Prodrugs of potent and selective protease inhibitors as tauopathy therapeutics

项目摘要 Myriel，Inc.是一家成立于2022年的制药初创公司，旨在寻找治疗tau蛋白病的方法，包括 阿尔茨海默氏病和相关痴呆症（ADRD），这损害了32%的美国65岁以上的成年人的认知能力， 老了第1阶段STTR应用的目标是为Myriel提供我们电极导线的脑渗透模拟物 化合物GPHR '739，第一个有效的，选择性的，可逆的Casp 2抑制剂，成功逆转 在ADRD的啮齿动物模型中病理性抑制的神经传递。抑制Casp 2是一种非常有前途的 治疗ADRD的策略，因为神经元蛋白tau的Casp 2切割损害了突触和 在几种不同的ADRD模型中的认知功能，并以这种方式阻止Casp 2切割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， GPHR ′ 739，其中它的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 血脑屏障，从而使它们有资格用于未来的药效学研究。米里哀会利用 合作PI的（沃尔特斯）的经验，发现脑渗透化合物和前药，成功地完成了 IND使研究和达到临床试验，并巧妙地适应战略，产生了大脑渗透 改善大鼠缺血性脑损伤的Casp 2/3抑制剂和 进入第二阶段临床试验。我们将实现我们的目标， 通过三个具体的目的：1）GPHR ′ 739中二酸侧链的酯化和酰胺化; 2）二酸侧链的环化， GPHR ′ 739中的二酸侧链;和3）五种GPHR ′ 739类似物的药代动力学研究。完成后 在这个项目中，我们期望至少有一种GPHR '739的前药，它可以渗透到大脑中， 水平，从而平衡它为未来的IND使能研究。这些结果将大大推进米里哀的进步 开发一种抑制Casp 2的药物，以降低老年人认知功能受损的患病率。

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.