Structure-activity studies on a series of a 2-aminopyrimidine-containing histamine H4 receptor ligands

J Med Chem. 2008 Oct 23;51(20):6571-80. doi: 10.1021/jm8005959. Epub 2008 Sep 24.


A series of 2-aminopyrimidines was synthesized as ligands of the histamine H4 receptor (H4R). Working in part from a pyrimidine hit that was identified in an HTS campaign, SAR studies were carried out to optimize the potency, which led to compound 3, 4- tert-butyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-ylamine. We further studied this compound by systematically modifying the core pyrimidine moiety, the methylpiperazine at position 4, the NH2 at position 2, and positions 5 and 6 of the pyrimidine ring. The pyrimidine 6 position benefited the most from this optimization, especially in analogs in which the 6- tert-butyl was replaced with aromatic and secondary amine moieties. The highlight of the optimization campaign was compound 4, 4-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzonitrile, which was potent in vitro and was active as an anti-inflammatory agent in an animal model and had antinociceptive activity in a pain model, which supports the potential of H 4R antagonists in pain.

MeSH terms

  • Animals
  • Biomarkers
  • Histamine Antagonists / chemical synthesis*
  • Histamine Antagonists / chemistry
  • Histamine Antagonists / pharmacology*
  • Humans
  • Hyperplasia / chemically induced
  • Hyperplasia / prevention & control
  • Ligands
  • Locomotion / drug effects
  • Mice
  • Molecular Structure
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Rats
  • Receptors, Histamine / metabolism*
  • Structure-Activity Relationship
  • Substrate Specificity


  • Biomarkers
  • Histamine Antagonists
  • Ligands
  • Pyrimidines
  • Receptors, Histamine
  • 2-aminopyrimidine