Development of Dual GABAA and alpah7 Nicotinic Receptor Modulators for AD

描述（由申请人提供）：各种药物发现工作集中在创建将增加烟碱胆碱能神经传递以增强痴呆症认知的分子。除了烟碱系统之外，含有α 5亚基的GABAA受体（GABAA α 5受体）可以调节海马神经传递。选择性抑制海马体中的GABAA α 5受体功能增强了学习和记忆的动物模型中的认知，表明GABAA α 5的抑制也可能是可行的治疗策略。与α 7 nAChR一样，据报道GABAA α 5受体的下降在轻度AD等病症中相对较少。此外，α 7 nAChR或GABAA α 5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，这表明有助于学习和记忆的两个治疗靶点在AD大脑中被保留并发挥作用，并且可以同时靶向。我们已经鉴定了α 7 nAChR和GABAA α 5受体的双重变构调节剂，称为522-054，在我们先前的R21资助（AG 028800）的资助下合成。拟议的工作将支持备份化合物优化，初始药物安全性评估，化学放大，药物配方，毒理学研究以及使用522-054作为初始临床前开发候选药物向FDA提交IND申请。我们将评价当前提案中合成的522-054和备用化合物：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-糖蛋白转运蛋白结合。这些研究将有助于预测和消除可能存在潜在药物安全性问题的候选化合物。当这些药物安全性研究中出现主要候选药物时，我们将确定一种提供最简单和最具成本效益的合成方法的化学路线。该优化途径将用于生产用于正式毒理学研究的GLP材料。还将为毒理学研究设计适当的制剂，以使试验种属（犬、啮齿动物等）中的药物暴露水平最大化。毒理学研究将确定暴露于药物是否会导致显著的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导致向FDA提交IND申请，以启动第一个烟碱和GABAA受体双重变构调节剂用于治疗阿尔茨海默病（AD）认知缺陷的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 Alzheimer's Disease (AD).