Development of novel pyridazinone-based adenosine receptor ligands

Bioorg Med Chem Lett. 2018 May 15;28(9):1484-1489. doi: 10.1016/j.bmcl.2018.03.086. Epub 2018 Mar 30.

Abstract

With the aim of finding new adenosine receptor (AR) ligands, a preliminary investigation focusing on the thieno[2,3-d]pyridazin-5(4H)-one scaffold was undertaken. The synthesized compounds 1-11 were evaluated for their binding at hA1, hA2A and hA3 ARs and efficacy at hA2B subtype in order to determine the affinity at the human adenosine receptor subtypes. Small structural changes on this scaffold highly influenced affinity; compound 5 (5-ethyl-7-(thiazol-2-yl)thieno[2,3-d]pyridazin-4(5H)-one) emerged as the best of this series. The simplicity of the synthetic process, the capability of the scaffold to be easily decorated, together with the predicted ADME properties confirm the role of these compounds as promising hits. A molecular docking investigation at the hA1AR crystal structure was performed to rationalize the SARs of the herein reported thienopyridazinones.

Keywords: ADME properties; Adenosine receptor ligands; G protein-coupled receptors; Thieno[2,3-d]pyridazin-5(4H)-ones.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Molecular Structure
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptor, Adenosine A1 / metabolism*
  • Receptor, Adenosine A2A / metabolism*
  • Receptor, Adenosine A3 / metabolism*
  • Structure-Activity Relationship

Substances

  • Ligands
  • Pyrimidines
  • Receptor, Adenosine A1
  • Receptor, Adenosine A2A
  • Receptor, Adenosine A3