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

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.
Michael Soth 1,  Johannes C Hermann,  Calvin Yee,  Muzaffar Alam,  Jim W Barnett,  Pamela Berry,  Michelle F Browner,  Karl Frank,  Sandra Frauchiger,  Seth Harris,  Yang He,  Mohammad Hekmat-Nejad,  Than Hendricks,  Robert Henningsen,  Ramona Hilgenkamp,  Hoangdung Ho,  Ann Hoffman,  Pei-Yuan Hsu,  Dong-Qing Hu,  Andrea Itano,  Saul Jaime-Figueroa,  Alam Jahangir,  Sue Jin,  Andreas Kuglstatter,  Alan K Kutach,  Cheng Liao,  Stephen Lynch,  John Menke,  Linghao Niu,  Vaishali Patel,  Aruna Railkar,  Douglas Roy,  Ada Shao,  David Shaw,  Sandra Steiner,  Yongliang Sun,  Seng-Lai Tan,  Sandra Wang,  Minh Diem Vu
Affiliations

Affiliation

  • 1 Hoffmann-La Roche, 340 Kingsland Street, Nutley, New Jersey 07110, USA. michael.soth@roche.com
PMID: 23214979 DOI: 10.1021/jm301646k
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.

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