Optimization of arylindenopyrimidines as potent adenosine A(2A)/A(1) antagonists

Bioorg Med Chem Lett. 2010 May 1;20(9):2868-71. doi: 10.1016/j.bmcl.2010.03.024. Epub 2010 Mar 7.

Abstract

Two reactive metabolites were identified in vivo for the dual A(2A)/A(1) receptor antagonist 1. Two strategies were implemented to successfully mitigate the metabolic liabilities associated with 1. Optimization of the arylindenopyrimidines led to a number of amide, ether, and amino analogs having comparable in vitro and in vivo activity.

MeSH terms

  • Adenosine A1 Receptor Antagonists*
  • Adenosine A2 Receptor Antagonists*
  • Animals
  • Catalepsy / drug therapy
  • Disease Models, Animal
  • Mice
  • Neurotransmitter Agents / chemical synthesis
  • Neurotransmitter Agents / chemistry*
  • Neurotransmitter Agents / therapeutic use
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / therapeutic use
  • Receptor, Adenosine A1 / metabolism
  • Receptor, Adenosine A2A / metabolism
  • Structure-Activity Relationship

Substances

  • Adenosine A1 Receptor Antagonists
  • Adenosine A2 Receptor Antagonists
  • Neurotransmitter Agents
  • Pyrimidines
  • Receptor, Adenosine A1
  • Receptor, Adenosine A2A