For the past 25 years the most common approach to targeting Alzheimer's Disease(AD), has followed the so-called β-amyloid (Aβ) hypothesis of AD, targeting the reduction of amyloid plaque deposits, through a variety of different molecular targets, with small molecules and biologicals. An alternate approach is to target the prevention of Neurofibrillary tangle (NFT) formation, which form from insoluble tau protein aggregates. To date, no single Aβ or tau-based therapy has successfully gained market entry. Herein, we focus recent studies on the further development of small molecules which target both amyloid and tauopathies through selective inhibition of the dual specificity tyrosine phosphorylation regulated kinase-1A (DYRK1A). Current published results reveal enticing amelioration of behavioral and neuropathological pathologies in vivo, in a 3x-TgAD mice model with our current lead DYR219. DYR219 is a potent, selective and brain-penetrant DYRK1A inhibitor, wherein our current focus centers on medicinal chemistry efforts in order to improve pharmacokinetic and pharmacodynamic (PK/PD) properties toward development of a clinical candidate for the treatment of Alzheimer’s Disease.

DYRK1A inhibition simultaneously targets amyloid-beta and tau pathology

255th National Meeting (2018)

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