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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos 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

项目摘要

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. 是一家成立于 2022 年的制药初创公司，致力于寻找 tau蛋白病的治疗方法，包括阿尔茨海默病和相关痴呆症 (ADRD) 会损害 32% 的 65 岁美国成年人的认知能力这一阶段 STTR 应用的目标是为 Myriel 提供我们先导药物的脑渗透类似物。化合物 GPHR ‘739，第一个有效的、选择性的、可逆的 Casp2 抑制剂，可成功逆转抑制 ADRD 啮齿动物模型中的病理性神经传递抑制是一种非常有前途的方法。治疗 ADRD 的策略是因为神经元蛋白 tau 的 Casp2 裂解会损害突触和几种不同 ADRD 模型中的认知功能，并阻止 Casp2 以这种方式裂解 tau 恢复突触功能并逆转先前存在的记忆丧失我们的中心假设是前药。 GPHR ‘739，其中两个带负电荷的羧酸通过酯化、环化、和/或酰胺化以满足代谢稳定性和膜渗透的预定属性将交叉血脑屏障，使他们有资格进行未来的药效学研究，从而使 Myriel 能够利用这一点。联合 PI（沃尔特斯）在发现脑渗透化合物和前药方面的经验已成功完成支持 IND 的研究并达到临床试验，并巧妙地调整策略，产生了脑渗透剂 Casp2/3 抑制剂可改善大鼠缺血性脑损伤，而一种脑渗透性 Casp1 抑制剂可改善大鼠缺血性脑损伤我们将实现生产脑穿透性 Casp2 抑制剂的 2 期临床试验。通过三个具体目标：1) GPHR ‘739 中二酸侧链的酯化和酰胺化；2) 环化 GPHR ‘739 中的二酸侧链；以及 3) 五种 GPHR ‘739 类似物的药代动力学研究。在这个项目中，我们期望至少有一种 GPHR ‘739 的前药能够渗透到大脑中以达到预定的效果水平，从而为未来的 IND 研究做好准备，这些结果将显着推进 Myriel 的进展。致力于开发一种 Casp2 抑制药物，以降低老年人认知障碍的发生率。