Kim, Mi Kyoung Shin, Heerim Park, Kwang-su Kim, Hyungmi Park, Jiseon Kim, Kangjeon Nam, Joonwoo Choo, Hyunah Chong, Youhoon 2024-01-20T06:03:29Z 2024-01-20T06:03:29Z 2021-09-05 2015-09-24 0022-2623 https://pubs.kist.re.kr/handle/201004/124997 The Janus kinase (JAR) family comprises four members (JAK1, JAK2, JAK3, and Tyk2) that play a key role in mediating cytokine receptor signaling. JAR 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-S-carboxamide derivatives was prepared and their inhibitory activities against all four JAR 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 R-2 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 mu M. English AMER CHEMICAL SOC JANUS KINASE INHIBITORS PRECLINICAL CHARACTERIZATION INFLAMMATORY DISEASES SELECTIVE INHIBITOR JAK INHIBITOR ARTHRITIS MODELS INCB018424 CP-690,550 DISCOVERY Benzimidazole Derivatives as Potent JAK1-Selective Inhibitors Article 10.1021/acs.jmedchem.5b01263 1 JOURNAL OF MEDICINAL CHEMISTRY, v.58, no.18, pp.7596 - 7602 JOURNAL OF MEDICINAL CHEMISTRY 58 18 7596 7602 scie scopus 000361921800038 2-s2.0-84942292010 Chemistry, Medicinal Pharmacology & Pharmacy Article JANUS KINASE INHIBITORS PRECLINICAL CHARACTERIZATION INFLAMMATORY DISEASES SELECTIVE INHIBITOR JAK INHIBITOR ARTHRITIS MODELS INCB018424 CP-690,550 DISCOVERY Janus Kinase JAK1 benzimidazole inhibitor