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，旨在寻找治疗肥胖症的方法，包括 阿尔茨海默病和相关痴呆(ADRD)，这种疾病损害了32%65岁和65岁以上美国成年人的认知能力 年纪更大了。此第一阶段STTR应用程序的目标是为Myriel提供与我们的Lead类似的大脑穿透性 化合物，GPHR‘739，第一个成功逆转的有效、选择性、可逆的Casp2抑制剂 ADRD啮齿动物模型中病理性抑制的神经传递。抑制Casp2是一种非常有希望的 治疗ADRD的策略，因为神经元蛋白tau的Casp2裂解损害了突触和 几种不同ADRD模型的认知功能，并阻止Casp2以这种方式切割tau 恢复突触功能并逆转先前存在的记忆丧失。我们的中心假设是前药 GPHR‘739，其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学研究。Myriel将利用 Co-Pi(Walters)发现脑渗透化合物和前药的经验成功完成 支持IND的研究和临床试验，并巧妙地调整策略，生产出一种脑渗透剂 改善大鼠缺血性脑损伤的Casp2/3抑制剂和脑穿透性CASP1抑制剂 进入第二阶段临床试验。我们将实现产生脑穿透性Casp2抑制剂的目标 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 3)5个GPHR‘739类似物的药代动力学研究。完工后 在这个项目中，我们希望至少有一种GPHR‘739的前药可以渗透到大脑中，以预先指定 水平，从而为未来支持IND的研究做好准备。这些结果将大大推动Myriel的进步 开发一种Casp2抑制药物，降低老年人认知障碍的患病率。

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.