Targeting JNK3 for Alzheimer's disease: Design and synthesis of novel inhibitors with aryl group diversity utilizing wide pocket.

JNK3, a brain-specific stress-activated protein kinase, plays a critical role in Alzheimer's disease pathogenesis through phosphorylation of Tau and APP. This study aimed to develop selective JNK3 inhibitors based on a pyrazole scaffold, focusing on (E)-1-(2-aminopyrimidin-4-yl)-4-styryl-1H-pyrazole-3-carboxamide derivatives. Through systematic structural modifications and extensive SAR analysis, we identified compounds 24a and 26a as highly potent JNK3 inhibitors, with IC values of 12 and 19 nM, respectively. Especially, 24a revealed its potent and selective inhibition of JNK3, coupled with inhibition of the GSK3α/β kinases involved in Tau phosphorylation. In vitro studies revealed significant neuroprotective effects against Aβ-induced toxicity in primary neuronal cells and western blot analyses confirmed the compounds' ability to mitigate Aβ-induced c-Jun and APP phosphorylation, suggesting a multi-faceted approach to neuroprotection. Docking studies validated the retention of optimal interactions within the JNK3 binding pocket. Importantly, BBB PAMPA assays and ADME predictions indicated favorable blood-brain barrier permeability and pharmacokinetic profiles for the lead compounds. These findings represent a significant advancement in the development of selective JNK3 inhibitors, providing a strong foundation for further preclinical development of potential Alzheimer's disease therapeutics.