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 4R) from which 2-(4-methyl-piperazin-1-yl)-quinoxaline ( 3) was identified as a new lead structure for H 4R 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(1 H)-one (VUF 10214, 57) and 2-benzyl-3-(4-methyl-piperazin-1-yl)quinoxaline (VUF 10148, 20) as potent H 4R 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.
Smits
Rogier A
RA
Leiden/Amsterdam Center for Drug Research (LACDR), Division of Medicinal Chemistry, Department of Pharmacochemistry, Faculty of Exact Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
Lim
Herman D
HD
Hanzer
Agnes
A
Zuiderveld
Obbe P
OP
Guaita
Elena
E
Adami
Maristella
M
Coruzzi
Gabriella
G
Leurs
Rob
R
de Esch
Iwan J P
IJ
D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011968:Receptors, Histamine / Q000187:drug effects* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D008024:Ligands; D011968:Receptors, Histamine