Thiophene carboxamide inhibitors of JAK2 as potential treatments for myleoproliferative neoplasms

Bioorg Med Chem Lett. 2014 Apr 15;24(8):1968-73. doi: 10.1016/j.bmcl.2014.02.064. Epub 2014 Mar 4.

Abstract

A series of carboxamide-substituted thiophenes demonstrating inhibition of JAK2 is described. Development of this chemical series began with the bioisosteric replacement of a urea substituent by a pyridyl ring. Issues of chemical and metabolic stability were solved using the results of both in vitro and in vivo studies, ultimately delivering compounds such as 24 and 25 that performed well in an acute PK/PD model measuring p-STAT5 inhibition.

Keywords: Bioisostere; Inhibitor; JAK2; Metabolite identification; Polycythemia vera; Protein kinase; Thiophene.

MeSH terms

  • Aminoimidazole Carboxamide / chemical synthesis*
  • Aminoimidazole Carboxamide / chemistry
  • Aminoimidazole Carboxamide / pharmacology*
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Leukemia, Myeloid, Acute / drug therapy
  • Microsomes / drug effects
  • Microsomes / enzymology
  • Models, Biological
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Thiophenes
  • Aminoimidazole Carboxamide
  • Janus Kinase 2