Development of Dual GABAA and alpah7 Nicotinic Receptor Modulators for AD

开发治疗 AD 的双 GABAA 和 alpah7 烟碱受体调节剂

基本信息

批准号：
8443820
负责人：
KELVIN W. GEE
金额：
$ 36.63万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8443820
关键词：
Acute Adverse effects Alzheimer&apos s Disease Animal Model Animals Area Back Benchmarking Binding Biological Assay Biological Availability Blood Brain Canis familiaris Cardiac Chemical Structure Chemicals Chemistry Chronic Clinical Clinical Research Cognition Cognitive deficits Contractor Contracts Cyclic GMP Cytochrome P450 Dementia Development Dosage Forms Dose Drug Exposure Drug Formulations Drug Kinetics Electrophysiology (science)Enzyme Interaction Enzymes Event Exposure to Funding Grant Hippocampus (Brain)Human In Vitro Kilogram Laboratories Lead Learning Maximum Tolerated Dose Memory Metabolic Methods Modification Mus Nicotine Nicotinic Receptors Nootropic Agents Oral P-Glycoprotein Pharmaceutical Preparations Phase Phase I Clinical Trials Plasma Proteins Potassium Channel Principal Investigator Protein Binding Radial Reporting Research Institute Research Personnel Rodent Route Safety System Testing Therapeutic Time Toxic effect Toxicokinetics Translating Work arm base chemical synthesis cholinergic cost cost effective cross reactivity design drug discovery gamma-Aminobutyric Acid meetings neurotransmission phase 1 study pre-clinical prevent programs receptor receptor function research clinical testing safety study scale up therapeutic target

项目摘要

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.

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烟碱胆碱能神经传递以增强痴呆症认知能力的分子。除了烟碱系统外，含有a5亚基的GABAA受体（GABAA a5受体）可以调节海马神经传递。选择性抑制海马 GABAA a5 受体功能可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。据报道，与 a7 nAChR 一样，GABAA a5 受体的下降在轻度 AD 等情况下相对较少。此外，a7 nAChR 或 GABAA a5 受体的选择性调节剂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，这表明促进学习和记忆的两个治疗靶标在 AD 大脑中得到了保留和发挥作用，并且可以同时靶向。我们已经确定了 a7 nAChR 和 GABAA a5 受体的双重变构调节剂，称为 522-054，是在我们之前的 R21 资助 (AG028800) 的资助下合成的。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、毒理学研究以及使用 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 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且最具成本效益的合成方法的化学路线。该优化路线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配方，以最大限度地提高测试物种（狗、啮齿动物等）的药物暴露水平。毒理学研究将确定药物暴露是否会导致显着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治疗 AD 认知缺陷的 I 期临床研究。