Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors

Bioorg Med Chem. 2014 Sep 1;22(17):4998-5012. doi: 10.1016/j.bmc.2014.06.025. Epub 2014 Jun 21.

Abstract

We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.

Keywords: Anti-cancer agents; JAK2; Myeloproliferative disorders; Protein kinase inhibitor; Tumour cell proliferation inhibition.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / metabolism
  • Mice
  • Mice, SCID
  • Models, Molecular
  • Molecular Structure
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / pathology
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • 5-(2-aminopyrimidin-4-yl)-2-(2-chloro-5-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • Janus Kinase 2