Benzimidazole Derivatives as Potent JAK1-Selective Inhibitors

The Janus kinase (JAK) family comprises
four members (JAK1, JAK2,
JAK3, and Tyk2) that play a key role in mediating cytokine receptor
signaling. JAK inhibition thus modulates cytokine-mediated effects.
In particular, selective inhibition of JAK1 or JAK3 may provide an
efficient therapeutic agent for the treatment of inflammatory diseases,
with minimized side effects. In this study, as part of our continued
efforts to develop a selective JAK1 inhibitor, a series of 1,2-disubstituted
benzimidazole-5-carboxamide derivatives was prepared and their inhibitory
activities against all four JAK isozymes were evaluated. A clear structure–activity
relationship was observed with respect to JAK1 selectivity; this highlighted
the importance of hydrogen bond donors at both N1 and R2 positions located within a specific distance
from the benzimidazole core. One of the synthesized compounds, 1-(2-aminoethyl)-2-(piperidin-4-yl)-1H-benzo­[d]­imidazole-5-carboxamide (5c), showed remarkable JAK1 selectivity (63-fold vs JAK2,
25-fold vs JAK3, and 74-fold vs Tyk2). Molecular docking revealed
that the 2-aminoethyl and piperidin-4-yl substituents of 5c function as probes to differentiate the ATP-binding site of JAK1
from that of JAK2, resulting in preferential JAK1 binding. A kinase
panel assay confirmed the JAK1 selectivity of 5c, which
showed no appreciable inhibitory activity against 26 other protein
kinases at 10 μM.