The CXC chemokine CXCL8/IL-8 plays a major role in the activation and recruitment of polymorphonuclear (PMN) cells at inflammatory sites. CXCL8 activates PMNs by binding the seven-transmembrane (7-TM) G-protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2). (R)-Ketoprofen (1) was previously reported to be a potent and specific noncompetitive inhibitor of CXCL8-induced human PMNS chemotaxis. We report here molecular modeling studies showing a putative interaction site of 1 in the TM region of CXCR1. The binding model was confirmed by alanine scanning mutagenesis and photoaffinity labeling experiments. The molecular model driven medicinal chemistry optimization of 1 led to a new class of potent and specific inhibitors of CXCL8 biological activity. Among these, repertaxin (13) was selected as a clinical candidate drug for prevention of post-ischemia reperfusion injury.
2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors / M. Allegretti, R. Bertini, M.C. Cesta, C. Bizzarri, R. Di Bitondo, V. Di Cioccio, E. Galliera, V. Berdini, A. Topai, G. Zampella, V. Russo, N. Di Bello, G. Nano, L. Nicolini, M. Locati, P. Fantucci, S. Florio, F. Colotta. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 48:13(2005), pp. 4312-4331.
|Titolo:||2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||2005|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1021/jm049082i|
|Appare nelle tipologie:||01 - Articolo su periodico|