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

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

  • Bioorg Med Chem Lett. 2013 May 1;23(9):2793-800. doi: 10.1016/j.bmcl.2013.02.012.
Stephen M Lynch 1,  Javier DeVicente,  Johannes C Hermann,  Saul Jaime-Figueroa,  Sue Jin,  Andreas Kuglstatter,  Hongju Li,  Allen Lovey,  John Menke,  Linghao Niu,  Vaishali Patel,  Douglas Roy,  Michael Soth,  Sandra Steiner,  Parcharee Tivitmahaisoon,  Minh Diem Vu,  Calvin Yee
Affiliations

Affiliation

  • 1 Discovery Chemistry, Hoffmann-La Roche, pRED, Pharma Research & Early Development, 340 Kingsland Street, Nutley, NJ 07110, USA. stephen.lynch@roche.com
PMID: 23540648 DOI: 10.1016/j.bmcl.2013.02.012
Abstract

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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