Benzimidazole Derivatives as Potent JAK1-Selective Inhibitors

Title
Benzimidazole Derivatives as Potent JAK1-Selective Inhibitors
Authors
김미경신희림박광수김형미박지선김강전남준우추현아정유훈
Keywords
Janus Kinase; JAK1; benzimidazole; inhibitor
Issue Date
2015-09
Publisher
Journal of medicinal chemistry
Citation
VOL 58, 7596-7602
Abstract
The Janus kinase (JAK) family comprises four members (JAK1, JAK2, JAK3, and Tyk2) that play a key role in mediating cytokine recept rsignaling. 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.
URI
http://pubs.kist.re.kr/handle/201004/50346
ISSN
00222623
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KIST Publication > Article
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