Targeting Neuroinflammation and Cognitive Decline: First-in-Class Dual Butyrylcholinesterase and p38α Mitogen-Activated Protein Kinase Inhibitors

The currently approved
drugs for the treatment of Alzheimer’s
disease (AD) fail to address its interconnected pathological processes.
Inhibition of butyrylcholinesterase (BChE) and p38α mitogen-activated
protein kinase (p38α MAPK) offers an innovative dual approach
to mitigate two major drivers of neurodegeneration in AD: cholinergic
deficit and neuroinflammation. Using structure-based drug design and
a library of known p38α MAPK inhibitors, we developed first-in-class,
selective dual BChE/p38α MAPK inhibitors with balanced activity
against both targets. The X-ray crystal structures of the two most
promising molecules bound to both enzymes were solved. Those ligands
effectively reduced the production of proinflammatory markers in vitro
and ex vivo in phytohemagglutinin/lipopolysaccharide neuroinflammation
models. Remarkably, these compounds also significantly improved cognition
in scopolamine- and lipopolysaccharide-induced models of cognitive
dysfunction in mice. Because our dual-acting inhibitors target both
the symptoms and the underlying neuropathology, they offer an innovative
and comprehensive strategy to combat AD.