Novel 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as high affinity and selective A2B adenosine receptor antagonists

Bioorg Med Chem Lett. 2006 Jan 15;16(2):302-6. doi: 10.1016/j.bmcl.2005.10.002. Epub 2005 Nov 4.

Abstract

A series of new 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as A(2B)-AdoR antagonists have been synthesized and evaluated for their binding affinities for the A(2B), A(1), A(2A), and A(3)-AdoRs. 8-(1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazol-4-yl)-1,3-dipropyl-1H-purine-2,6(3H,7H)-dione (4) displayed high affinity (K(i)=1 nM) and selectivity for the A(2B)-AdoR versus A(1), A(2A), and A(3)-AdoRs (A(1)/A(2B), A(2A)/A(2B), and A(3)/A(2B) selectivity ratios of 370, 1100, and 480, respectively). The synthesis and SAR of this novel class of compounds are presented herein.

MeSH terms

  • Adenosine A2 Receptor Antagonists*
  • Binding Sites
  • Drug Evaluation, Preclinical
  • Molecular Structure
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship
  • Xanthines / chemical synthesis
  • Xanthines / chemistry
  • Xanthines / pharmacology*

Substances

  • Adenosine A2 Receptor Antagonists
  • Pyrazoles
  • Xanthines