Prodrugs of potent and selective protease inhibitors as tauopathy therapeutics

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.