A JAK1 inhibitor
Upadacitinib (ABT-494) is a potent, orally active and selective Janus kinase 1 (JAK1) inhibitor (IC50=43 nM). Upadacitinib (ABT-494) displays approximately 74 fold selective for JAK1 over JAK2 (200 nM) in cellular assays dependent on specific, relevant cytokines. Upadacitinib (ABT-494) is used in development for the treatment of several autoimmune disorders[1][2].
In biochemical assays, Upadacitinib is 74-fold more selective for JAK-1 than for JAK-2 (which is involved in erythropoiesis) and 58-fold more selective for JAK-1 than for JAK-3 (which is involved in immunosurveillance)[1]. The enhanced selectivity of Upadacitinib for JAK-1 over JAK-2 and JAK-3 may offer an improved benefit–risk profile in patients with RA range[2].
Upadacitinib (0.1-10 mg/kg; oral gavage; twice a day for 10 days) demonstrates efficacy in rat arthritis models[3].
参考文献:
[1]. Nakayamada S, et al. Recent Progress in JAK Inhibitors for the Treatment of Rheumatoid Arthritis. BioDrugs. 2016 Oct;30(5):407-419.
[2]. J. Voss, et al. THU0127 Pharmacodynamics of A Novel JAK1 Selective Inhibitor in Rat Arthritis and Anemia Models and in Healthy Human Subjects. doi 10.1136/annrheumdis-2014-eular.3823.
[3]. Parmentier JM, et al. In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494). BMC Rheumatol. 2018 Aug 28;2:23.
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