Novel 7H-pyrrolo[2,3-d]pyrimidine derivatives as potent and orally active STAT6 inhibitors

Bioorg Med Chem. 2009 Oct 1;17(19):6926-36. doi: 10.1016/j.bmc.2009.08.021. Epub 2009 Aug 15.

Abstract

Signal transducers and activators of transcription 6 (STAT6) is an important transcription factor in interleukin (IL)-4 signaling pathway and a key regulator of the type 2 helper T (Th2) cell immune response. Therefore, STAT6 may be an excellent therapeutic target for allergic conditions, including asthma and atopic diseases. Previously, we reported 4-aminopyrimidine-5-carboxamide derivatives as STAT6 inhibitors. To search for novel STAT6 inhibitors, we synthesized fused bicyclic pyrimidine derivatives and identified a 7H-pyrrolo[2,3-d]pyrimidine derivative as a STAT6 inhibitor. Optimization of the pyrrolopyrimidine derivatives led to identification of 2-[4-(4-{[7-(3,5-difluorobenzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}phenyl)piperazin-1-yl]acetamide (24, AS1810722) which showed potent STAT6 inhibition and a good CYP3A4 inhibition profile. Compound 24 also inhibited in vitro Th2 differentiation without affecting type 1 helper T (Th1) cell differentiation and eosinophil infiltration in an antigen-induced mouse asthmatic model after oral administration.

MeSH terms

  • Administration, Oral
  • Animals
  • Asthma / drug therapy
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 CYP3A Inhibitors
  • Eosinophils / drug effects
  • Humans
  • Immunity
  • Mice
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Pyrroles / chemical synthesis*
  • Pyrroles / pharmacology
  • Pyrroles / therapeutic use
  • STAT6 Transcription Factor / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Th2 Cells / drug effects

Substances

  • Cytochrome P-450 CYP3A Inhibitors
  • Pyrimidines
  • Pyrroles
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • pyrrolopyrimidine
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human