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523011 
Journal Article 
Fragment based design of new H-4 receptor-ligands with anti-inflammatory properties in vivo 
Smits, RA; Lim, HD; Hanzer, A; Zuiderveld, OP; Guaita, E; Adami, M; Coruzzi, G; Leurs, R; de Esch, LJP 
2008 
Yes 
Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804 
51 
8 
2457-2467 
English 
Using a previously reported flexible alignment model we have designed, synthesized, and evaluated a series of compounds at the human histamine H-4 receptor (H4R) from which 2-(4-methyl-piperazin-1-yl)-quinoxaline (3) was identified as a new lead structure for H4R 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. 
human histamine-receptor; pharmacological characterization; antagonists; potent; cloning; benzimidazole; inflammation; expression; indole; cells