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 N(1) 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.
Despite a high level of interest in selective Janus kinase 1 (JAK1) inhibitors and their potential for the treatment of inflammatory diseases such as rheumatoid arthritis (RA), only a few such inhibitors have been reported to date. In this study, a novel 4-amino-1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold was designed through structural modification of the potent JAK1-selective inhibitor, C2-methyl imidazopyrrolopyridine. Among the series studied, the 4-(2-aminoethyl)amino-pyrrolopyridine derivative, 2j, exhibited a significant 24.7-fold JAK1/JAK2 selectivity along with reasonable inhibitory activity against JAK1 (IC 50 2.2 µM). The noticeable JAK1-selectivity of 2j was then tackled through a molecular docking study, which showed that the aminoethyl functionality of 2j is well positioned to discriminate the subtle but significant difference in the size of the ligand binding sites between JAK1 and JAK2.Key words Janus kinase 1 (JAK1); pyrrolopyridine; rheumatoid arthritisThe Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, a major signaling cascade in response to inflammatory and proliferative signals, consists of the Janus protein tyrosine kinase family (JAK3, JAK2, JAK1, and TYK2) and STAT family of transcription factors. Upon ligand-receptor binding, the JAKs get activated, resulting in the phosphorylation, dimerization, and nuclear translocation of the downstream STAT proteins, which regulate the transcription of STAT-dependent genes. Depending on the specific cytokines coupled with JAKs, ligand-receptor binding culminates in an intracellular response such as an immune function, 1) inflammation, 2) or hematopoiesis. 3,4) For instance, the gamma common (γ c ) family of cytokines, i.e., interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21, is exclusively associated with JAK1 and JAK3, 5) and a loss-of-function mutation in the γ c chain or JAK3 results in severe combined immunodeficiency (SCID). As a result, abrogation of signaling by γ c -cytokines through the inhibition of γ c -linked JAK3 has long been regarded as an attractive target for the treatment of immunologic disorders such as rheumatoid arthritis (RA). 2,6) Pfizer's Xeljanz (Tofacitinib, CP-690550), the first-in-class JAK inhibitor approved for the treatment of RA, 7) was initially reported to be a selective JAK3 inhibitor, 6) spurring many pharmaceutical companies to launch JAK3 medicinal chemistry programs.However, it has become clear that tofacitinib is not as specific for JAK3 as initially thought, but it is rather a potent pan-JAK inhibitor, 8) suggesting that the clinical efficacy of the compound against RA is unlikely to be driven by the selective inhibition of JAK3. In addition, accumulated evidence has revealed that in signal transduction through γ c -containing cytokine receptors, JAK1 plays a dominant role, while JAK3 exhibits only a secondary functional activity that merely enhances the effect of JAK1.9-13) Accordingly, JAK1 inhibition has become a relevant treatment option for RA. For successful ...
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