Structural refinement of pyrazolo[4,3-d]pyrimidine derivatives to obtain highly potent and selective antagonists for the human A3 adenosine receptor

Eur J Med Chem. 2016 Jan 27;108:117-133. doi: 10.1016/j.ejmech.2015.11.015. Epub 2015 Nov 17.

Abstract

In previous research, we identified some 7-oxo- and 7-acylamino-substituted pyrazolo[4,3-d]pyrimidine derivatives as potent and selective human (h) A3 adenosine receptor (AR) antagonists. Herein we report on the structural refinement of this class of antagonists aimed at achieving improved receptor-ligand recognition. Hence, substituents with different steric bulk, flexibility and lipophilicity (Me, Ar, heteroaryl, CH2Ph) were introduced at the 5- and 2-positions of the bicyclic scaffold of both the 7-oxo and 7-amino derivatives, and acyl residues were appended on the 7-amino group of the latter. All the 2-phenylpyrazolo[4,3-d]pyrimidin-7-amines and 7-acylamines bearing a 4-methoxyphenyl- or a 2-thienyl group at the 5-position showed high hA3 affinity and selectivity. In particular, the 2-phenyl-5-(2-thienyl)-pyrazolo[4,3-d]pyrimidin-7-(4-methoxybenzoyl)amine 25 (Ki = 0.027 nM) is one of the most potent and selective hA3 antagonists reported so far. By using an in silico receptor-driven approach the obtained binding data were rationalized and the molecular bases of the observed hA3 AR affinities were critically described.

Keywords: Adenosine receptor antagonists; G-protein-coupled receptors; Ligand-receptor modeling studies; Pyrazolopyrimidines.

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
  • Humans
  • Molecular Structure
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Receptor, Adenosine A3 / metabolism*
  • Structure-Activity Relationship

Substances

  • Adenosine A3 Receptor Antagonists
  • Pyrazoles
  • Pyrimidines
  • Receptor, Adenosine A3
  • pyrazolo(3,4-d)pyrimidine