Discovery of 7-(Prolinol-N-yl)-2-phenylamino-thiazolo[5,4-d]pyrimidines as Novel Non-Nucleoside Partial Agonists for the A2A Adenosine Receptor: Prediction from Molecular Modeling

J Med Chem. 2016 Jun 23;59(12):5922-8. doi: 10.1021/acs.jmedchem.6b00552. Epub 2016 Jun 7.

Abstract

We describe the identification of 7-(prolinol-N-yl)-2-phenylamino-thiazolo[5,4-d]pyrimidines as a novel chemotype of non-nucleoside partial agonists for the A2A adenosine receptor (A2AAR). Molecular-modeling indicated that the (S)-2-hydroxymethylene-pyrrolidine could mimic the interactions of agonists' ribose, suggesting that this class of compounds could have agonistic properties. This was confirmed by functional assays on the A2AAR, where their efficacy could be associated with the presence of the 2-hydroxymethylene moiety. Additionally, the best compound displays promising affinity, selectivity profile, and physicochemical properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A2 Receptor Agonists / chemistry*
  • Adenosine A2 Receptor Agonists / pharmacology*
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptor, Adenosine A2A / metabolism*
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*

Substances

  • 7-(prolinol-N-yl)-2-phenylamino-thiazolo(5,4-d)pyrimidine
  • Adenosine A2 Receptor Agonists
  • Pyrimidines
  • Receptor, Adenosine A2A
  • Thiazoles