Development of Dual GABAA and alpah7 Nicotinic Receptor Modulators for AD

描述(申请人提供)：各种药物发现的努力集中在创造分子，将增加尼古丁胆碱能神经传递，以增强痴呆症的认知。除了尼古丁系统，含有a5亚单位的GABAA受体(GABAA a5受体)还可以调节海马神经传递。选择性地抑制海马区的GABAA a5受体功能可以增强学习和记忆动物模型的认知能力，这表明抑制GABAA a5也可能是一种可行的治疗策略。与a7 nAChRs一样，GABAA a5受体的下降据报道在轻度AD等情况下相对较少。此外，对A7nAChRs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，这表明帮助学习和记忆的两个治疗靶点在阿尔茨海默病大脑中保存并发挥作用，可以同时靶向。我们已经确定了A7 nAChRs和GABAA a5受体的双重变构调节剂，命名为522-054，由我们之前的R21资助(AG028800)合成。拟议的工作将支持后备化合物优化、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作为初始主导临床前开发候选者向FDA提交IND申请。我们将评估522-054和在当前建议中合成的备用化合物：与其他已知受体类型的交叉反应、与HERG K通道(心脏QT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存在潜在药物安全问题的候选化合物。当这些药物安全性研究的主要候选者出现时，我们将确定一条提供最简单和最具成本效益的合成方法的化学路线。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)中的药物水平。毒理学研究将确定接触该药物是否会导致重大毒理学事件及其最大耐受量。拟议研究的成功完成将最终导致向FDA提交IND申请，以启动第一个用于治疗阿尔茨海默病(AD)认知缺陷的尼古丁和GABAA受体的双重变构调节剂的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 Alzheimer's Disease (AD).