Inhibition of PDGFR tyrosine kinase activity by a series of novel N-(3-(4-(pyridin-3-yl)-1H-imidazol-2-ylamino)phenyl)amides: a SAR study on the bioisosterism of pyrimidine and imidazole

Eur J Med Chem. 2008 Jul;43(7):1444-53. doi: 10.1016/j.ejmech.2007.09.021. Epub 2007 Oct 2.

Abstract

A series of N-(3-(4-(pyridin-3-yl)-1H-imidazol-2-ylamino)phenyl)amides were synthesized and tested for inhibition of PDGFR and FLT3 autophosphorylation. The novel N-(3-(4-(pyridin-3-yl)-1H-imidazol-2-ylamino)phenyl)amides, obtained by replacement of the pyrimidine system in Imatinib (1) with an imidazole ring, exhibit potent inhibitory activity on PDGFR, similar to the parent compound (IC(50) (9e)=0.2 microM; IC(50) Imatinib (1)=0.3 microM). Selectivity hereby seems to be conserved, as shown by the lack of activity on FLT3, a closely related class III receptor tyrosine kinase, which is not affected by the parent compound Imatinib.

MeSH terms

  • Imidazoles / chemistry*
  • Imidazoles / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors*
  • Spectrometry, Mass, Electrospray Ionization
  • Structure-Activity Relationship

Substances

  • Imidazoles
  • Pyrimidines
  • PDGF receptor tyrosine kinase
  • Receptors, Platelet-Derived Growth Factor
  • pyrimidine