Discovery and profiling of a selective and efficacious Syk inhibitor

  • J Med Chem. 2015 Feb 26;58(4):1950-63. doi: 10.1021/jm5018863.
Gebhard Thoma  1 ,  Alexander B Smith ,  Maurice J van Eis ,  Eric Vangrevelinghe ,  Joachim Blanz ,  Reiner Aichholz ,  Amanda Littlewood-Evans ,  Christian C Lee ,  Hong Liu ,  Hans-Günter Zerwes
Affiliations
  • 1. Global Discovery Chemistry, ‡Analytical Sciences & Imaging, §Autoimmunity, Transplantation and Inflammation Research, Novartis Institutes for Biomedical Research , 4056 Basel, Switzerland.
PMID: 25633741 DOI: 10.1021/jm5018863
Abstract

We describe the discovery of selective and potent Syk Inhibitor 11, which exhibited favorable PK profiles in rat and dog and was found to be active in a collagen-induced arthritis model in rats. Compound 11 was selected for further profiling, but, unfortunately, in GLP toxicological studies it showed liver findings in rat and dog. Nevertheless, 11 could become a valuable tool compound to investigate the rich biology of Syk in vitro and in vivo.