Structure-activity relationships of a series of pyrrolo[3,2-d]pyrimidine derivatives and related compounds as neuropeptide Y5 receptor antagonists

J Med Chem. 2000 Nov 2;43(22):4288-312. doi: 10.1021/jm000269t.


Neuropeptide Y (NPY) has been shown to play an important role in the regulation of food intake and energy balance. Pharmacological data suggests that the Y5 receptor subtype contributes to the effects of NPY on appetite, and therefore a Y5 antagonist might be a useful therapeutic agent for the treatment of obesity. In attempts to identify potential Y5 antagonists, a series of pyrrolo[3, 2-d]pyrimidine derivatives was prepared and evaluated for their ability to bind to Y5 receptors in vitro. We report here the synthesis and initial structure-activity relationship investigations for this class of compounds. The target compounds were prepared by a variety of synthetic routes designed to modify both the substitution and the heterocyclic core of the pyrrolo[3,2-d]pyrimidine lead 1. In addition to identifying several potent Y5 antagonists for evaluation as potential antiobesity agents, a pharmacophore model for the human Y5 receptor is presented.

MeSH terms

  • Anti-Obesity Agents / chemical synthesis*
  • Anti-Obesity Agents / chemistry
  • Anti-Obesity Agents / pharmacology
  • Cell Line
  • Drug Evaluation, Preclinical
  • Humans
  • Magnetic Resonance Spectroscopy
  • Membranes / metabolism
  • Models, Biological
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Radioligand Assay
  • Receptors, Neuropeptide Y / antagonists & inhibitors*
  • Receptors, Neuropeptide Y / metabolism
  • Structure-Activity Relationship


  • Anti-Obesity Agents
  • Pyrimidines
  • Receptors, Neuropeptide Y
  • neuropeptide Y5 receptor
  • pyrimidine