Orally bioavailable Syk inhibitors with activity in a rat PK/PD model

  • Bioorg Med Chem Lett. 2015 Oct 15;25(20):4642-7. doi: 10.1016/j.bmcl.2015.08.037.
Gebhard Thoma  1 ,  Siem Veenstra  2 ,  Ross Strang  2 ,  Joachim Blanz  3 ,  Eric Vangrevelinghe  2 ,  Jörg Berghausen  4 ,  Christian C Lee  5 ,  Hans-Günter Zerwes  6
Affiliations
  • 1. Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland. Electronic address: [email protected].
  • 2. Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
  • 3. Analytical Sciences & Imaging, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
  • 4. Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
  • 5. Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
  • 6. Autoimmunity, Transplantation and Inflammation Research, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
PMID: 26320624 DOI: 10.1016/j.bmcl.2015.08.037
Abstract

Design and optimization of benzo- and pyrido-thiazoles/isothiazoles are reported leading to the discovery of the potent, orally bioavailable Syk Inhibitor 5, which was found to be active in a rat PK/PD model. Compound 5 showed acceptable overall kinase selectivity. However, in addition to Syk it also inhibited Aurora Kinase in enzymatic and cellular settings leading to findings in the micronucleus assay. As a consequence, compound 5 was not further pursued.

Keywords
BIIB-057; Fostamatinib; GS-9973; Kinase inhibitors; Spleen Tyrosine Kinase.
Products