Upadacitinib is a JAK1 inhibitor (IC50 = 47 nM).1 It is selective for JAK1 over JAK3 and tyrosine kinase 2 (Tyk2; IC50s = 2,304 and 4,690 nM, respectively), as well as a panel of 83 additional kinases at 1 µM, but does inhibit JAK2, Rho-associated kinase I (ROCK1), and ROCK2 (IC50s = 120, 920, and 430 nM, respectively). Upadacitinib decreases cytokine-induced STAT phosphorylation in a variety of human cells with IC50 values ranging from 1.6 to 649 nM. It reduces M. tuberculosis-induced paw swelling and bone erosion in a rat model of arthritis when administered at doses of 1, 3, and 10 mg/kg twice per day for 17 days. Formulations containing upadacitinib have been used in the treatment of rheumatoid arthritis.

1: hydrogen; triethylamine; (S)-Ru(OAc)2(SEGPHOS) / methanol / 80 °C
2: 1,1'-carbonyldiimidazole
3: lithium bromide; toluene-4-sulfonic acid
4: lithium tert-butoxide / N,N-dimethyl acetamide
5: pyridine; trifluoroacetic anhydride / acetonitrile / 75 °C
6: sodium hydroxide / 2-methyltetrahydrofuran / 55 °C
7: hydrogen; Pd(OH)2/C
8: dipotassium hydrogenphosphate; potassium hydroxide / tetrahydrofuran

1.Drugs of the Future, 2018, vol. 43, # 10, p. 731 - 743

2.Parmentier, J.M., Voss, J., Graff, C., et al. In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494). BMC Rheumatol. 2, 23 (2018).