New pyrazolo[3,4-b]pyridones as selective A(1) adenosine receptor antagonists: synthesis, biological evaluation and molecular modelling studies

Org Biomol Chem. 2005 Jun 21;3(12):2262-70. doi: 10.1039/b502831k. Epub 2005 May 19.

Abstract

A series of ethyl 4-amino-1-(2-chloro-2-phenylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylates () has been synthesized as potential A(1) adenosine receptor (A(1) AR) ligands. Binding affinities of the new compounds were determined for adenosine A(1), A(2A) and A(3) receptors. Compounds and showed good affinity (K(i)= 299 nM and 517 nM, respectively) and selectivity towards A(1) AR, whereas showed good affinity for A(2A) AR (K(i)= 290 nM), higher than towards A(1) AR (K(i)= 1000 nM). The only arylamino derivative of the series displayed high affinity (K(i)= 4.6 nM) and selectivity for A(3) AR. Molecular modelling and 3D-QSAR (CoMFA) studies carried out on the most active compounds gave further support to the pharmacological results.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Models, Molecular
  • Purinergic P1 Receptor Antagonists*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Quantitative Structure-Activity Relationship

Substances

  • Purinergic P1 Receptor Antagonists
  • Pyrazoles
  • Pyridines
  • pyrazolo(3,4-b)pyridine