strategy. Like a7 nAChRs, the decline in GABAA a5 receptors is reported to be relatively spared in conditions like mild AD. Moreover, tests of selective modulators of either a7 nAChRs or GABAA a5 receptors show positive results in clinical studies for cognition and memory. Importantly, this suggests that two therapeutic targets that subserve learning and memory are preserved and functional in AD brains and can be targeted simultaneously. We have identified a dual allosteric modulator of both a7 nAChRs and GABAA a5 receptors, termed 522-054, synthesized under funding from our previous R21 grant (AG028800). The proposed work will support back-up compound optimization, initial drug safety assessment, chemistry scale-up, drug formulation, toxicological studies and submission of an IND application to the FDA using 522-054 as the initial lead preclinical development candidate. We will evaluate 522-054 and back-up compounds synthesized in the current proposal for: cross reactivity with other known receptor types, interaction with the hERG K+ channel (a predictor for cardiac QT prolongation), interaction with drug- metabolizing P450 cytochrome enzymes, plasma protein and p-glycoprotein transporter binding. These studies will help predict and eliminate candidate compounds that may have potential drug safety issues. When a lead candidate emerges from these drug safety studies we will identify a chemistry route that affords the simplest and most cost-effective means of synthesis. This optimized route will be used to produce GLP material for formal toxicological studies. An appropriate formulation will also be devised for toxicological studies to maximize exposure to levels of drug in the test species (dog, rodent, etc.) The toxicological studies will determine whether exposure to the drug causes significant toxicological events and its maximal tolerated dose. Successful completion of the proposed studies will culminate in the filing of an IND application with the FDA to initiate phase I clinical studies with the first dual allosteric modulator of nicotinic and GABAA receptors for treating the cognitive deficits of AD.