Exploring the 7-oxo-thiazolo[5,4-d]pyrimidine core for the design of new human adenosine A3 receptor antagonists. Synthesis, molecular modeling studies and pharmacological evaluation

Eur J Med Chem. 2015:96:105-21. doi: 10.1016/j.ejmech.2015.04.010. Epub 2015 Apr 4.

Abstract

A new series of 5-methyl-thiazolo[5,4-d]pyrimidine-7-ones bearing different substituents at position 2 (aryl, heteroaryl and arylamino groups) was synthesized and evaluated in radioligand binding assays to determine their affinities at the human (h) A1, A2A, and A3 adenosine receptors (ARs). Efficacy at the hA(2B) and antagonism of selected ligands at the hA3 were also assessed through cAMP experiments. Some of the new derivatives exhibited good to high hA3AR affinity and selectivity versus all the other AR subtypes. Compound 2-(4-chlorophenyl)-5-methyl-thiazolo[5,4-d]pyrimidine-7-one 4 was found to be the most potent and selective ligand of the series (K(I) hA3 = 18 nM). Molecular docking studies of the reported derivatives were carried out to depict their hypothetical binding mode in our hA3 receptor model.

Keywords: Adenosine receptor antagonists; Bicyclic heteroaromatic systems; G protein-coupled receptors; Ligand-receptor modeling studies; Thiazolopyrimidine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A3 Receptor Antagonists / chemical synthesis*
  • Adenosine A3 Receptor Antagonists / chemistry
  • Adenosine A3 Receptor Antagonists / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Receptor, Adenosine A3 / metabolism*
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology*

Substances

  • 7-oxo-thiazolo(5,4-d)pyrimidine
  • Adenosine A3 Receptor Antagonists
  • Pyrimidines
  • Receptor, Adenosine A3
  • Thiazoles