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.

阿尔茨海默病（AD）是一种破坏性痴呆，没有疾病修饰疗法。根据 FDA，AD临床试验超过200个，但到目前为止，在减缓AD进展方面没有取得任何成功。这种连续 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。 作为一种神经退行性疾病，神经元死亡是AD发病的基础。当前治疗 策略集中于对抗与AD有关的神经毒性损伤（即，Aβ磷酸化tau蛋白自由基 炎性毒素等）。由于神经元的防御能力较弱， 死亡是防御和侮辱之间的不平衡。我们实验室的研究表明， 在患有G蛋白偶联受体（GPCR）激酶-5的受试者中，AD的中枢胆碱能系统受损 （GRK 5）缺乏;后者出现在衰老和AD中。受损的神经元防御系统 对过量Aβ或缺氧引发的变性易感，而活性邻氨基苯甲酰胺 CN 168衍生物能够预防GRK 5缺陷型小鼠的神经变性和认知障碍。 瑞典APP转基因（GAP）小鼠。因此，新出现的证据支持这样一种观点，即加强 神经元防御提高了神经元死亡阈值，从而增加了各种神经毒性损伤的难度， 引发神经元死亡这种新的治疗策略侧重于防御，而不是个人的侮辱， 同时对抗多种侮辱。这种治疗努力不会取代，而是补充， 现有的治疗努力，因此为发现AD的疾病修饰疗法带来了新的希望。 虽然CN 168在概念验证（proof-of-concept，ESTA）水平上被证明在预防认知障碍方面是有效的， 下降，我们还注意到CN 168有两个违反五个类药规则（MW>500; LogP>5），中枢作用持续时间短。这需要进一步优化药代动力学（PK） 在未来的临床研究之前，CN 168的性质。由于CN 168已被证明具有体内疗效， 由于CN 168对毒蕈碱受体-2表现出极好的选择性和敏感性，我们建议使用CN 168作为 活性药物成分（API）和使用前药方法改善其脑与血浆（B2 P）的比率。 在本项目中，我们将通过比较CN 168的三种精心挑选的前药的PK特性来表征它们， 并在研究新药（IND）前进行药效学（PD）和毒理学研究 申请最终选择的前药。我们将通过以下三个具体目标实现我们的目标： 目标1。API（CN 168）及其前药的药代动力学：为此，我们将（1）合成 CN 168及其前药，其量足以进行体内PK分析;然后（2）进行PK分析 表征和选择具有改善的B2 P比率的优于CN 168的前药。 目的2：所选CN 168前药的药效学和毒理学：为此，我们 将进行（1）PD研究，用于靶点接合验证、有效剂量范围确定和评价 GRK 5缺失小鼠与野生型小鼠沿着的潜在副作用;和（2）药物毒性研究，包括 体外和体内急性毒性、重复给药毒性和长期（9个月）毒性。 目标3：药品cGMP生产和IND申请：为此，我们将（1）生产 最终前药在美国国内的cGMP设施;和（2）准备向FDA提交IND申请。 AD是世界上最持久和最具破坏性的痴呆症。然而，临床试验旨在寻找一种 AD的疾病改善疗法相继失败。通过对GRK 5缺陷的数十年研究 在AD中，我们提出了一种新的治疗策略，该策略与现有的 专注于个人侮辱的治疗努力。我们已经获得了API CN 168的证据。进一步 其PK性质的改善将确保其在临床前阶段的成功，并使其易于实现成功的 转化为未来的临床试验。我们相信这是一个机会，开发一种疾病修饰治疗AD。