Design and synthesis of novel, potent and selective hypoxanthine analogs as adenosine A1 receptor antagonists and their biological evaluation

Bioorg Med Chem. 2017 Mar 15;25(6):1963-1975. doi: 10.1016/j.bmc.2017.02.029. Epub 2017 Feb 16.

Abstract

Multipronged approach was used to synthesize a library of diverse C-8 cyclopentyl hypoxanthine analogs from a common intermediate III. Several potent and selective compounds were identified and evaluated for pharmacokinetic (PK) properties in Wistar rats. One of the compounds 14 with acceptable PK parameters was selected for testing in in vivo primary acute diuresis model. The compound demonstrated significant diuretic activity in this model.

Keywords: Adenosine; BG-9928; Diuresis; Glomerular; Hypoxanthine; Rolofylline.

MeSH terms

  • Adenosine A1 Receptor Antagonists / chemical synthesis
  • Adenosine A1 Receptor Antagonists / chemistry*
  • Adenosine A1 Receptor Antagonists / pharmacokinetics
  • Adenosine A1 Receptor Antagonists / pharmacology*
  • Animals
  • Carbon-13 Magnetic Resonance Spectroscopy
  • Chromatography, Liquid
  • Drug Design
  • HEK293 Cells
  • Humans
  • Hypoxanthines / chemical synthesis
  • Hypoxanthines / chemistry*
  • Hypoxanthines / pharmacokinetics
  • Hypoxanthines / pharmacology*
  • Male
  • Mass Spectrometry
  • Proton Magnetic Resonance Spectroscopy
  • Radioligand Assay
  • Rats
  • Rats, Wistar

Substances

  • Adenosine A1 Receptor Antagonists
  • Hypoxanthines