Identification and hit-to-lead exploration of a novel series of histamine H4 receptor inverse agonists

The identification and hit-to-lead exploration of a novel, potent and selective series of histamine H4 receptor inverse agonists is described. The initial hit, 3A (IC50 19 nM) was identified by means of a ligand-based virtual screening approach. Subsequent medicinal chemistry exploration yielded 18I which possessed increased potency (R-enantiomer IC50 1 nM) as well as enhanced microsomal stability.

Graphical abstractThe hit-to-lead exploration of a series of novel, potent and selective series of histamine H4 receptor inverse agonists originating from a virtual screening approach is described.Figure optionsDownload full-size imageDownload as PowerPoint slide