Optimization and preclinical characterization of anthranilamide derivatives for Alzheimer prevention

用于预防阿尔茨海默病的邻氨基苯甲酰胺衍生物的优化和临床前表征

• 批准号: 10514633
• 负责人: WILLIAM Z. SUO
• 金额: --
• 依托单位: KANSAS CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10514633
• 关键词: Address; Affect; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; American; Amyloid beta-Protein; Animal Model; Animals; Attention; Attenuated; Autoreceptors; Award; Axon; Biological Availability; Brain; Cell Death; Cell membrane; Chronic; Clinic; Clinical Research; Clinical Trials; Cognitive deficits; Communication; Complement; Cyclic GMP; Data; Defense Mechanisms; Dementia; Disease; Disease Progression; Dose; Drug Kinetics; Drug toxicity; Elderly; Ensure; Equilibrium; Etiology; Evaluation; Exhibits; Failure; Foundations; Free Radicals; Functional disorder; Future; G protein coupled receptor kinase; GRK5 gene; Genes; Goals; Health; Hippocampus; Human; Hypoxia; Impaired cognition; Impairment; In Vitro; Individual; Inflammatory; Investigational Drugs; Investigational New Drug Application; Knock-out; Lead; Life; Memory; Mus; Muscarinic Acetylcholine Receptor; Nerve Degeneration; Neurodegenerative Disorders; Neurons; New Drug Approvals; Nobel Prize; Oral; Pathogenesis; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacy (field); Physiological Processes; Plasma; Population; Predisposition; Prodrugs; Property; Proteins; Research; Role; Running; Serum; Synapses; System; Testing; Therapeutic; Toxic effect; Toxicology; Toxin; Transgenic Organisms; Translations; Transportation; United States Food and Drug Administration; Wild Type Mouse; Work; acute toxicity; aged; antagonist; axonopathy; basal forebrain; cholinergic; desensitization; drug candidate; improved; in vivo; manufacture; mild cognitive impairment; neuron loss; neurotoxic; novel therapeutic intervention; pre-clinical; presynaptic; prevent; screening; side effect; success; tau-1

Alzheimer's disease (AD) is a devastating dementia without a disease-modifying therapy. According to FDA, AD clinical trials are over 200 but so far have made zero success in slowing AD progression. This continuous failure speaks for the difficulty of this task and calls for re-evaluating the existing therapeutic strategies. As a neurodegenerative disorder, neuronal death is fundamental to AD pathogenesis. Current therapeutic strategies concentrate on combating neurotoxic insults implicated in AD (i.e., Aβ, phospho-tau, free radicals, inflammatory toxins, etc.). Less attention has been paid to strengthening neuronal defense given that neuronal death is an imbalance between its defense and insult. Studies in our lab revealed that defense mechanism of central cholinergic system in AD is compromised in subjects with G protein-coupled receptor (GPCR) kinase-5 (GRK5) deficiency; the latter appears during aging and worsens in AD. The compromised neuronal defense leads to susceptibility to degeneration triggered by excessive Aβ or hypoxia whereas an active anthranilamide derivative CN168 was able to prevent the neurodegeneration and the cognitive impairments in GRK5-deficient Swedish APP transgenic (GAP) mice. Therefore, emerging evidence supports the idea that strengthening neuronal defense raises neuronal death threshold thus increasing the difficulty for various neurotoxic insults to trigger neuronal death. This new therapeutic strategy focuses on the defense rather than individual insult but works against multiple insults simultaneously. Such a therapeutic effort will not replace, but rather complement, the existing therapeutic effort, therefore bringing new hope for discovering disease-modifying therapy for AD. While CN168 was proven to be effective at the level of proof-of-concept (PoC) in preventing cognitive decline in GAP mice, we also noticed that CN168 has two violations of the five drug-likeness rules (MW>500; LogP>5), with a short duration of central action. This requires further optimization of the pharmacokinetic (PK) properties of CN168 prior to future clinical studies. Because CN168 has proven in vivo efficacy and previously demonstrated superb selectivity and sensitivity towards muscarinic receptor-2, we propose to use CN168 as the active pharmaceutical ingredient (API) and to improve its brain to plasma (B2P) ratio using prodrug approach. In this project, we will characterize three carefully selected prodrugs of CN168 by comparing their PK properties, and study their pharmacodynamics (PD) and toxicology before preparing the investigational new drug (IND) application for the finally selected prodrug(s). We will achieve our goals with the following three Specific Aims: Aim 1. Pharmacokinetics of the API (CN168) and its prodrugs: in this aim we will (1) synthesize CN168 and its prodrugs in quantities sufficient for their PK profiling in vivo; and then (2) carry out their PK characterization and select the prodrug(s) outperforming CN168 with improved B2P ratios. Aim 2: Pharmacodynamics and toxicology of the selected CN168 prodrugs: in this aim, we will perform (1) PD studies for target engagement verification, effective dose range finding, and evaluation of potential side effects in GRK5-deifienct mice along with wild type mice; and (2) Drug toxicity studies, including in vitro and in vivo acute toxicity, and repeated dosing toxicity and long-term (9 months) toxicity. Aim 3: Drug cGMP manufacturing and IND application: In this aim, we will (1) manufacture the final prodrugs domestically in the US at a cGMP facility; and (2) prepare for the IND application to FDA. AD is the most persistent and devastating dementia worldwide. Yet the clinical trials aimed at finding a disease-modifying therapy for AD have failed one after another. Through decades of research on GRK5 deficiency in AD we came up a new therapeutic strategy that is distinct from, but may complement with, the existing therapeutic efforts that focus on individual insult. We have obtained PoC evidence with the API CN168. Further improvement of its PK properties will ensure its success at preclinical stage and ease its way towards a successful translation to future clinical trial. We believe this is a chance to develop a disease-modifying therapy for AD.

阿尔茨海默氏病（AD）是一种毁灭性的痴呆症，没有修改疾病的疗法。根据 FDA，AD临床试验超过200个，但到目前为止，在减慢AD进展方面取得了零成功。这继续 失败说明了这项任务的困难，并要求重新评估现有的治疗策略。 作为神经退行性疾病，神经元死亡对AD发病是基础。当前的疗法 策略专注于对抗AD中实施的神经毒性损伤（即Aβ，磷酸-TAU，自由基，， 炎性毒素等）。考虑到神经元，对加强神经元防御的关注较少 死亡是其防御与侮辱之间的不平衡。我们实验室的研究表明，国防机制 在具有G蛋白偶联受体（GPCR）激酶-5的受试者中，AD中的中央胆碱能系统被妥协 （GRK5）缺乏症；后者出现在衰老期间，并在AD中恶化。受损的神经元防御线索 易感性易于退化，由过度的Aβ或缺氧触发，而活性蒽酰胺 衍生CN168能够预防GRK5缺乏症的神经变性和认知障碍 瑞典应用转基因（GAP）小鼠。因此，新兴的证据支持加强的观念 神经元防御提高了神经元死亡阈值，因此增加了各种神经毒性感染的困难 触发神经元死亡。这种新理论策略的重点是辩护，而不是个人侮辱，但 简单地反对多种侮辱。这样的治疗努力不会取代，而是完成，而是 现有的治疗努力，因此为发现AD的疾病改良疗法带来了新的希望。 虽然CN168被证明在预防认知方面的概念验证水平（POC）水平上有效 间隙小鼠的下降，我们还注意到CN168对五个毒品规则有两种违反（MW> 500； logp> 5），中央动作的持续时间很短。这需要进一步优化药代动力学（PK） 在未来的临床研究之前，CN168的特性。因为CN168已证明体内效率和以前 我们对毒蕈碱受体-2具有极好的选择性和敏感性，我们建议将CN168用作 活性药物成分（API），并使用前药方法改善其大脑对血浆（B2P）的比率。 在这个项目中，我们将通过比较其PK属性（即 并在准备研究新药之前先研究他们的药效学（PD）和毒理学（IND） 最终选择的前药的申请。我们将通过以下三个具体目标来实现我们的目标： AIM 1。API的药代动力学（CN168）及其前药：在此目的中，我们将（1）合成 CN168及其在体内PK分析的数量量；然后（2）执行他们的PK 表征并选择具有提高B2P比率的Protrug（S）优于CN168。 目标2：选定CN168前药的药效学和毒理学：在此目标中，我们 将执行（1）PD研究，以进行目标参与验证，有效的剂量范围查找和评估 GRK5-脱米克小鼠的潜在副作用以及野生型小鼠； （2）药物毒性研究，包括 体外和体内急性毒性，并反复剂量毒性和长期（9个月）的毒性。 目标3：药物CGMP制造和IND应用：在此目标中，我们将（1）制造 在美国CGMP设施的国内最终前药； （2）为IND申请做准备。 广告是全球最持久和毁灭性的痴呆症。然而，旨在找到一个临床试验 AD的疾病改良疗法接一个地失败了。通过数十年的GRK5缺乏症的研究 在广告中，我们提出了一种新的理论策略，与现有的不同，但可能与现有 专注于个人侮辱的治疗努力。我们已经获得了使用API​​ CN168的POC证据。更远 其PK属性的改善将确保其在临床前阶段的成功，并简化成功的方式 转化为未来的临床试验。我们认为，这是开发用于AD疾病的疗法的机会。