Synthesis and optimization of furano[3,2-d]pyrimidines as selective spleen tyrosine kinase (Syk) inhibitors

Bioorg Med Chem Lett. 2016 Nov 15;26(22):5562-5567. doi: 10.1016/j.bmcl.2016.09.077. Epub 2016 Oct 11.

Abstract

A series of furano[3,2-d]pyrimidine Syk inhibitors were synthesized and optimized for their enzyme potency and selectivity versus other kinases. In addition, ADME properties were assessed and compounds were prepared with optimized profiles for in vivo experiments. Compound 23 was identified as having acceptable pharmacokinetic properties and demonstrated efficacy in a rat collagen induced arthritis model.

Keywords: Furano[3,2-d]pyrimidine; Kinase inhibitor; Rheumatoid arthritis; Spleen tyrosine kinase; Syk.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / enzymology
  • Dogs
  • Furans / chemical synthesis
  • Furans / chemistry
  • Furans / pharmacology
  • Furans / therapeutic use
  • Humans
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Rats
  • Syk Kinase / antagonists & inhibitors*
  • Syk Kinase / metabolism

Substances

  • Furans
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Syk Kinase