Optimization of a series of potent, selective and orally bioavailable SYK inhibitors

Bioorg Med Chem Lett. 2020 Oct 1;30(19):127433. doi: 10.1016/j.bmcl.2020.127433. Epub 2020 Jul 24.

Abstract

Spleen tyrosine kinase (SYK) is a non-receptor cytosolic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signaling, inhibition of SYK has been targeted in a variety of disease areas. Herein, we report the optimization of a series of potent and selective SYK inhibitors, focusing on improving metabolic stability, pharmacokinetics and hERG inhibition. As a result, we identified 30, which exhibited no hERG activity but unfortunately was poorly absorbed in rats and mice. We also identified a SYK chemical probe, 17, which exhibits excellent potency at SYK, and an adequate rodent PK profile to support in vivo efficacy/PD studies.

Keywords: Bioavailable; SYK; Small molecule.

MeSH terms

  • Animals
  • Binding Sites
  • Caco-2 Cells
  • Crystallography, X-Ray
  • ERG1 Potassium Channel / antagonists & inhibitors
  • Humans
  • Indazoles / chemical synthesis
  • Indazoles / metabolism
  • Indazoles / pharmacokinetics
  • Indazoles / pharmacology*
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Rats, Wistar
  • Structure-Activity Relationship
  • Syk Kinase / antagonists & inhibitors*
  • Syk Kinase / chemistry
  • Syk Kinase / metabolism

Substances

  • ERG1 Potassium Channel
  • Indazoles
  • KCNH2 protein, human
  • Protein Kinase Inhibitors
  • SYK protein, human
  • Syk Kinase