2. Academic Validation
  3. Orally bioavailable Syk inhibitors with activity in a rat PK/PD model

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

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.

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