2. Academic Validation
  3. Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors

Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors

  • Bioorg Med Chem Lett. 2013 May 1;23(9):2522-6. doi: 10.1016/j.bmcl.2013.03.015.
Saul Jaime-Figueroa 1,  Javier De Vicente,  Johannes Hermann,  Alam Jahangir,  Sue Jin,  Andreas Kuglstatter,  Stephen M Lynch,  John Menke,  Linghao Niu,  Vaishali Patel,  Ada Shao,  Michael Soth,  Minh Diem Vu,  Calvin Yee
Affiliations

Affiliation

  • 1 Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 340 Kingsland Street, Nutley, NJ 07110-1199, USA. saul.jaime@roche.com
PMID: 23541670 DOI: 10.1016/j.bmcl.2013.03.015
Abstract

We report the discovery of a novel series of ATP-competitive Janus kinase 3 (JAK3) inhibitors based on the 5H-pyrrolo[2,3-b]pyrazine scaffold. The initial leads in this series, compounds 1a and 1h, showed promising potencies, but a lack of selectivity against Other isoforms in the JAK family. Computational and crystallographic analysis suggested that the phenyl ether moiety possessed a favorable vector to achieve selectivity. Exploration of this vector resulted in the identification of 12b and 12d, as potent JAK3 inhibitors, demonstrating improved JAK family and kinase selectivity.

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