Synthesis and SAR studies of analogues of 4-(3,3-dimethyl-butyrylamino)-3,5-difluoro-N-thiazol-2-yl-benzamide (Lu AA41063) as adenosine A2A receptor ligands with improved aqueous solubility

Bioorg Med Chem Lett. 2015 Mar 15;25(6):1212-6. doi: 10.1016/j.bmcl.2015.01.062. Epub 2015 Feb 7.

Abstract

An adenosine A2A receptor antagonist may be useful for the treatment of Parkinson's disease. Synthesis and structure-activity studies starting from 4-(3,3-dimethylbutyrylamino)-3,5-difluoro-N-thiazol-2-yl-benzamide (Lu AA41063, 4) led to a novel series of human (h) A2A receptor antagonists with improved aqueous solubility. Compound 22 was identified as a key representative from the series, displaying submicromolar hA2A receptor affinity and excellent aqueous solubility. Compound 22 also displayed good in vitro pharmacokinetic properties and is considered a good starting point for further lead optimisation toward hA2A receptor antagonists with improved druggability properties.

Keywords: Solubility; hA(2A).

MeSH terms

  • Adenosine A2 Receptor Antagonists / chemical synthesis*
  • Adenosine A2 Receptor Antagonists / chemistry
  • Adenosine A2 Receptor Antagonists / metabolism
  • Binding Sites
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Protein Binding
  • Receptor, Adenosine A2A / chemistry*
  • Receptor, Adenosine A2A / metabolism
  • Solubility
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry
  • Water / chemistry
  • para-Aminobenzoates / chemical synthesis*
  • para-Aminobenzoates / chemistry

Substances

  • 4-(3,3-dimethylbutyrylamino)-3,5-difluoro-N-thiazol-2-ylbenzamide
  • Adenosine A2 Receptor Antagonists
  • Ligands
  • Receptor, Adenosine A2A
  • Thiazoles
  • para-Aminobenzoates
  • Water