Prodrugs of potent and selective protease inhibitors as tauopathy therapeutics

作为 tau 蛋白病治疗剂的有效和选择性蛋白酶抑制剂的前药

• 批准号: 10761291
• 负责人: Karen H Ashe
• 金额: $ 35万
• 依托单位: MYRIEL, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761291
• 关键词: AMPA Receptors; Academia; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapy; Antibodies; Back; Brain; CASP2 gene; Carboxylic Acids; Charge; Cholinesterase Inhibitors; Clinical Trials; Communication; Cyclization; Dementia; Dendritic Spines; Depressed mood; Disease; Drug Kinetics; Elderly; Esterification; Financial Support; Foundations; Frontotemporal Dementia; Frustration; Functional disorder; Future; General Population; Goals; Impaired cognition; Investigational Drugs; Ischemic Brain Injury; Lead; Letters; Lewy Body Dementia; Mediating; Medical; Medicine; Memantine; Membrane; Memory Loss; Metabolic; Modeling; Nature; Neurons; Paper; Pathologic; Pathology; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase II Clinical Trials; Prevalence; Prodrugs; Protease Inhibitor; Publications; Qualifying; Rattus; Reproducibility; Research Personnel; Rodent Model; Route; Small Business Technology Transfer Research; Specific qualifier value; Structure-Activity Relationship; Synapses; Synaptic Receptors; Synaptic Transmission; Tauopathies; Therapeutic; Validation; amidation; analog; blood-brain barrier crossing; cognitive function; design; drug development; experience; fatty acid amide hydrolase; human old age (65+); improved; inhibitor; innovation; mild cognitive impairment; nervous system disorder; neuropathology; neurotransmission; postsynaptic; prevent; receptor; repaired; small molecule; synaptic function; tau Proteins

PROJECT ABSTRACT Myriel, Inc., is a pharmaceutical start-up company founded in 2022 to find cures for tauopathies, including Alzheimer’s disease and related dementias (ADRD), which impair cognition in 32% of US adults 65 years and older. The goal of this Phase 1 STTR application is to provide Myriel with a brain-penetrant analogue of our lead compound, GPHR ‘739, the first potent, selective, reversible Casp2 inhibitor that successfully reverses pathologically depressed neurotransmission in a rodent model of ADRD. Inhibiting Casp2 is a highly promising strategy for treating ADRD because Casp2-cleavage of the neuronal protein tau compromises synaptic and cognitive function in models of several different ADRD, and preventing Casp2 from cleaving tau in this manner restores synaptic function and reverses preexisting memory loss. Our central hypothesis is that prodrugs of GPHR ‘739 in which its two negatively charged carboxylic acids are neutralized by esterification, cyclization, and/or amidation to meet predetermined attributes for metabolic stability and membrane penetration will cross the blood-brain-barrier, thereby qualifying them for future pharmacodynamic studies. Myriel will capitalize on the co-PI’s (Walters) experience discovering brain-penetrant compounds and prodrugs that successfully completed IND-enabling studies and reached clinical trials, and skillfully adapt strategies that produced a brain-penetrant Casp2/3 inhibitor which improves ischemic brain injury in rats and a brain-penetrant Casp1 inhibitor that advanced to Phase 2 clinical trials. We will achieve our goal of generating a brain-penetrant Casp2 inhibitor through three specific aims: 1) esterification and amidation of diacid side-chains in GPHR ‘739; 2) cyclization of diacid side-chains in GPHR ‘739; and 3) pharmacokinetic studies of five GPHR ‘739 analogues. Upon completion of this project, we expect to have at least one prodrug of GPHR ‘739 that penetrates into the brain to prespecified levels, thus poising it for future IND-enabling studies. These results will significantly advance Myriel’s progress toward developing a Casp2-inhibiting drug that reduces the prevalence of impaired cognition in the elderly.

项目摘要 Myriel，Inc。是一家制药初创公司 阿尔茨海默氏病和相关痴呆症（ADRD），这会损害32％的美国成年人65岁的认知 年龄较大。该阶段1 STTR应用的目的是为Myriel提供我们铅的脑渗透剂类似物 化合物，GPHR'739，第一个潜力，选择性，可逆CASP2抑制剂，成功逆转 在ADRD的啮齿动物模型中，病理抑郁的神经传递。抑制CASP2是一个非常有前途的 治疗ADRD的策略是因为神经元蛋白Tau的CASP2裂解会损害突触和 在几种不同ADRD的模型中的认知功能，并防止Casp2以这种方式切割Tau 恢复突触功能并逆转以前的内存丢失。我们的中心假设是 GPHR'739，其中两个带负电荷的羧酸通过酯化，环化，环化中和 和/或胺以满足代谢稳定性和膜穿透的预定属性 血脑屏障，从而使它们有资格进行未来的药效研究。 Myriel将利用 Co-Pi（Walters）的经验发现了成功完成的脑渗透剂化合物和前药 辅助研究并进行了临床试验，并巧妙地适应了产生脑渗透剂的策略 CASP2/3抑制剂可改善大鼠的缺血性脑损伤和脑穿透剂CASP1抑制剂 先进到第2阶段临床试验。我们将实现产生脑渗透剂CASP2抑制剂的目标 通过三个特定的目的：1）GPHR'739中的二齿侧链酯化和脑集； 2）环化 GPHR'739中的二芯侧链; 3）五个GPHR'739个类似物的药代动力学研究。完成后 在这个项目中，我们预计至少有一个GPHR'739，可以渗透到大脑中以预先指定 水平，从而使其中毒以进行未来的辅助研究。这些结果将大大提高Myriel的进步 为了开发一种抑制CASP2的药物，以降低老年认知受损的流行。