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
  • 1. Discovery Chemistry, Hoffmann-La Roche, pRED, Pharma Research & Early Development, 340 Kingsland Street, Nutley, NJ 07110, USA. [email protected]
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.