Description:
- Small-molecule carboxamides that inhibit and disassemble tau fibrils associated with Alzheimer’s disease
- Optimized for blood-brain barrier penetration and favorable pharmacokinetic properties
- Demonstrated efficacy in Alzheimer’s disease brain tissue and cell-based models
Abstract
USC researchers have developed carboxamide-based small molecules that selectively inhibit tau aggregation and disassemble existing tau fibrils, a key driver of Alzheimer’s disease and other tauopathies. Optimized for low polar surface area, these compounds exhibit efficient blood-brain barrier penetration, favorable pharmacokinetics, and metabolic stability for enhanced CNS delivery. Efficacy has been demonstrated in Alzheimer’s disease brain homogenates and cell-based models. Structure-activity optimization of amino- and hydroxy-substituted carboxamides further improves therapeutic potential, including use in PROTAC-based targeted protein degradation strategies. This platform represents a promising disease-modifying approach for treating tau-driven neurodegenerative disorders.
Benefit
- Excellent brain penetration for effective CNS targeting
- Directly inhibits and disassembles tau fibrils, beyond amyloid-based approaches
- Improved pharmacokinetics and reduced off-target effects compared to other tau-targeting compounds
- Platform potential for PROTAC-driven tau clearance
- Strong preclinical validation as a disease-modifying Alzheimer’s therapy
Market Application
- Alzheimer’s disease therapeutics
- Tau-targeted neurodegenerative disease therapies (e.g., frontotemporal dementia, chronic traumatic encephalopathy)
- CNS small-molecule drug discovery
Publications
https://pmc.ncbi.nlm.nih.gov/articles/PMC9481533/
Other
- Proof of concept demonstrated in vitro using radioactive binding assays