Detailed structure-activity relationship of indolecarboxamides as H4 receptor ligands

Eur J Med Chem. 2012 Aug;54:660-8. doi: 10.1016/j.ejmech.2012.06.016. Epub 2012 Jun 18.


A series of 76 derivatives of the indolecarboxamide 1 were synthesized, which allows a detailed SAR investigation of this well known scaffold. The data enable the definition of a predictive QSAR model which identifies several compounds with an activity comparable to 1. A selection of these new H(4)R antagonists was synthesized and a comparison of predicted and measured values demonstrates the robustness of the model (47-55). In addition to the H(4)-receptor activity general CMC and DMPK properties were investigated. Some of the new analogs are not only excellently soluble, but display a significantly increased half-life in mouse liver microsomes as well. These properties qualify these compounds as a possible new standard for future in vivo studies (e.g 51, 52 and 55). Moreover, the current studies also provide valuable information on the potential receptor ligand interactions between the indolcarboxamides and the H(4)R protein.

MeSH terms

  • Animals
  • Drug Stability
  • Humans
  • Indoles / chemistry*
  • Indoles / metabolism*
  • Ligands
  • Mice
  • Microsomes, Liver / metabolism
  • Protein Binding
  • Quantitative Structure-Activity Relationship
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Histamine / metabolism*
  • Receptors, Histamine H4
  • Solubility
  • Structure-Activity Relationship


  • HRH4 protein, human
  • Indoles
  • Ligands
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine
  • Receptors, Histamine H4