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：
8236959
负责人：
KELVIN W. GEE
金额：
$ 42.03万
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 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8236959
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建分子，这些分子会增加烟碱胆碱能神经递质以增强痴呆症的认知。除烟碱系统外，含有A5亚基（GABAA A5受体）的GABAA受体还可以调节海马神经传递。在海马中对GABAA A5受体功能的选择性抑制可以增强动物学习和记忆模型中的认知，这表明抑制GABAA A5也可能是一种可行的治疗策略。像A7 NACHR一样，在轻度AD等条件下，GABAA A5受体的下降相对幸免。此外，对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，这表明两个治疗目标可以保留学习和记忆，并在AD大脑中起作用，并且可以同时靶向。我们已经确定了A7 NACHRS和GABAA A5受体的双重变构调节剂，称为522-054，该受体根据我们以前的R21 Grant（AG028800）的资金合成。拟议的工作将支持备份化合物优化，初始药物安全评估，化学量表，药物制剂，毒理学研究以及使用522-054作为初始铅临床前开发候选者向FDA提出IND应用。我们将评估522-054及其在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+通道的相互作用（心脏QT延长的预测因子），与药物代谢的P450细胞色素酶，血浆蛋白质蛋白，血清蛋白和p glycoprotein transporterin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。当这些药物安全研究中出现主要候选人时，我们将确定一条化学途径，提供最简单，最具成本效益的合成方式。该优化的途径将用于生产GLP材料进行正式毒理学研究。还将为毒理学研究设计一种适当的表述，以最大程度地提高测试物种（狗，啮齿动物等）中药物水平的暴露水平。毒理学研究将确定对药物的暴露是否引起重大毒理学事件及其最大耐受剂量。拟议的研究的成功完成将在向FDA提交IND应用方面，以启动I期临床研究，并使用烟碱和GABAA受体的第一个双重变构调节剂来治疗AD的认知缺陷。