Developing Novel Ambroxol Analogs as Disease-Modifying Therapies for Alzheimer's Disease and Related Dementias

Zywie Llc, Reno NV

Investigators

Abstract

Project Summary/Abstract Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that affects millions of older adults worldwide, leading to cognitive decline, loss of independence, and significant healthcare burdens. Despite the emergence of monoclonal antibodies (mAbs) targeting beta amyloid, these therapies are costly, carry notable safety risks, and offer only partial clinical benefits. An urgently needed complementary approach is to stimulate the cell’s own clearance machinery for pathogenic proteins—particularly amyloid beta (Aβ) and tau—which accumulate and disrupt neuronal function. This project will advance pharmacokinetically stabilized analogs of the ambroxol – a small molecule drug with a long safety record in humans, excellent brain penetrance, and potent effect on the lysosomal waste clearance system – towards development as small molecule Alzheimer’s disease therapeutic. Our preliminary evidence shows that ambroxol can reverse AD pathology, but low stability affects its clinical performance. As a result we have now engineered two ambroxol analogs (ZW-002, ZW-010) with markedly improved metabolic stability. These compounds retain ambroxol’s lysosomal-enhancing capacity yet exhibit extended half-lives, potentially allowing safer, more efficacious dosing. This Phase I SBIR proposal seeks to: 1. Scale up manufacturing of ZW-002 and ZW-010 under non-GLP conditions (Aim 1), optimizing synthetic methods and partially validating analytical assays. 2. Conduct short-term toxicology in healthy adult mice (Aim 2) to identify any unanticipated toxicities and establish safe dosing parameters. 3. Evaluate efficacy in the 3xTg AD model under both prevention and treatment paradigms (Aim 3) to confirm whether these analogs can reduce or even reverse Aβ and tau accumulation. By the end of Phase I, we will determine which analog best balances manufacturability, safety, and disease- modifying capability, paving the way for IND-enabling studies and clinical translation. Ultimately, our approach aims to deliver a safe, orally available, and cost-effective therapy that harnesses the intrinsic power of lysosomal clearance to combat Alzheimer’s disease—potentially transforming how we treat neurodegenerative disorders characterized by toxic protein aggregates.