Download MendeleyDiscovery of a Series of Novel 5H-Pyrrolo[2,3-B]Pyrazine-2-Phenyl Ethers, as Potent Jak3 Kinase Inhibitors.
Jaime-Figueroa, S., De Vicente, J., Hermann, J., Jahangir, A., Jin, S., Kuglstatter, A., Lynch, S.M., Menke, J., Niu, L., Patel, V., Shao, A., Soth, M., Vu, M.D., Yee, C.(2013) Bioorg Med Chem Lett 23: 2522
- PubMed: 23541670
- DOI: https://doi.org/10.1016/j.bmcl.2013.03.015
- Primary Citation of Related Structures:
3ZEP, 4I6Q - PubMed 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.
Organizational Affiliation:
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
