Drug-likeness approach of 2-aminopyrimidines as histamine H3 receptor ligands

Drug Des Devel Ther. 2014 Sep 19;8:1499-513. doi: 10.2147/DDDT.S66179. eCollection 2014.


A small series of compounds containing derivatives of 2,4-diamino- and 2,4,6-triaminopyrimidine (compounds 2-7) was synthesized and tested for binding affinity to human histamine H3 receptors (hH3Rs) stably expressed in HEK-293 cells and human H4Rs (hH4Rs) co-expressed with Gαi2 and Gβ1γ2 subunits in Sf9 cells. Working in part from the lead compound 6-(4-methylpiperazin-1-yl)-N (4)-(3-(piperidin-1-yl)propyl)pyrimidine-2,4-diamine (compound 1) with unsatisfactory affinity and selectivity to hH3Rs, our structure-activity relationship studies revealed that replacement of 4-methylpiperazino by N-benzylamine and substitution of an amine group at the 2-position of the 2-aminopyrimidine core structure with 3-piperidinopropoxyphenyl moiety as an hH3R pharmacophore resulted in N (4)-benzyl-N (2)-(4-(3-(piperidin-1-yl)propoxy)phenyl)pyrimidine-2,4-diamine (compound 5) with high hH3R affinity (k(i) =4.49 ± 1.25 nM) and H3R receptor subtype selectivity of more than 6,500×. Moreover, initial metric analyses were conducted based on their target-oriented drug-likeness for predictively quantifying lipophilicity, ligand efficiency, lipophilicity-dependent ligand efficiency, molecular size-independent efficiency, and topological molecular polar surface. As to the development of potential H3R ligands, results showed that integration of the hH3R pharmacophore in hH4R-affine structural scaffolds resulted in compounds with high hH3R affinity (4.5-650 nM), moderate to low hH4R affinity (4,500-30,000 nM), receptor subtype selectivity (ratio hH4R/hH3R; 8-6,500), and promising calculated drug-likeness properties.

Keywords: H3 receptors; H4 receptors; drug-likeness; histamine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Histamine Agents / chemical synthesis
  • Histamine Agents / chemistry
  • Histamine Agents / pharmacology*
  • Humans
  • Ligands
  • Molecular Structure
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptors, Histamine H3 / metabolism*
  • Structure-Activity Relationship


  • Histamine Agents
  • Ligands
  • Pyrimidines
  • Receptors, Histamine H3
  • 2-aminopyrimidine