Fragment based design of new H4 receptor-ligands with anti-inflammatory properties in vivo

Using a previously reported flexible alignment model we have designed, synthesized, and evaluated a series of compounds at the human histamine H(4) receptor (H(4)R) from which 2-(4-methyl-piperazin-1-yl)-quinoxaline (3) was identified as a new lead structure for H(4)R ligands. Exploration of the structure- activity relationship (SAR) of this scaffold led to the identification of 6,7-dichloro 3-(4-methylpiperazin-1-yl)quinoxalin-2(1H)one (VUF 10214, 57) and 2-benzyl-3-(4-methyl-piperazin-1-yl)quinoxaline (VUF 10148, 20) as potent H4R ligands with nanomolar affinities. In vivo studies in the rat reveal that compound 57 has significant anti-inflammatory properties in the carrageenan -induced paw-edema model.