Given the limited benefits of anticholinergic drugs and the repeated clinical failures of anti-amyloid therapies, the therapeutic focus in Alzheimer's disease (AD) is gradually shifting toward addressing both disease symptoms and its major underlying cause - neuroinflammation. We have developed novel multi-target directed ligands that inhibit butyrylcholinesterase (BChE) and p38α mitogen-activated protein kinase (p38α MAPK) to simultaneously target cholinergic deficits and neuroinflammation in AD. Following in silico design, we converted known allosteric pyrazolyl urea p38α MAPK ligands into N,N-disubstituted carbamates that pseudo-irreversibly inhibit hBChE while retaining p38α MAPK inhibitory activity. The lead compound 13a has favourable central nervous system (CNS) drug-like properties in vitro and shows procognitive effects in an in vivo scopolamine-induced amnesia model. Our series demonstrates that targeted structural modifications of selective kinase inhibitors, based on a comprehensive knowledge of cholinesterase structure and function, enable expansion of the effect to the CNS. This approach offers critical insights to pave the way for the development of novel dual-target agents that modulate both cholinergic and neuroinflammatory pathways in neurodegenerative diseases.

• Klíčová slova
• Butyrylcholinesterase, Carbamate, Dual inhibitors, p38α mitogen-activated protein kinase, pseudo-irreversible inhibition,
• Publikační typ
• časopisecké články MeSH

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.

• MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• butyrylcholinesterasa * chemie   metabolismus   MeSH
• cholinesterasové inhibitory * farmakologie   chemie   terapeutické užití   MeSH
• inhibitory proteinkinas * farmakologie   chemie   terapeutické užití   MeSH
• kognitivní dysfunkce * farmakoterapie   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• lipopolysacharidy MeSH
• mitogenem aktivovaná proteinkinasa 14 * antagonisté a inhibitory   metabolismus   MeSH
• molekulární modely MeSH
• myši MeSH
• neurozánětlivé nemoci * farmakoterapie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• butyrylcholinesterasa * MeSH
• cholinesterasové inhibitory * MeSH
• inhibitory proteinkinas * MeSH
• lipopolysacharidy MeSH
• mitogenem aktivovaná proteinkinasa 14 * MeSH

The multitarget approach is a promising paradigm in drug discovery, potentially leading to new treatment options for complex disorders, such as Alzheimer's disease. Herein, we present the discovery of a unique series of 1-benzylamino-2-hydroxyalkyl derivatives combining inhibitory activity against butyrylcholinesterase, β-secretase, β-amyloid, and tau protein aggregation, all related to mechanisms which underpin Alzheimer's disease. Notably, diphenylpropylamine derivative 10 showed balanced activity against both disease-modifying targets, inhibition of β-secretase (IC50 hBACE-1 = 41.60 μM), inhibition of amyloid β aggregation (IC50 Aβ = 3.09 μM), inhibition of tau aggregation (55% at 10 μM); as well as against symptomatic targets, butyrylcholinesterase inhibition (IC50 hBuChE = 7.22 μM). It might represent an encouraging starting point for development of multifunctional disease-modifying anti-Alzheimer's agents.

• Klíčová slova
• Alzheimer’s disease, Aβ aggregation, BACE-1 inhibitors, butyrylcholinesterase inhibitors, molecular docking, multifunctional agents, tau aggregation,
• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• amyloidní beta-protein účinky léků   metabolismus   MeSH
• butyrylcholinesterasa farmakologie   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• lidé MeSH
• peptidové fragmenty metabolismus   MeSH
• proteiny tau účinky léků   MeSH
• racionální návrh léčiv * MeSH
• simulace molekulového dockingu metody   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amyloidní beta-protein MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• peptidové fragmenty MeSH
• proteiny tau MeSH