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Bioorg Med Chem Lett. 2013 May 1;23(9):2793-800. doi: 10.1016/j.bmcl.2013.02.012. Epub 2013 Feb 13.

Strategic use of conformational bias and structure based design to identify potent JAK3 inhibitors with improved selectivity against the JAK family and the kinome.

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Discovery Chemistry, Hoffmann-La Roche, pRED, Pharma Research & Early Development, 340 Kingsland Street, Nutley, NJ 07110, USA.


Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family.

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