3-Amido pyrrolopyrazine JAK kinase inhibitors: development of a JAK3 vs JAK1 selective inhibitor and evaluation in cellular and in vivo models.

Article Details

Citation
Copy to clipboard

Soth M, Hermann JC, Yee C, Alam M, Barnett JW, Berry P, Browner MF, Frank K, Frauchiger S, Harris S, He Y, Hekmat-Nejad M, Hendricks T, Henningsen R, Hilgenkamp R, Ho H, Hoffman A, Hsu PY, Hu DQ, Itano A, Jaime-Figueroa S, Jahangir A, Jin S, Kuglstatter A, Kutach AK, Liao C, Lynch S, Menke J, Niu L, Patel V, Railkar A, Roy D, Shao A, Shaw D, Steiner S, Sun Y, Tan SL, Wang S, Vu MD

3-Amido pyrrolopyrazine JAK kinase inhibitors: development of a JAK3 vs JAK1 selective inhibitor and evaluation in cellular and in vivo models.

J Med Chem. 2013 Jan 10;56(1):345-56. doi: 10.1021/jm301646k. Epub 2012 Dec 19.

PubMed ID
23214979 [ View in PubMed
]
Abstract

The Janus kinases (JAKs) are involved in multiple signaling networks relevant to inflammatory diseases, and inhibition of one or more members of this class may modulate disease activity or progression. We optimized a new inhibitor scaffold, 3-amido-5-cyclopropylpyrrolopyrazines, to a potent example with reasonable kinome selectivity, including selectivity for JAK3 versus JAK1, and good biopharmaceutical properties. Evaluation of this analogue in cellular and in vivo models confirmed functional selectivity for modulation of a JAK3/JAK1-dependent IL-2 stimulated pathway over a JAK1/JAK2/Tyk2-dependent IL-6 stimulated pathway.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
TofacitinibTyrosine-protein kinase JAK2IC 50 (nM)4N/AN/ADetails
TofacitinibTyrosine-protein kinase JAK2IC 50 (nM)184N/AN/ADetails
TofacitinibTyrosine-protein kinase JAK3IC 50 (nM)2.2N/AN/ADetails