Targeting Janus Kinase (JAK) for Fighting Diseases: The Research of
JAK Inhibitor Drugs

Min-Yan      Zhao; Wen      Zhang; Guo-Wu      Rao
Abstract

Janus Kinase (JAK), a nonreceptor protein tyrosine kinase, has emerged as an excellent target through research and development since its discovery in the 1990s. As novel small-molecule targeted drugs, JAK inhibitor drugs have been successfully used in the treatment of rheumatoid arthritis (RA), myelofibrosis (MF), and ulcerative colitis (UC). With the gradual development of JAK targets in the market, JAK inhibitors have also received considerable feedback in the treatment of autoimmune diseases, such as atopic dermatitis (AD), Crohn's disease (CD), and graft-versus-host disease (GVHD). This article reviews the research progress of JAK inhibitor drugs, focusing on the existing JAK inhibitors in the market and some JAK inhibitors in clinical trials currently. In addition, the synthesis of various types of JAK inhibitors and the effects of different drug structures on drug inhibition and selectivity are summarized.
Keywords: JAK inhibitors, rheumatoid arthritis, autoimmune diseases, approved drugs synthesis, structure-activity relationship, atopic dermatitis.
[1] 
Firmbach-Kraft, I.; Byers, M.; Shows, T.; Dalla-Favera, R.; Krolewski, J.J. tyk2, prototype of a novel class of non-receptor tyrosine kinase genes. Oncogene,  1990, 5(9), 1329-1336.
[PMID: 2216457] 
[2] 
Wilks, A.F.; Harpur, A.G.; Kurban, R.R.; Ralph, S.J.; Zürcher, G.; Ziemiecki, A. Two novel protein-tyrosine kinases, each with a sec-ond phosphotransferase-related catalytic domain, define a new class of protein kinase. Mol. Cell. Biol.,  1991, 11(4), 2057-2065.
[http://dx.doi.org/10.1128/mcb.11.4.2057-2065.1991] [PMID:  1848670] 
[3] 
Harpur, A.G.; Andres, A.C.; Ziemiecki, A.; Aston, R.R.; Wilks, A.F. JAK2, a third member of the JAK family of protein tyrosine ki-nases. Oncogene,  1992, 7(7), 1347-1353.
[PMID: 1620548] 
[4] 
Rane, S.G.; Reddy, E.P. JAK3: a novel JAK kinase associated with terminal differentiation of hematopoietic cells. Oncogene,  1994, 9(8), 2415-2423.
[PMID: 7518579] 
[5] 
Hall, T.; Emmons, T.L.; Chrencik, J.E.; Gormley, J.A.; Weinberg, R.A.; Leone, J.W.; Hirsch, J.L.; Saabye, M.J.; Schindler, J.F.; Day, J.E.; Williams, J.M.; Kiefer, J.R.; Lightle, S.A.; Harris, M.S.; Guru, S.; Fischer, H.D.; Tomasselli, A.G. Expression, purification, char-acterization and crystallization of non- and phosphorylated states of JAK2 and JAK3 kinase domain. Protein Expr. Purif.,  2010, 69(1), 54-63.
[http://dx.doi.org/10.1016/j.pep.2009.09.011] [PMID:  19781647] 
[6] 
Ungureanu, D.; Wu, J.; Pekkala, T.; Niranjan, Y.; Young, C.; Jensen, O.N.; Xu, C.F.; Neubert, T.A.; Skoda, R.C.; Hubbard, S.R.; Sil-vennoinen, O. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat. Struct. Mol. Biol.,  2011, 18(9), 971-976.
[http://dx.doi.org/10.1038/nsmb.2099] [PMID:  21841788] 
[7] 
Silvennoinen, O.; Witthuhn, B.A.; Quelle, F.W.; Cleveland, J.L.; Yi, T.; Ihle, J.N. Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction. Proc. Natl. Acad. Sci. USA,  1993, 90(18), 8429-8433.
[http://dx.doi.org/10.1073/pnas.90.18.8429] [PMID:  8378315] 
[8] 
Pawson, T.; Gish, G.D. SH2 and SH3 domains: from structure to function. Cell,  1992, 71(3), 359-362.
[http://dx.doi.org/10.1016/0092-8674(92)90504-6] [PMID:  1423600] 
[9] 
Silvennoinen, O.; Ihle, J.N.; Schlessinger, J.; Levy, D.E. Interferon-induced nuclear signalling by Jak protein tyrosine kinases. Nature,  1993, 366(6455), 583-585.
[http://dx.doi.org/10.1038/366583a0] [PMID:  7504785] 
[10] 
Pallard, C.; Gouilleux, F.; Charon, M.; Groner, B.; Gisselbrecht, S.; Dusanter-Fourt, I. Interleukin-3, erythropoietin, and prolactin acti-vate a STAT5-like factor in lymphoid cells. J. Biol. Chem.,  1995, 270(27), 15942-15945.
[http://dx.doi.org/10.1074/jbc.270.27.15942] [PMID:  7608147] 
[11] 
Beadling, C.; Guschin, D.; Witthuhn, B.A.; Ziemiecki, A.; Ihle, J.N.; Kerr, I.M.; Cantrell, D.A. Activation of JAK kinases and STAT proteins by interleukin-2 and interferon alpha, but not the T cell antigen receptor, in human T lymphocytes. EMBO J.,  1994, 13(23), 5605-5615.
[http://dx.doi.org/10.1002/j.1460-2075.1994.tb06898.x] [PMID:  7988557] 
[12] 
Wang, Y.; Morella, K.K.; Ripperger, J.; Lai, C.F.; Gearing, D.P.; Fey, G.H.; Campos, S.P.; Baumann, H. Receptors for interleukin-3 (IL-3) and growth hormone mediate an IL-6-type transcriptional induction in the presence of JAK2 or STAT3. Blood,  1995, 86(5), 1671-1679.
[http://dx.doi.org/10.1182/blood.V86.5.1671.bloodjournal8651671] [PMID:  7654999] 
[13] 
Dong, Y.; Li, X.; Yu, Y.; Lv, F.; Chen, Y. JAK/STAT signaling is involved in IL-35-induced inhibition of hepatitis B virus antigen-specific cytotoxic T cell exhaustion in chronic hepatitis B. Life Sci.,  2020, 252, 117663.
[http://dx.doi.org/10.1016/j.lfs.2020.117663] [PMID:  32302624] 
[14] 
Le Vée, M.; Bruyère, A.; Jouan, E.; Fardel, O. Janus kinase-dependent regulation of drug detoxifying protein expression by interleukin-22 in human hepatic cells. Int. Immunopharmacol.,  2020, 83, 106439.
[http://dx.doi.org/10.1016/j.intimp.2020.106439] [PMID:  32234672] 
[15] 
Ihle, J.N. Signaling by the cytokine receptor superfamily just another kinase story. Trends Endocrinol. Metab.,  1994, 5(3), 137-143.
[http://dx.doi.org/10.1016/1043-2760(94)90096-5] [PMID:  18407200] 
[16] 
Ihle, J.N.; Witthuhn, B.A.; Quelle, F.W.; Yamamoto, K.; Thierfelder, W.E.; Kreider, B.; Silvennoinen, O. Signaling by the cytokine receptor superfamily: JAKs and STATs. Trends Biochem. Sci.,  1994, 19(5), 222-227.
[http://dx.doi.org/10.1016/0968-0004(94)90026-4] [PMID:  8048164] 
[17] 
Yamamoto, K.; Quelle, F.W.; Thierfelder, W.E.; Kreider, B.L.; Gilbert, D.J.; Jenkins, N.A.; Copeland, N.G.; Silvennoinen, O.; Ihle, J.N. Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation. Mol. Cell. Biol.,  1994, 14(7), 4342-4349.
[http://dx.doi.org/10.1128/mcb.14.7.4342-4349.1994] [PMID:  8007943] 
[18] 
Lin, J.X.; Mietz, J.; Modi, W.S.; John, S.; Leonard, W.J. Cloning of human Stat5B. Reconstitution of interleukin-2-induced Stat5A and Stat5B DNA binding activity in COS-7 cells. J. Biol. Chem.,  1996, 271(18), 10738-10744.
[http://dx.doi.org/10.1074/jbc.271.18.10738] [PMID:  8631883] 
[19] 
Liu, L.K.; Chen, X.X.; Gao, R.L.; Wang, K.J.; Zheng, W.Y.; Liu, H.P. A cytokine receptor domeless promotes white spot syndrome virus infection via JAK/STAT signaling pathway in red claw crayfish Cherax quadricarinatus. Dev. Comp. Immunol.,  2020, 111, 103749.
[http://dx.doi.org/10.1016/j.dci.2020.103749] [PMID:  32505616] 
[20] 
Darnell, J.E.J., Jr; Kerr, I.M.; Stark, G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science,  1994, 264(5164), 1415-1421.
[http://dx.doi.org/10.1126/science.8197455] [PMID:  8197455] 
[21] 
Schindler, C.; Darnell, J.E.J., Jr Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu. Rev. Biochem.,  1995, 64(1), 621-651.
[http://dx.doi.org/10.1146/annurev.bi.64.070195.003201] [PMID:  7574495] 
[22] 
Yang, X.; Chung, D.; Cepko, C.L. Molecular cloning of the murine JAK1 protein tyrosine kinase and its expression in the mouse central nervous system. J. Neurosci.,  1993, 13(7), 3006-3017.
[http://dx.doi.org/10.1523/JNEUROSCI.13-07-03006.1993] [PMID:  8331382] 
[23] 
Stepensky, P.; Keller, B.; Shamriz, O. NaserEddin, A.; Rumman, N.; Weintraub, M.; Warnatz, K.; Elpeleg, O.; Barak, Y. Deep intronic mis-splicing mutation in JAK3 gene underlies T−B+NK− severe combined immunodeficiency phenotype. J. Clin. Immunol.,  2016, 163, 91-95.
[http://dx.doi.org/10.1016/j.clim.2016.01.001] [PMID:  26769277] 
[24] 
Xu, P.; Shen, P.; Yu, B.; Xu, X.; Ge, R.; Cheng, X.; Chen, Q.; Bian, J.; Li, Z.; Wang, J. Janus kinases (JAKs): The efficient therapeutic targets for autoimmune diseases and myeloproliferative disorders. Eur. J. Med. Chem.,  2020, 192, 112155.
[http://dx.doi.org/10.1016/j.ejmech.2020.112155] [PMID:  32120325] 
[25] 
Gruber, C.N.; Calis, J.J.A.; Buta, S.; Evrony, G.; Martin, J.C.; Uhl, S.A.; Caron, R.; Jarchin, L.; Dunkin, D.; Phelps, R.; Webb, B.D.; Saland, J.M.; Merad, M.; Orange, J.S.; Mace, E.M.; Rosenberg, B.R.; Gelb, B.D.; Bogunovic, D. Complex autoinflammatory syndrome unveils fundamental principles of JAK1 Kinase Transcriptional and Biochemical Function. Immunity,  2020, 53(3), 672-684.e11.
[http://dx.doi.org/10.1016/j.immuni.2020.07.006] [PMID:  32750333] 
[26] 
Levine, R.L.; Wadleigh, M.; Cools, J.; Ebert, B.L.; Wernig, G.; Huntly, B.J.P.; Boggon, T.J.; Wlodarska, I.; Clark, J.J.; Moore, S.; Ad-elsperger, J.; Koo, S.; Lee, J.C.; Gabriel, S.; Mercher, T.; D’Andrea, A.; Fröhling, S.; Döhner, K.; Marynen, P.; Vandenberghe, P.; Me-sa, R.A.; Tefferi, A.; Griffin, J.D.; Eck, M.J.; Sellers, W.R.; Meyerson, M.; Golub, T.R.; Lee, S.J.; Gilliland, D.G. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell,  2005, 7(4), 387-397.
[http://dx.doi.org/10.1016/j.ccr.2005.03.023] [PMID:  15837627] 
[27] 
Alves de Medeiros, A.K.; Speeckaert, R.; Desmet, E.; Van Gele, M.; De Schepper, S.; Lambert, J. JAK3 as an emerging target for topi-cal treatment of inflammatory skin diseases. PLoS One,  2016, 11(10), e0164080.
[http://dx.doi.org/10.1371/journal.pone.0164080] [PMID:  27711196] 
[28] 
Luo, W.; Li, Y.X.; Jiang, L.J.; Chen, Q.; Wang, T.; Ye, D.W. Targeting JAK-STAT signaling to control cytokine release syndrome in COVID-19. Trends Pharmacol. Sci.,  2020, 41(8), 531-543.
[http://dx.doi.org/10.1016/j.tips.2020.06.007] [PMID:  32580895] 
[29] 
Lightfoot, H.L.; Goldberg, F.W.; Sedelmeier, J. Evolution of Small Molecule Kinase Drugs. ACS Med. Chem. Lett.,  2018, 10(2), 153-160.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00445] [PMID:  30783496] 
[30] 
Clark, J.D.; Flanagan, M.E.; Telliez, J.B. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J. Med. Chem.,  2014, 57(12), 5023-5038.
[http://dx.doi.org/10.1021/jm401490p] [PMID:  24417533] 
[31] 
Iorizzo, M.; Tosti, A. Emerging drugs for alopecia areata: JAK inhibitors. Expert Opin. Emerg. Drugs,  2018, 23(1), 77-81.
[http://dx.doi.org/10.1080/14728214.2018.1444750] [PMID:  29466675] 
[32] 
Cotter, D.G.; Schairer, D.; Eichenfield, L. Emerging therapies for atopic dermatitis: JAK inhibitors. J. Am. Acad. Dermatol.,  2018, 78(3)(Suppl. 1), S53-S62.
[http://dx.doi.org/10.1016/j.jaad.2017.12.019] [PMID:  29248518] 
[33] 
Moore, C.A.; Iasella, C.J.; Venkataramanan, R.; Lakkis, F.G.; Smith, R.B.; McDyer, J.F.; Zeevi, A.; Ensor, C.R. Janus kinase inhibition for immunosuppression in solid organ transplantation: Is there a role in complex immunologic challenges? Hum. Immunol.,  2017, 78(2), 64-71.
[http://dx.doi.org/10.1016/j.humimm.2016.12.005] [PMID:  27998802] 
[34] 
Sarzi-Puttini, P.; Ceribelli, A.; Marotto, D.; Batticciotto, A.; Atzeni, F. Systemic rheumatic diseases: From biological agents to small molecules. Autoimmun. Rev.,  2019, 18(6), 583-592.
[http://dx.doi.org/10.1016/j.autrev.2018.12.009] [PMID:  30959214] 
[35] 
Przepiorka, D.; Luo, L.; Subramaniam, S.; Qiu, J.; Gudi, R.; Cunningham, L.C.; Nie, L.; Leong, R.; Ma, L.; Sheth, C.; Deisseroth, A.; Goldberg, K.B.; Blumenthal, G.M.; Pazdur, R. FDA approval summary: ruxolitinib for treatment of steroid-refractory acute graft-versus-host disease. Oncologist,  2020, 25(2), e328-e334.
[http://dx.doi.org/10.1634/theoncologist.2019-0627] [PMID:  32043777] 
[36] 
Machado-Neto, J.A.; Coelho-Silva, J.L.; Santos, F.P.S.; Scheucher, P.S.; Campregher, P.V.; Hamerschlak, N.; Rego, E.M.; Traina, F. Autophagy inhibition potentiates ruxolitinib-induced apoptosis in JAK2V617F cells. Invest. New Drugs,  2020, 38(3), 733-745.
[http://dx.doi.org/10.1007/s10637-019-00812-5] [PMID:  31286322] 
[37] 
Quintás-Cardama, A.; Vaddi, K.; Liu, P.; Manshouri, T.; Li, J.; Scherle, P.A.; Caulder, E.; Wen, X.; Li, Y.; Waeltz, P.; Rupar, M.; Burn, T.; Lo, Y.; Kelley, J.; Covington, M.; Shepard, S.; Rodgers, J.D.; Haley, P.; Kantarjian, H.; Fridman, J.S.; Verstovsek, S. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: Therapeutic implications for the treatment of myeloproliferative neo-plasms. Blood,  2010, 115(15), 3109-3117.
[http://dx.doi.org/10.1182/blood-2009-04-214957] [PMID:  20130243] 
[38] 
Kuykendall, A.T.; Horvat, N.P.; Pandey, G.; Komrokji, R.; Reuther, G.W. Finding a Jill for JAK: Assessing past, present, and future jak inhibitor combination approaches in myelofibrosis. Cancers (Basel),  2020, 12(8), 2278.
[http://dx.doi.org/10.3390/cancers12082278] [PMID:  32823910] 
[39] 
Breccia, M.; Luciano, L.; Pugliese, N.; Rossi, E.; Tiribelli, M.; Scalzulli, E.; Bonifacio, M.; Martino, B.; Latagliata, R.; Benevolo, G.; Caocci, G.; Binotto, G.; Martinelli, V.; Cavo, M.; Pane, F.; De Stefano, V.; Foà, R.; Palandri, F. Efficacy and safety of ruxolitinib and hydroxyurea combination in patients with hyperproliferative myelofibrosis. Ann. Hematol.,  2019, 98(8), 1933-1936.
[http://dx.doi.org/10.1007/s00277-019-03727-6] [PMID:  31201513] 
[40] 
Modemann, F.; Ayuk, F.; Wolschke, C.; Christopeit, M.; Janson, D.; von Pein, U.M.; Kröger, N. Ruxolitinib plus extracorporeal pho-topheresis (ECP) for steroid refractory acute graft-versus-host disease of lower GI-tract after allogeneic stem cell transplantation leads to increased regulatory T cell level. Bone Marrow Transplant.,  2020, 55(12), 2286-2293.
[http://dx.doi.org/10.1038/s41409-020-0952-z] [PMID:  32447349] 
[41] 
Shilling, A.D.; Nedza, F.M.; Emm, T.; Diamond, S.; McKeever, E.; Punwani, N.; Williams, W.; Arvanitis, A.; Galya, L.G.; Li, M.; Shepard, S.; Rodgers, J.; Yue, T.Y.; Yeleswaram, S. Metabolism, excretion, and pharmacokinetics of [14C]INCB018424, a selective Janus tyrosine kinase 1/2 inhibitor, in humans. Drug Metab. Dispos.,  2010, 38(11), 2023-2031.
[http://dx.doi.org/10.1124/dmd.110.033787] [PMID:  20699411] 
[42] 
Rosmarin, D.; Pandya, A.G.; Lebwohl, M.; Grimes, P.; Hamzavi, I.; Gottlieb, A.B.; Butler, K.; Kuo, F.; Sun, K.; Ji, T.; Howell, M.D.; Harris, J.E. Ruxolitinib cream for treatment of vitiligo: a randomised, controlled, phase 2 trial. Lancet,  2020, 396(10244), 110-120.
[http://dx.doi.org/10.1016/S0140-6736(20)30609-7] [PMID:  32653055] 
[43] 
Rothstein, B.; Joshipura, D.; Saraiya, A.; Abdat, R.; Ashkar, H.; Turkowski, Y.; Sheth, V.; Huang, V.; Au, S.C.; Kachuk, C.; Dumont, N.; Gottlieb, A.B.; Rosmarin, D. Treatment of vitiligo with the topical Janus kinase inhibitor ruxolitinib. J. Am. Acad. Dermatol.,  2017, 76(6), 1054-1060.e1.
[http://dx.doi.org/10.1016/j.jaad.2017.02.049] [PMID:  28390737] 
[44] 
Lin, Q.; Meloni, D.; Pan, Y.; Xia, M.; Rodgers, J.; Shepard, S.; Li, M.; Galya, L.; Metcalf, B.; Yue, T.Y.; Liu, P.; Zhou, J. Enantioselec-tive synthesis of Janus kinase inhibitor INCB018424 via an organocatalytic aza-Michael reaction. Org. Lett.,  2009, 11(9), 1999-2002.
[http://dx.doi.org/10.1021/ol900350k] [PMID:  19385672] 
[45] 
Meyer, D.M.; Jesson, M.I.; Li, X.; Elrick, M.M.; Funckes-Shippy, C.L.; Warner, J.D.; Gross, C.J.; Dowty, M.E.; Ramaiah, S.K.; Hirsch, J.L.; Saabye, M.J.; Barks, J.L.; Kishore, N.; Morris, D.L. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J. Inflamm. (Lond.),  2010, 7(1), 41.
[http://dx.doi.org/10.1186/1476-9255-7-41] [PMID:  20701804] 
[46] 
Borie, D.C.; Changelian, P.S.; Larson, M.J.; Si, M.S.; Paniagua, R.; Higgins, J.P.; Holm, B.; Campbell, A.; Lau, M.; Zhang, S.; Flores, M.G.; Rousvoal, G.; Hawkins, J.; Ball, D.A.; Kudlacz, E.M.; Brissette, W.H.; Elliott, E.A.; Reitz, B.A.; Morris, R.E. Immunosuppres-sion by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates. Transplantation,  2005, 79(7), 791-801.
[http://dx.doi.org/10.1097/01.TP.0000157117.30290.6F] [PMID:  15818321] 
[47] 
Sanachai, K.; Mahalapbutr, P.; Choowongkomon, K.; Poo-Arporn, R.P.; Wolschann, P.; Rungrotmongkol, T. Insights into the binding recognition and susceptibility of Tofacitinib toward Janus Kinases. ACS Omega,  2020, 5(1), 369-377.
[http://dx.doi.org/10.1021/acsomega.9b02800] [PMID:  31956784] 
[48] 
van Beuningen, H.M.; de Vries-van Melle, M.L.; Vitters, E.L.; Schreurs, W.; van den Berg, W.B.; van Osch, G.J.; van der Kraan, P.M. Inhibition of TAK1 and/or JAK can rescue impaired chondrogenic differentiation of human mesenchymal stem cells in osteoarthritis-like conditions. Tissue Eng. Part A,  2014, 20(15-16), 2243-2252.
[http://dx.doi.org/10.1089/ten.tea.2013.0553] [PMID:  24547725] 
[49] 
Boyle, D.L.; Soma, K.; Hodge, J.; Kavanaugh, A.; Mandel, D.; Mease, P.; Shurmur, R.; Singhal, A.K.; Wei, N.; Rosengren, S.; Kaplan, I.; Krishnaswami, S.; Luo, Z.; Bradley, J.; Firestein, G.S. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann. Rheum. Dis.,  2015, 74(6), 1311-1316.
[http://dx.doi.org/10.1136/annrheumdis-2014-206028] [PMID:  25398374] 
[50] 
Finckh, A.; Tellenbach, C.; Herzog, L.; Scherer, A.; Moeller, B.; Ciurea, A.; von Muehlenen, I.; Gabay, C.; Kyburz, D.; Brulhart, L.; Müller, R.; Hasler, P.; Zufferey, P. Comparative effectiveness of antitumour necrosis factor agents, biologics with an alternative mode of action and tofacitinib in an observational cohort of patients with rheumatoid arthritis in Switzerland. RMD Open,  2020, 6(1), e001174.
[http://dx.doi.org/10.1136/rmdopen-2020-001174] [PMID:  32385143] 
[51] 
Cohen, S.B.; Pope, J.; Haraoui, B.; Irazoque-Palazuelos, F.; Korkosz, M.; Diehl, A.; Keystone, E.C. Methotrexate withdrawal in patients with rheumatoid arthritis who achieve low disease activity with tofacitinib modified-release 11 mg once daily plus methotrexate (ORAL Shift): a randomised, phase 3b/4, non-inferiority trial. Lancet Rheumatol.,  2019, 7(2), e001673.
[http://dx.doi.org/10.1016/S2665-9913(19)30005-0] [PMID:  34103405] 
[52] 
Kivitz, A.J.; Cohen, S.; Keystone, E.; van Vollenhoven, R.F.; Haraoui, B.; Kaine, J.; Fan, H.; Connell, C.A.; Bananis, E.; Takiya, L.; Fleischmann, R. A pooled analysis of the safety of tofacitinib as monotherapy or in combination with background conventional synthetic disease-modifying antirheumatic drugs in a Phase 3 rheumatoid arthritis population. Semin. Arthritis Rheum.,  2018, 48(3), 406-415.
[http://dx.doi.org/10.1016/j.semarthrit.2018.07.006] [PMID:  30177460] 
[53] 
Merola, J.F.; Elewski, B.; Tatulych, S.; Lan, S.; Tallman, A.; Kaur, M. Efficacy of tofacitinib for the treatment of nail psoriasis: Two 52-week, randomized, controlled phase 3 studies in patients with moderate-to-severe plaque psoriasis. J. Am. Acad. Dermatol.,  2017, 77(1), 79-87.e1.
[http://dx.doi.org/10.1016/j.jaad.2017.01.053] [PMID:  28396102] 
[54] 
Bachelez, H.; van de Kerkhof, P.C.M.; Strohal, R.; Kubanov, A.; Valenzuela, F.; Lee, J.H.; Yakusevich, V.; Chimenti, S.; Papa-charalambous, J.; Proulx, J.; Gupta, P.; Tan, H.; Tawadrous, M.; Valdez, H.; Wolk, R. Tofacitinib versus etanercept or placebo in mod-erate-to-severe chronic plaque psoriasis: A phase 3 randomised non-inferiority trial. Lancet,  2015, 386(9993), 552-561.
[http://dx.doi.org/10.1016/S0140-6736(14)62113-9] [PMID:  26051365] 
[55] 
Feldman, S.R.; Thaçi, D.; Gooderham, M.; Augustin, M.; de la Cruz, C.; Mallbris, L.; Buonanno, M.; Tatulych, S.; Kaur, M.; Lan, S.; Valdez, H.; Mamolo, C. Tofacitinib improves pruritus and health-related quality of life up to 52 weeks: Results from 2 randomized phase III trials in patients with moderate to severe plaque psoriasis. J. Am. Acad. Dermatol.,  2016, 75(6), 1162-1170.e3.
[http://dx.doi.org/10.1016/j.jaad.2016.07.040] [PMID:  27692733] 
[56] 
Wu, J.J.; Strober, B.E.; Hansen, P.R.; Ahlehoff, O.; Egeberg, A.; Qureshi, A.A.; Robertson, D.; Valdez, H.; Tan, H.; Wolk, R. Effects of tofacitinib on cardiovascular risk factors and cardiovascular outcomes based on phase III and long-term extension data in patients with plaque psoriasis. J. Am. Acad. Dermatol.,  2016, 75(5), 897-905.
[http://dx.doi.org/10.1016/j.jaad.2016.06.012] [PMID:  27498960] 
[57] 
Li, Y.; Liu, X.; Yu, J.; Li, Z.; Chen, Y.; Li, H.; Chen, X.; Su, W.; Liang, D. Tofacitinib suppresses mast cell degranulation and attenuates experimental allergic conjunctivitis. Int. Immunopharmacol.,  2020, 86, 106737.
[http://dx.doi.org/10.1016/j.intimp.2020.106737] [PMID:  32615452] 
[58] 
van Gurp, E.; Weimar, W.; Gaston, R.; Brennan, D.; Mendez, R.; Pirsch, J.; Swan, S.; Pescovitz, M.D.; Ni, G.; Wang, C.; Krishnaswa-mi, S.; Chow, V.; Chan, G. Phase 1 dose-escalation study of CP-690 550 in stable renal allograft recipients: preliminary findings of safety, tolerability, effects on lymphocyte subsets and pharmacokinetics. Am. J. Transplant.,  2008, 8(8), 1711-1718.
[http://dx.doi.org/10.1111/j.1600-6143.2008.02307.x] [PMID:  18557720] 
[59] 
Guo, L.; Feng, S.; Sun, B.; Jiang, X.; Liu, Y.; Guo, L.; Feng, S.; Liu, Y.; Guo, L.; Feng, S.; Liu, Y.; Liu, Y. Benefit and risk profile of tofacitinib for the treatment of alopecia areata: a systemic review and meta-analysis. J. Eur. Acad. Dermatol. Venereol.,  2020, 34(1), 192-201.
[http://dx.doi.org/10.1111/jdv.15937] [PMID:  31494993] 
[60] 
Tanida, S.; Ozeki, K.; Mizoshita, T.; Kitagawa, M.; Ozeki, T.; Tanaka, M.; Nishie, H.; Shimura, T.; Kubota, E.; Kataoka, H. Combina-tion therapy with tofacitinib plus intensive granulocyte and monocyte adsorptive apheresis as induction therapy for refractory ulcerative colitis. J. Clin. Med. Res.,  2020, 12(1), 36-40.
[http://dx.doi.org/10.14740/jocmr4037] [PMID:  32010420] 
[61] 
Guimarães, P.O.; Quirk, D.; Furtado, R.H.; Maia, L.N.; Saraiva, J.F.; Antunes, M.O.; Kalil Filho, R.; Junior, V.M.; Soeiro, A.M.; Tognon, A.P.; Veiga, V.C.; Martins, P.A.; Moia, D.D.F.; Sampaio, B.S.; Assis, S.R.L.; Soares, R.V.P.; Piano, L.P.A.; Castilho, K.; Momesso, R.G.R.A.P.; Monfardini, F.; Guimarães, H.P.; Ponce de Leon, D.; Dulcine, M.; Pinheiro, M.R.T.; Gunay, L.M.; Deuring, J.J.; Rizzo, L.V.; Koncz, T.; Berwanger, O. Tofacitinib in patients hospitalized with Covid-19 pneumonia. N. Engl. J. Med.,  2021, 385(5), 406-415.
[http://dx.doi.org/10.1056/NEJMoa2101643] [PMID:  34133856] 
[62] 
Guo, X.; Li, W.; Li, Q.; Chen, Y.; Zhao, G.; Peng, Y.; Zheng, J.; Zheng, J. Tofacitinib is a mechanism-based inactivator of Cytochrome P450 3A4. Chem. Res. Toxicol.,  2019, 32(9), 1791-1800.
[http://dx.doi.org/10.1021/acs.chemrestox.9b00141] [PMID:  31414593] 
[63] 
Adolfo, M.; Mario, J.S.; Leonardo, S.S. Asymmetric total synthesis of Tofacitinib. Tetrahedron Lett.,  2013, 54(37), 5096-5098.
[http://dx.doi.org/10.1016/j.tetlet.2013.07.042] 
[64] 
Fridman, J.S.; Scherle, P.A.; Collins, R.; Burn, T.C.; Li, Y.; Li, J.; Covington, M.B.; Thomas, B.; Collier, P.; Favata, M.F.; Wen, X.; Shi, J.; McGee, R.; Haley, P.J.; Shepard, S.; Rodgers, J.D.; Yeleswaram, S.; Hollis, G.; Newton, R.C.; Metcalf, B.; Friedman, S.M.; Vaddi, K. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J. Immunol.,  2010, 184(9), 5298-5307.
[http://dx.doi.org/10.4049/jimmunol.0902819] [PMID:  20363976] 
[65] 
d’Alessandro, M.; Perillo, F.; Metella Refini, R.; Bergantini, L.; Bellisai, F.; Selvi, E.; Cameli, P.; Manganelli, S.; Conticini, E.; Canta-rini, L.; Sestini, P.; Frediani, B.; Bargagli, E. Efficacy of baricitinib in treating rheumatoid arthritis: Modulatory effects on fibrotic and in-flammatory biomarkers in a real-life setting. Int. Immunopharmacol.,  2020, 86, 106748.
[http://dx.doi.org/10.1016/j.intimp.2020.106748] [PMID:  32645631] 
[66] 
Liu, C.; Arnold, R.; Henriques, G.; Djabali, K. Inhibition of JAK-STAT signaling with baricitinib reduces inflammation and improves cellular homeostasis in progeria cells. Cells,  2019, 8(10), 1276.
[http://dx.doi.org/10.3390/cells8101276] [PMID:  31635416] 
[67] 
Keystone, E.C.; Taylor, P.C.; Drescher, E.; Schlichting, D.E.; Beattie, S.D.; Berclaz, P.Y.; Lee, C.H.; Fidelus-Gort, R.K.; Luchi, M.E.; Rooney, T.P.; Macias, W.L.; Genovese, M.C. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann. Rheum. Dis.,  2015, 74(2), 333-340.
[http://dx.doi.org/10.1136/annrheumdis-2014-206478] [PMID:  25431052] 
[68] 
Simpson, E.L.; Lacour, J.P.; Spelman, L.; Galimberti, R.; Eichenfield, L.F.; Bissonnette, R.; King, B.A.; Thyssen, J.P.; Silverberg, J.I.; Bieber, T.; Kabashima, K.; Tsunemi, Y.; Costanzo, A.; Guttman-Yassky, E.; Beck, L.A.; Janes, J.M.; DeLozier, A.M.; Gamalo, M.; Brinker, D.R.; Cardillo, T.; Nunes, F.P.; Paller, A.S.; Wollenberg, A.; Reich, K. Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: Results from two randomized monotherapy phase III trials. Br. J. Dermatol.,  2020, 183(2), 242-255.
[http://dx.doi.org/10.1111/bjd.18898] [PMID:  31995838] 
[69] 
Guttman-Yassky, E.; Silverberg, J.I.; Nemoto, O.; Forman, S.B.; Wilke, A.; Prescilla, R.; de la Peña, A.; Nunes, F.P.; Janes, J.; Gama-lo, M.; Donley, D.; Paik, J.; DeLozier, A.M.; Nickoloff, B.J.; Simpson, E.L. Baricitinib in adult patients with moderate-to-severe atopic dermatitis: A phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study. J. Am. Acad. Dermatol.,  2019, 80(4), 913-921.e9.
[http://dx.doi.org/10.1016/j.jaad.2018.01.018] [PMID:  29410014] 
[70] 
Shi, J.G.; Chen, X.; Lee, F.; Emm, T.; Scherle, P.A.; Lo, Y.; Punwani, N.; Williams, W.V.; Yeleswaram, S. The pharmacokinetics, pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers. J. Clin. Pharmacol.,  2014, 54(12), 1354-1361.
[http://dx.doi.org/10.1002/jcph.354] [PMID:  24965573] 
[71] 
Jabbari, A.; Dai, Z.; Xing, L.; Cerise, J.E.; Ramot, Y.; Berkun, Y.; Sanchez, G.A.; Goldbach-Mansky, R.; Christiano, A.M.; Clynes, R.; Zlotogorski, A.; Clynes, R. Reversal of Alopecia areata following treatment with the JAK1/2 inhibitor Baricitinib. EBioMedicine,  2015, 2(4), 351-355.
[http://dx.doi.org/10.1016/j.ebiom.2015.02.015] [PMID:  26137574] 
[72] 
Jorgensen, S.C.J.; Tse, C.L.Y.; Burry, L.; Dresser, L.D. Baricitinib: A review of pharmacology, safety, and emerging clinical experience in COVID-19. Pharmacotherapy,  2020, 40(8), 843-856.
[http://dx.doi.org/10.1002/phar.2438] [PMID:  32542785] 
[73] 
Wallace, D.J.; Furie, R.A.; Tanaka, Y.; Kalunian, K.C.; Mosca, M.; Petri, M.A.; Dörner, T.; Cardiel, M.H.; Bruce, I.N.; Gomez, E.; Carmack, T.; DeLozier, A.M.; Janes, J.M.; Linnik, M.D.; de Bono, S.; Silk, M.E.; Hoffman, R.W. Baricitinib for systemic lupus ery-thematosus: A double-blind, randomised, placebo-controlled, phase 2 trial. Lancet,  2018, 392(10143), 222-231.
[http://dx.doi.org/10.1016/S0140-6736(18)31363-1] [PMID:  30043749] 
[74] 
Xu, J.J.; Cai, J.; Chen, J.D.; Zong, X.; Wu, X.; Ji, M.; Wang, P. An efficient synthesis of baricitinib. J. Chem. Res.,  2016, 40(4), 205-208.
[http://dx.doi.org/10.3184/174751916X14569294811333] 
[75] 
Mohamed, M.F.; Beck, D.; Camp, H.S.; Othman, A.A. Preferential inhibition of JAK1 relative to JAK3 by Upadacitinib: Exposure-response analyses of ex vivo data from 2 Phase 1 Clinical Trials and comparison to Tofacitinib. J. Clin. Pharmacol.,  2020, 60(2), 188-197.
[http://dx.doi.org/10.1002/jcph.1513] [PMID:  31448433] 
[76] 
Kremer, J.M.; Emery, P.; Camp, H.S.; Friedman, A.; Wang, L.; Othman, A.A.; Khan, N.; Pangan, A.L.; Jungerwirth, S.; Keystone, E.C. A Phase IIb study of ABT-494, a selective JAK-1 inhibitor, in patients with rheumatoid arthritis and an inadequate response to anti-tumor necrosis factor therapy. Arthritis Rheumatol.,  2016, 68(12), 2867-2877.
[http://dx.doi.org/10.1002/art.39801] [PMID:  27389975] 
[77] 
Genovese, M.C.; Smolen, J.S.; Weinblatt, M.E.; Burmester, G.R.; Meerwein, S.; Camp, H.S.; Wang, L.; Othman, A.A.; Khan, N.; Pan-gan, A.L.; Jungerwirth, S. Efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in a Phase IIb Study in patients with rheumatoid arthritis and an inadequate response to Methotrexate. Arthritis Rheumatol.,  2016, 68(12), 2857-2866.
[http://dx.doi.org/10.1002/art.39808] [PMID:  27390150] 
[78] 
Sandborn, W.J.; Feagan, B.G.; Loftus, E.V.J., Jr; Peyrin-Biroulet, L.; Van Assche, G.; D’Haens, G.; Schreiber, S.; Colombel, J.F.; Lewis, J.D.; Ghosh, S.; Armuzzi, A.; Scherl, E.; Herfarth, H.; Vitale, L.; Mohamed, M.F.; Othman, A.A.; Zhou, Q.; Huang, B.; Thak-kar, R.B.; Pangan, A.L.; Lacerda, A.P.; Panes, J. efficacy and safety of Upadacitinib in a randomized trial of patients with Crohn’s Dis-ease. Gastroenterology,  2020, 158(8), 2123-2138.e8.
[http://dx.doi.org/10.1053/j.gastro.2020.01.047] [PMID:  32044319] 
[79] 
Nader, A.; Stodtmann, S.; Friedel, A.; Mohamed, M.F.; Othman, A.A. Pharmacokinetics of Upadacitinib in healthy subjects and sub-jects with rheumatoid arthritis, Crohn’s disease, ulcerative colitis, or atopic dermatitis: Population analyses of Phase 1 and 2 clinical tri-als. J. Clin. Pharmacol.,  2020, 60(4), 528-539.
[http://dx.doi.org/10.1002/jcph.1550] [PMID:  31701537] 
[80] 
Sandborn, W.J.; Ghosh, S.; Panes, J.; Schreiber, S.; D’Haens, G.; Tanida, S.; Siffledeen, J.; Enejosa, J.; Zhou, W.; Othman, A.A.; Huang, B.; Higgins, P.D.R. Efficacy of upadacitinib in a randomized trial of patients with active ulcerative colitis. Gastroenterology,  2020, 158(8), 2139-2149.e14.
[http://dx.doi.org/10.1053/j.gastro.2020.02.030] [PMID:  32092309] 
[81] 
Zheng, X.C.; Zhang, Y.P.; Fu, C.C.; Wu, Y.H. Method for synthesizing upadacitinib. Patent CN 201811422977, 2018.
[82] 
Geron, I.; Abrahamsson, A.E.; Barroga, C.F.; Kavalerchik, E.; Gotlib, J.; Hood, J.D.; Durocher, J.; Mak, C.C.; Noronha, G.; Soll, R.M.; Tefferi, A.; Kaushansky, K.; Jamieson, C.H.M. Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors. Cancer Cell,  2008, 13(4), 321-330.
[http://dx.doi.org/10.1016/j.ccr.2008.02.017] [PMID:  18394555] 
[83] 
Chen, D.; Zhang, F.; Wang, J.; He, H.; Duan, S.; Zhu, R.; Chen, C.; Yin, L.; Chen, Y. Biodegradable nanoparticles mediated co-delivery of erlotinib (ELTN) and fedratinib (FDTN) toward the treatment of ELTN-resistant non-small cell lung cancer (NSCLC) via suppression of the JAK2/STAT3 signaling pathway. Front. Pharmacol.,  2018, 9, 1214.
[http://dx.doi.org/10.3389/fphar.2018.01214] [PMID:  30483119] 
[84] 
Wernig, G.; Kharas, M.G.; Okabe, R.; Moore, S.A.; Leeman, D.S.; Cullen, D.E.; Gozo, M.; McDowell, E.P.; Levine, R.L.; Doukas, J.; Mak, C.C.; Noronha, G.; Martin, M.; Ko, Y.D.; Lee, B.H.; Soll, R.M.; Tefferi, A.; Hood, J.D.; Gilliland, D.G. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell,  2008, 13(4), 311-320.
[http://dx.doi.org/10.1016/j.ccr.2008.02.009] [PMID:  18394554] 
[85] 
Liu, H.C.; Lu, S.; Zhang, Y.M.; Zhou, W.N.; Yin, L.F.; Zhu, L.; Zhao, J.N.; Lu, T.; Chen, Y.D. Molecular dynamics simulation of the selectivity of Fedratinib complex with JAK2/JAK3. Chem. J. Chin. Univ.,  2018, 39(7), 1540-1548.
[86] 
Ogasawara, K.; Smith, W.B.; Xu, C.; Yin, J.; Palmisano, M.; Krishna, G. Pharmacokinetics and tolerability of fedratinib, an oral, selec-tive Janus kinase 2 inhibitor, in subjects with renal or hepatic impairment. Cancer Chemother. Pharmacol.,  2020, 85(6), 1109-1117.
[http://dx.doi.org/10.1007/s00280-020-04084-2] [PMID:  32449142] 
[87] 
Ogasawara, K.; Xu, C.; Kanamaluru, V.; Siebers, N.; Surapaneni, S.; Ridoux, L.; Palmisano, M.; Krishna, G. Excretion balance and pharmacokinetics following a single oral dose of [14C]-fedratinib in healthy subjects. Cancer Chemother. Pharmacol.,  2020, 86(2), 307-314.
[http://dx.doi.org/10.1007/s00280-020-04121-0] [PMID:  32748109] 
[88] 
Emori, T.; Kasahara, M.; Sugahara, S.; Hashimoto, M.; Ito, H.; Narumiya, S.; Higashi, Y.; Fujii, Y. Role of JAK-STAT signaling in the pathogenic behavior of fibroblast-like synoviocytes in rheumatoid arthritis: Effect of the novel JAK inhibitor peficitinib. Eur. J. Pharmacol.,  2020, 882, 173238.
[http://dx.doi.org/10.1016/j.ejphar.2020.173238] [PMID:  32561292] 
[89] 
Ikari, Y.; Isozaki, T.; Tsubokura, Y.; Kasama, T. Peficitinib Inhibits the chemotactic activity of monocytes via proinflammatory cytokine production in rheumatoid arthritis fibroblast-like synoviocytes. Cells,  2019, 8(6), 561.
[http://dx.doi.org/10.3390/cells8060561] [PMID:  31181818] 
[90] 
Diller, M.; Hasseli, R.; Hülser, M.L.; Aykara, I.; Frommer, K.; Rehart, S.; Müller-Ladner, U.; Neumann, E. Targeting activated synovial fibroblasts in rheumatoid arthritis by peficitinib. Front. Immunol.,  2019, 10, 541.
[http://dx.doi.org/10.3389/fimmu.2019.00541] [PMID:  30984167] 
[91] 
Takeuchi, T.; Tanaka, Y.; Tanaka, S.; Kawakami, A.; Iwasaki, M.; Katayama, K.; Rokuda, M.; Izutsu, H.; Ushijima, S.; Kaneko, Y.; Shiomi, T.; Yamada, E.; van der Heijde, D. Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an in-adequate response to methotrexate: Results of a phase III randomised, double-blind, placebo-controlled trial (RAJ4) in Japan. Ann. Rheum. Dis.,  2019, 78(10), 1305-1319.
[http://dx.doi.org/10.1136/annrheumdis-2019-215164] [PMID:  31350269] 
[92] 
Genovese, M.C.; Greenwald, M.; Codding, C.; Zubrzycka-Sienkiewicz, A.; Kivitz, A.J.; Wang, A.; Shay, K.; Wang, X.; Garg, J.P.; Cardiel, M.H. Peficitinib, a JAK inhibitor, in combination with limited conventional synthetic disease-modifying antirheumatic drugs in the treatment of moderate-to-severe rheumatoid arthritis. Arthritis Rheumatol.,  2017, 69(5), 932-942.
[http://dx.doi.org/10.1002/art.40054] [PMID:  28118538] 
[93] 
Zhu, T.; Moy, S.; Valluri, U.; Cao, Y.; Zhang, W.; Sawamoto, T.; Chindalore, V.; Akinlade, B.; Akinlade, B. Investigation of Potential Drug-Drug Interactions between Peficitinib (ASP015K) and Methotrexate in Patients with Rheumatoid Arthritis. Clin. Drug Investig.,  2020, 40(9), 827-838.
[http://dx.doi.org/10.1007/s40261-020-00937-z] [PMID:  32591978] 
[94] 
Miyatake, D.; Shibata, T.; Shibata, M.; Kaneko, Y.; Oda, K.; Nishimura, T.; Katashima, M.; Sekino, H.; Furihata, K.; Urae, A. Pharma-cokinetics and Safety of a Single Oral Dose of Peficitinib (ASP015K) in Japanese Subjects with Normal and Impaired Renal Function. Clin. Drug Investig.,  2020, 40(2), 149-159.
[http://dx.doi.org/10.1007/s40261-019-00873-7] [PMID:  31729626] 
[95] 
Hamaguchi, H.; Amano, Y.; Moritomo, A.; Shirakami, S.; Nakajima, Y.; Nakai, K.; Nomura, N.; Ito, M.; Higashi, Y.; Inoue, T. Dis-covery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor. Bioorg. Med. Chem.,  2018, 26(18), 4971-4983.
[http://dx.doi.org/10.1016/j.bmc.2018.08.005] [PMID:  30145050] 
[96] 
Nakajima, Y.; Tojo, T.; Morita, M.; Hatanaka, K.; Shirakami, S.; Tanaka, A.; Sasaki, H.; Nakai, K.; Mukoyoshi, K.; Hamaguchi, H.; Takahashi, F.; Moritomo, A.; Higashi, Y.; Inoue, T. Synthesis and evaluation of 1H-pyrrolo[2,3-b]pyridine derivatives as novel im-munomodulators targeting Janus kinase 3. Chem. Pharm. Bull. (Tokyo),  2015, 63(5), 341-353.
[http://dx.doi.org/10.1248/cpb.c15-00036] [PMID:  25786493] 
[97] 
Tanimoto, A.; Ogawa, Y.; Oki, C.; Kimoto, Y.; Nozawa, K.; Amano, W.; Noji, S.; Shiozaki, M.; Matsuo, A.; Shinozaki, Y.; Matsushita, M. Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo. Inflamm. Res.,  2015, 64(1), 41-51.
[http://dx.doi.org/10.1007/s00011-014-0782-9] [PMID:  25387665] 
[98] 
Amano, W.; Nakajima, S.; Kunugi, H.; Numata, Y.; Kitoh, A.; Egawa, G.; Dainichi, T.; Honda, T.; Otsuka, A.; Kimoto, Y.; Yamamoto, Y.; Tanimoto, A.; Matsushita, M.; Miyachi, Y.; Kabashima, K. The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling. J. Allergy Clin. Immunol.,  2015, 136(3), 667-677.e7.
[http://dx.doi.org/10.1016/j.jaci.2015.03.051] [PMID:  26115905] 
[99] 
Nakagawa, H.; Nemoto, O.; Igarashi, A.; Saeki, H.; Kaino, H.; Nagata, T. Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study. J. Am. Acad. Dermatol.,  2020, 82(4), 823-831.
[http://dx.doi.org/10.1016/j.jaad.2019.12.015] [PMID:  32029304] 
[100] 
Nakagawa, H.; Nemoto, O.; Igarashi, A.; Saeki, H.; Oda, M.; Kabashima, K.; Nagata, T. Phase 2 clinical study of delgocitinib ointment in pediatric patients with atopic dermatitis. J. Allergy Clin. Immunol.,  2019, 144(6), 1575-1583.
[http://dx.doi.org/10.1016/j.jaci.2019.08.004] [PMID:  31425780] 
[101] 
Nakagawa, H.; Nemoto, O.; Igarashi, A.; Saeki, H.; Murata, R.; Kaino, H.; Nagata, T. Long-term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis. J. Dermatol.,  2020, 47(2), 114-120.
[http://dx.doi.org/10.1111/1346-8138.15173] [PMID:  31820485] 
[102] 
Takiguchi, H.; Higashi, A.; Inaba, T.; Watanabe, T.; Takeichi, T.; Petersen, A.K.; Vedsoe, P.; Jensen, K.L.; Bornholdt, J.; Ebdrup, S. Process for preparation of 7Hpyrrolo[2,3-d]pyrimidine derivatives and synthetic intermediates.  Patent WO 2018117152, 2018.
[103] 
Xu, X.N. Preparation method of delgocitinib.  Patent CN 111606929, 2020.
[104] 
Menet, C.J.; Fletcher, S.R.; Van Lommen, G.; Geney, R.; Blanc, J.; Smits, K.; Jouannigot, N.; Deprez, P.; van der Aar, E.M.; Clement-Lacroix, P.; Lepescheux, L.; Galien, R.; Vayssiere, B.; Nelles, L.; Christophe, T.; Brys, R.; Uhring, M.; Ciesielski, F.; Van Rompaey, L. Triazolopyridines as selective JAK1 inhibitors: from hit identification to GLPG0634. J. Med. Chem.,  2014, 57(22), 9323-9342.
[http://dx.doi.org/10.1021/jm501262q] [PMID:  25369270] 
[105] 
Wang, Y.; Chen, L.; Xie, L.; Li, L.; Li, X.; Li, H.; Liu, J.; Chen, X.; Mao, B.; Song, T.; Lian, Q.; Ge, R.S. Interleukin 6 inhibits the dif-ferentiation of rat stem Leydig cells. Mol. Cell. Endocrinol.,  2018, 472, 26-39.
[http://dx.doi.org/10.1016/j.mce.2017.11.016] [PMID:  29180110] 
[106] 
Van Rompaey, L.; Galien, R.; van der Aar, E.M.; Clement-Lacroix, P.; Nelles, L.; Smets, B.; Lepescheux, L.; Christophe, T.; Conrath, K.; Vandeghinste, N.; Vayssiere, B.; De Vos, S.; Fletcher, S.; Brys, R.; van ’t Klooster, G.; Feyen, J.H.; Menet, C. Preclinical character-ization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases. J. Immunol.,  2013, 191(7), 3568-3577.
[http://dx.doi.org/10.4049/jimmunol.1201348] [PMID:  24006460] 
[107] 
Lee, Y.H.; Song, G.G. Comparison of the efficacy and safety of tofacitinib and filgotinib in patients with active rheumatoid arthritis: A Bayesian network meta-analysis of randomized controlled trials. Z. Rheumatol.,  2020, 79(6), 590-603.
[http://dx.doi.org/10.1007/s00393-019-00733-x] [PMID:  31781849] 
[108] 
Genovese, M.; Westhovens, R.; Meuleners, L.; Van der Aa, A.; Harrison, P.; Tasset, C.; Kavanaugh, A. Effect of filgotinib, a selective JAK 1 inhibitor, with and without methotrexate in patients with rheumatoid arthritis: Patient-reported outcomes. Arthritis Res. Ther.,  2018, 20(1), 57.
[http://dx.doi.org/10.1186/s13075-018-1541-z] [PMID:  29566740] 
[109] 
Vermeire, S.; Schreiber, S.; Petryka, R.; Kuehbacher, T.; Hebuterne, X.; Roblin, X.; Klopocka, M.; Goldis, A.; Wisniewska-Jarosinska, M.; Baranovsky, A.; Sike, R.; Stoyanova, K.; Tasset, C.; Van der Aa, A.; Harrison, P. Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study): Results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet,  2017, 389(10066), 266-275.
[http://dx.doi.org/10.1016/S0140-6736(16)32537-5] [PMID:  27988142] 
[110] 
Orbai, A.M.; Ogdie, A.; Gossec, L.; Tillett, W.; Leung, Y.Y.; Gao, J.; Trivedi, M.; Tasset, C.; Meuleners, L.; Besuyen, R.; Hendrikx, T.; Coates, L.C. Effect of filgotinib on health-related quality of life in active psoriatic arthritis: A randomized phase 2 trial (EQUATOR). Rheumatology (Oxford),  2020, 59(7), 1495-1504.
[http://dx.doi.org/10.1093/rheumatology/kez408] [PMID:  31624837] 
[111] 
van der Heijde, D.; Baraliakos, X.; Gensler, L.S.; Maksymowych, W.P.; Tseluyko, V.; Nadashkevich, O.; Abi-Saab, W.; Tasset, C.; Meuleners, L.; Besuyen, R.; Hendrikx, T.; Mozaffarian, N.; Liu, K.; Greer, J.M.; Deodhar, A.; Landewé, R. Efficacy and safety of filgo-tinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): Results from a randomised, place-bo-controlled, phase 2 trial. Lancet,  2018, 392(10162), 2378-2387.
[http://dx.doi.org/10.1016/S0140-6736(18)32463-2] [PMID:  30360970] 
[112] 
Sathe, D.G.; Das, A.; Patel, B.; Kshirsagar, E.; Patil, D.; Matale, A. Novel process for the preparation of filgotinib and intermediates thereof. Pantent WO 2020201975, 2020.
[113] 
Farmer, L.J.; Ledeboer, M.W.; Hoock, T.; Arnost, M.J.; Bethiel, R.S.; Bennani, Y.L.; Black, J.J.; Brummel, C.L.; Chakilam, A.; Dorsch, W.A.; Fan, B.; Cochran, J.E.; Halas, S.; Harrington, E.M.; Hogan, J.K.; Howe, D.; Huang, H.; Jacobs, D.H.; Laitinen, L.M.; Liao, S.; Mahajan, S.; Marone, V.; Martinez-Botella, G.; McCarthy, P.; Messersmith, D.; Namchuk, M.; Oh, L.; Penney, M.S.; Pierce, A.C.; Raybuck, S.A.; Rugg, A.; Salituro, F.G.; Saxena, K.; Shannon, D.; Shlyakter, D.; Swenson, L.; Tian, S.K.; Town, C.; Wang, J.; Wang, T.; Wannamaker, M.W.; Winquist, R.J.; Zuccola, H.J. Discovery of VX-509 (Decernotinib): A potent and selective Janus Kinase 3 inhibitor for the treatment of autoimmune diseases. J. Med. Chem.,  2015, 58(18), 7195-7216.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00301] [PMID:  26230873] 
[114] 
Mahajan, S.; Hogan, J.K.; Shlyakhter, D.; Oh, L.; Salituro, F.G.; Farmer, L.; Hoock, T.C. VX-509 (decernotinib) is a potent and selec-tive janus kinase 3 inhibitor that attenuates inflammation in animal models of autoimmune disease. J. Pharmacol. Exp. Ther.,  2015, 353(2), 405-414.
[http://dx.doi.org/10.1124/jpet.114.221176] [PMID:  25762693] 
[115] 
Fleischmann, R.M.; Damjanov, N.S.; Kivitz, A.J.; Legedza, A.; Hoock, T.; Kinnman, N. A randomized, double-blind, placebo-controlled, twelve-week, dose-ranging study of decernotinib, an oral selective JAK-3 inhibitor, as monotherapy in patients with active rheumatoid arthritis. Arthritis Rheumatol.,  2015, 67(2), 334-343.
[http://dx.doi.org/10.1002/art.38949] [PMID:  25385260] 
[116] 
Genovese, M.C.; van Vollenhoven, R.F.; Pacheco-Tena, C.; Zhang, Y.; Kinnman, N. VX-509 (Decernotinib), an oral selective JAK-3 inhibitor, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheumatol.,  2016, 68(1), 46-55.
[http://dx.doi.org/10.1002/art.39473] [PMID:  26473751] 
[117] 
Coffey, G.; Betz, A.; DeGuzman, F.; Pak, Y.; Inagaki, M.; Baker, D.C.; Hollenbach, S.J.; Pandey, A.; Sinha, U. The novel kinase inhib-itor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J. Pharmacol. Exp. Ther.,  2014, 351(3), 538-548.
[http://dx.doi.org/10.1124/jpet.114.218164] [PMID:  25253883] 
[118] 
Ishikawa, C.; Senba, M.; Mori, N. Anti-adult T cell leukemia/lymphoma activity of cerdulatinib, a dual SYK/JAK kinase inhibitor. Int. J. Oncol.,  2018, 53(4), 1681-1690.
[http://dx.doi.org/10.3892/ijo.2018.4513] [PMID:  30066853] 
[119] 
Lai, P.C.; Fang, T.C.; Cheng, C.C.; Chiu, T.H.; Huang, Y.T. Lestaurtinib is cytotoxic to oxaliplatin-resistant transitional cell carcinoma cell Line T24 in vitro. Tzu-Chi Med. J.,  2010, 22(3), 125-130.
[http://dx.doi.org/10.1016/S1016-3190(10)60056-0] 
[120] 
Cao, Y.; Kong, S.; Xin, Y.; Meng, Y.; Shang, S.; Qi, Y. Lestaurtinib potentiates TRAIL-induced apoptosis in glioma via CHOP-dependent DR5 induction. J. Cell. Mol. Med.,  2020, 24(14), 7829-7840.
[http://dx.doi.org/10.1111/jcmm.15415] [PMID:  32441887] 
[121] 
Pinto, N.; Prokopec, S.D.; Vizeacoumar, F.; Searle, K.; Lowerison, M.; Ruicci, K.M.; Yoo, J.; Fung, K.; MacNeil, D.; Lacefield, J.C.; Leong, H.S.; Mymryk, J.S.; Barrett, J.W.; Datti, A.; Boutros, P.C.; Nichols, A.C. Lestaurtinib is a potent inhibitor of anaplastic thyroid cancer cell line models. PLoS One,  2018, 13(11), e0207152.
[http://dx.doi.org/10.1371/journal.pone.0207152] [PMID:  30419054] 
[122] 
Verstovsek, S.; Odenike, O.; Singer, J.W.; Granston, T.; Al-Fayoumi, S.; Deeg, H.J. Phase 1/2 study of pacritinib, a next generation JAK2/FLT3 inhibitor, in myelofibrosis or other myeloid malignancies. J. Hematol. Oncol.,  2016, 9(1), 137.
[http://dx.doi.org/10.1186/s13045-016-0367-x] [PMID:  27931243] 
[123] 
Singer, J.W.; Al-Fayoumi, S.; Taylor, J.; Velichko, S.; O’Mahony, A. Comparative phenotypic profiling of the JAK2 inhibitors rux-olitinib, fedratinib, momelotinib, and pacritinib reveals distinct mechanistic signatures. PLoS One,  2019, 14(9), e0222944.
[http://dx.doi.org/10.1371/journal.pone.0222944] [PMID:  31560729] 
[124] 
Betts, B.C.; Bastian, D.; Iamsawat, S.; Nguyen, H.; Heinrichs, J.L.; Wu, Y.; Daenthanasanmak, A.; Veerapathran, A.; O’Mahony, A.; Walton, K.; Reff, J.; Horna, P.; Sagatys, E.M.; Lee, M.C.; Singer, J.; Chang, Y.J.; Liu, C.; Pidala, J.; Anasetti, C.; Yu, X.Z. Targeting JAK2 reduces GVHD and xenograft rejection through regulation of T cell differentiation. Proc. Natl. Acad. Sci. USA,  2018, 115(7), 1582-1587.
[http://dx.doi.org/10.1073/pnas.1712452115] [PMID:  29382747] 
[125] 
Wu, H.; Yan, S.; Chen, J.; Luo, X.; Li, P.; Jia, X.; Dai, X.; Wang, C.; Huang, Q.; Liu, L.; Zhang, Y.; Zhou, A.; Chang, Y.; Zhang, L.; Wei, W. JAK1-STAT3 blockade by JAK inhibitor SHR0302 attenuates inflammatory responses of adjuvant-induced arthritis rats and decreases Th17 and total B cells. Joint Bone Spine,  2016, 83(5), 525-532.
[http://dx.doi.org/10.1016/j.jbspin.2015.09.002] [PMID:  26832189] 
[126] 
Gu, Y.J.; Sun, W.Y.; Zhang, S.; Li, X.R.; Wei, W. Targeted blockade of JAK/STAT3 signaling inhibits proliferation, migration and collagen production as well as inducing the apoptosis of hepatic stellate cells. Int. J. Mol. Med.,  2016, 38(3), 903-911.
[http://dx.doi.org/10.3892/ijmm.2016.2692] [PMID:  27460897] 
[127] 
Monaghan, K.A.; Khong, T.; Burns, C.J.; Spencer, A. The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, pre-vents proliferation and induces apoptosis in phenotypically diverse myeloma cells. Leukemia,  2011, 25(12), 1891-1899.
[http://dx.doi.org/10.1038/leu.2011.175] [PMID:  21788946] 
[128] 
Liu, T.; Li, A.; Xu, Y.; Xin, Y. Momelotinib sensitizes glioblastoma cells to temozolomide by enhancement of autophagy via JAK2/STAT3 inhibition. Oncol. Rep.,  2019, 41(3), 1883-1892.
[http://dx.doi.org/10.3892/or.2019.6970] [PMID:  30664175] 
[129] 
Cosenza, M.; Civallero, M.; Marcheselli, L.; Sacchi, S.; Pozzi, S. Citarinostat and Momelotinib co-target HDAC6 and JAK2/STAT3 in lymphoid malignant cell lines: a potential new therapeutic combination. Apoptosis,  2020, 25(5-6), 370-387.
[http://dx.doi.org/10.1007/s10495-020-01607-3] [PMID:  32394008] 
[130] 
Beatty, G.L.; Shahda, S.; Beck, T.; Uppal, N.; Cohen, S.J.; Donehower, R.; Gabayan, A.E.; Assad, A.; Switzky, J.; Zhen, H.; Von Hoff, D.D. A Phase Ib/II study of the JAK1 inhibitor, Itacitinib, plus nab-Paclitaxel and gemcitabine in advanced solid tumors. Oncologist,  2019, 24(1), 14-e10.
[http://dx.doi.org/10.1634/theoncologist.2017-0665] [PMID:  30115734] 
[131] 
Dai, Z.; Zeng, W.; Christiano, A.M. Efficacy of selective next-generation JAK inhibitors in the treatment of alopecia areata. J. Invest. Dermatol.,  2018, 138(5), S186.
[http://dx.doi.org/10.1016/j.jid.2018.03.1111] [PMID:  33830087] 
[132] 
Ismail, F.F.; Sinclair, R. JAK inhibition in the treatment of alopecia areata - a promising new dawn? Expert Rev. Clin. Pharmacol.,  2020, 13(1), 43-51.
[http://dx.doi.org/10.1080/17512433.2020.1702878] [PMID:  31865802] 
[133] 
Robinson, M.F.; Damjanov, N.; Stamenkovic, B.; Radunovic, G.; Kivitz, A.; Cox, L.; Manukyan, Z.; Banfield, C.; Saunders, M.; Chan-dra, D.; Vincent, M.S.; Mancuso, J.; Peeva, E.; Beebe, J.S. Efficacy and safety of PF-06651600 (Ritlecitinib), a novel JAK3/TEC inhibi-tor, in patients with moderate-to-severe rheumatoid arthritis and an inadequate response to Methotrexate. Arthritis Rheumatol.,  2020, 72(10), 1621-1631.
[http://dx.doi.org/10.1002/art.41316] [PMID:  32419304] 
[134] 
Peeva, E.; Hodge, M.R.; Kieras, E.; Vazquez, M.L.; Goteti, K.; Tarabar, S.G.; Alvey, C.W.; Banfield, C. Evaluation of a Janus kinase 1 inhibitor, PF-04965842, in healthy subjects: A phase 1, randomized, placebo-controlled, dose-escalation study. Br. J. Clin. Pharmacol.,  2018, 84(8), 1776-1788.
[http://dx.doi.org/10.1111/bcp.13612] [PMID:  29672897] 
[135] 
Schmieder, G.J.; Draelos, Z.D.; Pariser, D.M.; Banfield, C.; Cox, L.; Hodge, M.; Kieras, E.; Parsons-Rich, D.; Menon, S.; Salganik, M.; Page, K.; Peeva, E. Efficacy and safety of the Janus kinase 1 inhibitor PF-04965842 in patients with moderate-to-severe psoriasis: phase II, randomized, double-blind, placebo-controlled study. Br. J. Dermatol.,  2018, 179(1), 54-62.
[http://dx.doi.org/10.1111/bjd.16004] [PMID:  28949012] 
[136] 
D’Amico, F.; Fiorino, G.; Furfaro, F.; Allocca, M.; Danese, S. Janus kinase inhibitors for the treatment of inflammatory bowel diseases: developments from phase I and phase II clinical trials. Expert Opin. Investig. Drugs,  2018, 27(7), 595-599.
[http://dx.doi.org/10.1080/13543784.2018.1492547] [PMID:  29938545] 
[137] 
Thorarensen, A.; Dowty, M.E.; Banker, M.E.; Juba, B.; Jussif, J.; Lin, T.; Vincent, F.; Czerwinski, R.M.; Casimiro-Garcia, A.; Unwal-la, R.; Trujillo, J.I.; Liang, S.; Balbo, P.; Che, Y.; Gilbert, A.M.; Brown, M.F.; Hayward, M.; Montgomery, J.; Leung, L.; Yang, X.; Soucy, S.; Hegen, M.; Coe, J.; Langille, J.; Vajdos, F.; Chrencik, J.; Telliez, J.B. Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) allowing for the inter-rogation of JAK3 signaling in humans. J. Med. Chem.,  2017, 60(5), 1971-1993.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01694] [PMID:  28139931] 
[138] 
Liang, X.; Zang, J.; Zhu, M.; Gao, Q.; Wang, B.; Xu, W.; Zhang, Y. Design, synthesis, and antitumor evaluation of 4-Amino-(1H)-pyrazole derivatives as JAKs inhibitors. ACS Med. Chem. Lett.,  2016, 7(10), 950-955.
[http://dx.doi.org/10.1021/acsmedchemlett.6b00247] [PMID:  27774135] 
[139] 
Ioannidis, S.; Lamb, M.L.; Wang, T.; Almeida, L.; Block, M.H.; Davies, A.M.; Peng, B.; Su, M.; Zhang, H.J.; Hoffmann, E.; Rivard, C.; Green, I.; Howard, T.; Pollard, H.; Read, J.; Alimzhanov, M.; Bebernitz, G.; Bell, K.; Ye, M.; Huszar, D.; Zinda, M. Discovery of 5-chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a novel inhibi-tor of the Jak/Stat pathway. J. Med. Chem.,  2011, 54(1), 262-276.
[http://dx.doi.org/10.1021/jm1011319] [PMID:  21138246] 
[140] 
Fensome, A.; Ambler, C.M.; Arnold, E.; Banker, M.E.; Brown, M.F.; Chrencik, J.; Clark, J.D.; Dowty, M.E.; Efremov, I.V.; Flick, A.; Gerstenberger, B.S.; Gopalsamy, A.; Hayward, M.M.; Hegen, M.; Hollingshead, B.D.; Jussif, J.; Knafels, J.D.; Limburg, D.C.; Lin, D.; Lin, T.H.; Pierce, B.S.; Saiah, E.; Sharma, R.; Symanowicz, P.T.; Telliez, J.B.; Trujillo, J.I.; Vajdos, F.F.; Vincent, F.; Wan, Z.K.; Xing, L.; Yang, X.; Yang, X.; Zhang, L. Dual Inhibition of TYK2 and JAK1 for the treatment of autoimmune diseases: Discovery of ((S)-2,2-Difluorocyclopropyl)((1 R,5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841). J. Med. Chem.,  2018, 61(19), 8597-8612.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00917] [PMID:  30113844] 
[141] 
Su, Q.; Banks, E.; Bebernitz, G.; Bell, K.; Borenstein, C.F.; Chen, H.; Chuaqui, C.E.; Deng, N.; Ferguson, A.D.; Kawatkar, S.; Grim-ster, N.P.; Ruston, L.; Lyne, P.D.; Read, J.A.; Peng, X.; Pei, X.; Fawell, S.; Tang, Z.; Throner, S.; Vasbinder, M.M.; Wang, H.; Winter-Holt, J.; Woessner, R.; Wu, A.; Yang, W.; Zinda, M.; Kettle, J.G. Discovery of (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a Potent and Selective Janus Kinase 1 Inhibitor. J. Med. Chem.,  2020, 63(9), 4517-4527.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01392] [PMID:  32297743] 
[142] 
Yin, Y.; Chen, C.J.; Yu, R.N.; Shu, L.; Zhang, T.T.; Zhang, D.Y. Discovery of novel selective Janus kinase 2 (JAK2) inhibitors bearing a 1H-pyrazolo[3,4-d]pyrimidin-4-amino scaffold. Bioorg. Med. Chem.,  2019, 27(8), 1562-1576.
[http://dx.doi.org/10.1016/j.bmc.2019.02.054] [PMID:  30846405] 
[143] 
Kim, M.K.; Shin, H.; Park, K.S.; Kim, H.; Park, J.; Kim, K.; Nam, J.; Choo, H.; Chong, Y. Benzimidazole derivatives as potent JAK1-selective inhibitors. J. Med. Chem.,  2015, 58(18), 7596-7602.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01263] [PMID:  26351728] 
[144] 
Ritzén, A.; Sørensen, M.D.; Dack, K.N.; Greve, D.R.; Jerre, A.; Carnerup, M.A.; Rytved, K.A.; Bagger-Bahnsen, J. Fragment-based discovery of 6-Arylindazole JAK inhibitors. ACS Med. Chem. Lett.,  2016, 7(6), 641-646.
[http://dx.doi.org/10.1021/acsmedchemlett.6b00087] [PMID:  27326341] 
[145] 
Jones, P.; Storer, R.I.; Sabnis, Y.A.; Wakenhut, F.M.; Whitlock, G.A.; England, K.S.; Mukaiyama, T.; Dehnhardt, C.M.; Coe, J.W.; Kortum, S.W.; Chrencik, J.E.; Brown, D.G.; Jones, R.M.; Murphy, J.R.; Yeoh, T.; Morgan, P.; Kilty, I. Design and synthesis of a Pan-Janus Kinase inhibitor clinical candidate (PF-06263276) suitable for inhaled and topical delivery for the treatment of inflammatory dis-eases of the lungs and skin. J. Med. Chem.,  2017, 60(2), 767-786.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01634] [PMID:  27983835] 
[146] 
Bach, J.; Eastwood, P.; González, J.; Gómez, E.; Alonso, J.A.; Fonquerna, S.; Lozoya, E.; Orellana, A.; Maldonado, M.; Calaf, E.; Al-bertí, J.; Pérez, J.; Andrés, A.; Prats, N.; Carreño, C.; Calama, E.; De Alba, J.; Calbet, M.; Miralpeix, M.; Ramis, I. Identification of 2-Imidazopyridine and 2-Aminopyridone Purinones as Potent Pan-Janus Kinase (JAK) inhibitors for the inhaled treatment of respiratory diseases. J. Med. Chem.,  2019, 62(20), 9045-9060.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00533] [PMID:  31609613] 
[147] 
Yogo, T.; Nagamiya, H.; Seto, M.; Sasaki, S.; Shih-Chung, H.; Ohba, Y.; Tokunaga, N.; Lee, G.N.; Rhim, C.Y.; Yoon, C.H.; Cho, S.Y.; Skene, R.; Yamamoto, S.; Satou, Y.; Kuno, M.; Miyazaki, T.; Nakagawa, H.; Okabe, A.; Marui, S.; Aso, K.; Yoshida, M. Struc-ture-based design and synthesis of 3-Amino-1,5-dihydro-4H-pyrazolopyridin-4-one Derivatives as Tyrosine Kinase 2 Inhibitors. J. Med. Chem.,  2016, 59(2), 733-749.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01857] [PMID:  26701356] 
[148] 
Kulagowski, J.J.; Blair, W.; Bull, R.J.; Chang, C.; Deshmukh, G.; Dyke, H.J.; Eigenbrot, C.; Ghilardi, N.; Gibbons, P.; Harrison, T.K.; Hewitt, P.R.; Liimatta, M.; Hurley, C.A.; Johnson, A.; Johnson, T.; Kenny, J.R.; Bir Kohli, P.; Maxey, R.J.; Mendonca, R.; Mortara, K.; Murray, J.; Narukulla, R.; Shia, S.; Steffek, M.; Ubhayakar, S.; Ultsch, M.; van Abbema, A.; Ward, S.I.; Waszkowycz, B.; Zak, M. Identification of imidazo-pyrrolopyridines as novel and potent JAK1 inhibitors. J. Med. Chem.,  2012, 55(12), 5901-5921.
[http://dx.doi.org/10.1021/jm300438j] [PMID:  22591402] 
[149] 
Leonard, K.A.; Madge, L.A.; Krawczuk, P.J.; Wang, A.; Kreutter, K.D.; Bacani, G.M.; Chai, W.; Smith, R.C.; Tichenor, M.S.; Harris, M.C.; Malaviya, R.; Seierstad, M.; Johnson, M.E.; Venable, J.D.; Kim, S.; Hirst, G.C.; Mathur, A.S.; Rao, T.S.; Edwards, J.P.; Riz-zolio, M.C.; Koudriakova, T. Discovery of a gut-restricted JAK inhibitor for the treatment of inflammatory bowel disease. J. Med. Chem.,  2020, 63(6), 2915-2929.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01439] [PMID:  32134643] 
[150] 
Zak, M.; Mendonca, R.; Balazs, M.; Barrett, K.; Bergeron, P.; Blair, W.S.; Chang, C.; Deshmukh, G.; Devoss, J.; Dragovich, P.S.; Eigenbrot, C.; Ghilardi, N.; Gibbons, P.; Gradl, S.; Hamman, C.; Hanan, E.J.; Harstad, E.; Hewitt, P.R.; Hurley, C.A.; Jin, T.; Johnson, A.; Johnson, T.; Kenny, J.R.; Koehler, M.F.; Bir Kohli, P.; Kulagowski, J.J.; Labadie, S.; Liao, J.; Liimatta, M.; Lin, Z.; Lupardus, P.J.; Maxey, R.J.; Murray, J.M.; Pulk, R.; Rodriguez, M.; Savage, S.; Shia, S.; Steffek, M.; Ubhayakar, S.; Ultsch, M.; van Abbema, A.; Ward, S.I.; Xiao, L.; Xiao, Y. Discovery and optimization of C-2 methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. J. Med. Chem.,  2012, 55(13), 6176-6193.
[http://dx.doi.org/10.1021/jm300628c] [PMID:  22698084] 
[151] 
Forster, M.; Chaikuad, A.; Dimitrov, T.; Döring, E.; Holstein, J.; Berger, B.T.; Gehringer, M.; Ghoreschi, K.; Müller, S.; Knapp, S.; Laufer, S.A. Development, optimization, and structure-activity relationships of covalent-reversible JAK3 inhibitors based on a Tricyclic Imidazo[5,4- d]pyrrolo[2,3- b]pyridine Scaffold. J. Med. Chem.,  2018, 61(12), 5350-5366.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00571] [PMID:  29852068] 
[152] 
Wan, H.; Schroeder, G.M.; Hart, A.C.; Inghrim, J.; Grebinski, J.; Tokarski, J.S.; Lorenzi, M.V.; You, D.; Mcdevitt, T.; Penhallow, B.; Vuppugalla, R.; Zhang, Y.; Gu, X.; Iyer, R.; Lombardo, L.J.; Trainor, G.L.; Ruepp, S.; Lippy, J.; Blat, Y.; Sack, J.S.; Khan, J.A.; Stef-anski, K.; Sleczka, B.; Mathur, A.; Sun, J.H.; Wong, M.K.; Wu, D.R.; Li, P.; Gupta, A.; Arunachalam, P.N.; Pragalathan, B.; Nara-yanan, S. K C, N.; Kuppusamy, P.; Purandare, A.V. Discovery of a highly selective JAK2 Inhibitor, BMS-911543, for the treatment of myeloproliferative neoplasms. ACS Med. Chem. Lett.,  2015, 6(8), 850-855.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00226] [PMID:  26288683] 
[153] 
Dugan, B.J.; Gingrich, D.E.; Mesaros, E.F.; Milkiewicz, K.L.; Curry, M.A.; Zulli, A.L.; Dobrzanski, P.; Serdikoff, C.; Jan, M.; Ange-les, T.S.; Albom, M.S.; Mason, J.L.; Aimone, L.D.; Meyer, S.L.; Huang, Z.; Wells-Knecht, K.J.; Ator, M.A.; Ruggeri, B.A.; Dorsey, B.D. A selective, orally bioavailable 1,2,4-triazolo[1,5-a]pyridine-based inhibitor of Janus kinase 2 for use in anticancer therapy: Dis-covery of CEP-33779. J. Med. Chem.,  2012, 55(11), 5243-5254.
[http://dx.doi.org/10.1021/jm300248q] [PMID:  22594690] 
[154] 
Gunasekaran, P.; Lee, S.R.; Jeong, S.M.; Kwon, J.W.; Takei, T.; Asahina, Y.; Bang, G.; Kim, S.; Ahn, M.; Ryu, E.K.; Kim, H.N.; Nam, K.Y.; Shin, S.Y.; Hojo, H.; Namgoong, S.; Kim, N.H.; Bang, J.K. Pyrrole-based macrocyclic small-molecule inhibitors that target oo-cyte maturation. ChemMedChem,  2017, 12(8), 580-589.
[http://dx.doi.org/10.1002/cmdc.201700048] [PMID:  28296169] 
[155] 
William, A.D.; Lee, A.C.H.; Poulsen, A.; Goh, K.C.; Madan, B.; Hart, S.; Tan, E.; Wang, H.; Nagaraj, H.; Chen, D.; Lee, C.P.; Sun, E.T.; Jayaraman, R.; Pasha, M.K.; Ethirajulu, K.; Wood, J.M.; Dymock, B.W. Discovery of the macrocycle (9E)-15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a potent inhibitor of janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) for the treatment of rheumatoid arthritis. J. Med. Chem.,  2012, 55(6), 2623-2640.
[http://dx.doi.org/10.1021/jm201454n] [PMID:  22339472] 
Cite As
Current Medicinal Chemistry

Targeting Janus Kinase (JAK) for Fighting Diseases: The Research of JAK Inhibitor Drugs

Abstract
