Benzimidazole Derivatives as Potent JAK1-Selective Inhibitors

Journal of Medicinal Chemistry
Mi Kyoung KimYouhoon Chong

Abstract

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 prefe...Continue Reading

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Citations

Feb 9, 2017·Bioorganic & Medicinal Chemistry Letters·Wen GuShi-Fa Wang
Mar 29, 2018·Current Medicinal Chemistry·Francesca MusumeciSilvia Schenone
Nov 28, 2018·Scientific Reports·Xinzhong LiJames Scott
Apr 5, 2021·European Journal of Medicinal Chemistry·Pengfei XuZhixia Qiu
May 28, 2019·Cytokine & Growth Factor Reviews·Nicolas SaillietSophie Brouard
Jun 6, 2018·Journal of Medicinal Chemistry·Marian C Bryan, Naomi S Rajapaksa

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