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 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.
Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University , 1 Hwayang-dong, Gwangjin-gu, Seoul 05029, Korea.
Mi Kyoung
MK
Kim
Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University , 1 Hwayang-dong, Gwangjin-gu, Seoul 05029, Korea.
Heerim
H
Shin
Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University , 1 Hwayang-dong, Gwangjin-gu, Seoul 05029, Korea.
Kwang-su
KS
Park
Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University , 1 Hwayang-dong, Gwangjin-gu, Seoul 05029, Korea.
Hyungmi
H
Kim
R&D Center, Jeil Pharmaceutical Co., Ltd. 7 Cheongganggachangro, Baegam-myun, Cheoin-gu, Yongin-City, Kyunggi-Do 17172, Korea.
Jiseon
J
Park
R&D Center, Jeil Pharmaceutical Co., Ltd. 7 Cheongganggachangro, Baegam-myun, Cheoin-gu, Yongin-City, Kyunggi-Do 17172, Korea.
Kangjeon
K
Kim
R&D Center, Jeil Pharmaceutical Co., Ltd. 7 Cheongganggachangro, Baegam-myun, Cheoin-gu, Yongin-City, Kyunggi-Do 17172, Korea.
Joonwoo
J
Nam
Center for Neuro-Medicine, Korea Institute of Science and Technology , 5, Hwarang-ro 14-gil, Seoungbuk-gu, Seoul 02792, Korea.|Department of Biological Chemistry, University of Science and Technology , 217 Gajeong-ro, Youseong-gu, Daejeon 34113, Korea.
Hyunah
H
Choo
Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University , 1 Hwayang-dong, Gwangjin-gu, Seoul 05029, Korea.
Youhoon
Y
Chong
D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry*; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship
C000603807:1-(2-aminoethyl)-2-(piperidin-4-yl)-1H-benzo(d)imidazole-5-carboxamide; D001562:Benzimidazoles; D010880:Piperidines; D053613:Janus Kinase 1