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) 是一种毁灭性的痴呆症，没有缓解疾病的疗法。根据 FDA 开展的 AD 临床试验超过 200 项，但迄今为止在减缓 AD 进展方面取得的成功为零。这种连续的 失败说明了这项任务的难度，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 发病机制的基础。目前治疗 策略集中于对抗 AD 中涉及的神经毒性损伤（即 Aβ、磷酸化 tau、自由基、 炎症毒素等）。鉴于神经元防御能力的增强，人们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，防御机制 AD 中枢胆碱能系统在 G 蛋白偶联受体 (GPCR) 激酶 5 受试者中受到损害 (GRK5) 缺乏；后者在衰老过程中出现，并在 AD 中恶化。受损的神经元防御导致 容易因过量 Aβ 或缺氧而引发变性，而活性邻氨基苯甲酰胺 衍生物 CN168 能够预防 GRK5 缺陷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的观点：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侮辱，但 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 疾病缓解疗法带来了新的希望。 CN168在概念验证（PoC）水平上被证明可以有效预防认知障碍 GAP小鼠中的下降，我们还注意到CN168有两次违反五种药物相似性规则（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了解 CN168 的特性。因为 CN168 已被证明具有体内功效并且之前 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 CN168 作为 活性药物成分（API）并使用前药方法提高其脑与血浆（B2P）比率。 在这个项目中，我们将通过比较 CN168 的 3 种精心挑选的前药的 PK 特性来表征它们， 在准备研究新药（IND）之前研究其药效学（PD）和毒理学 申请最终选定的前药。我们将通过以下三个具体目标来实现我们的目标： 目标 1. API (CN168) 及其前药的药代动力学：在此目标中，我们将 (1) 合成 CN168及其前药的量足以进行体内PK分析；然后（2）进行他们的PK 表征并选择性能优于 CN168 并具有改善的 B2P 比率的前药。 目标 2：所选 CN168 前药的药效学和毒理学：在这个目标中，我们 将执行 (1) PD 研究，以验证目标参与度、寻找有效剂量范围以及评估 GRK5 缺陷小鼠和野生型小鼠的潜在副作用； (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：在这个目标中，我们将 (1) 生产 在美国国内的 cGMP 设施中生产最终前药； (2) 准备向 FDA 提交 IND 申请。 AD 是全世界最持久、最具破坏性的痴呆症。然而，临床试验的目的是寻找一种 AD 疾病缓解疗法相继失败。通过数十年对 GRK5 缺陷的研究 在 AD 中，我们提出了一种新的治疗策略，该策略不同于现有的治疗策略，但可以补充 专注于个人侮辱的治疗努力。我们已经通过 API CN168 获得了 PoC 证据。更远 其 PK 特性的改善将确保其在临床前阶段的成功，并为成功迈向成功铺平道路。 转化为未来的临床试验。我们相信这是开发 AD 疾病缓解疗法的机会。