Advances in N- and S-Heterocycles as c-Jun-N-Terminal Kinase 3 Inhibitors for Alzheimer's Disease Treatment.

c-Jun-N-terminal kinase 3 (JNK3) inhibitors are emerging as promising therapeutic agents for the treatment of Alzheimer's disease (AD). Predominantly expressed in the central nervous system (CNS), JNK3 plays a crucial role in neuronal apoptosis and inflammation, processes that are often dysregulated in neurodegenerative conditions. In recent years, a diverse range of heterocycle scaffolds has been explored as selective JNK3 inhibitors, demonstrating significant potential in modulating disease pathology. Structure-activity relationship (SAR) studies have further facilitated the rational design and optimization of these compounds, improving their potency, selectivity, and pharmacokinetic profiles. By selectively inhibiting JNK3, these small compounds can mitigate neuroinflammation and promote neuronal survival. The development of small molecule JNK3 inhibitors offers a targeted approach that may minimize side effects. This article explores various heterocyclic molecules such as pyrazoles, thiazoles, imidazoles, and thiophenes, evaluated for JNK3 inhibition. This review will help medicinal chemists to design and develop new molecules based on established data on isoform-selective JNK3 inhibitors.