354902-70-8Relevant academic research and scientific papers
2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors
Allegretti, Marcello,Bertini, Riccardo,Cesta, Maria Candida,Bizzarri, Cinzia,Di Bitondo, Rosa,Di Cioccio, Vito,Galliera, Emanuela,Berdini, Valerio,Topai, Alessandra,Zampella, Giuseppe,Russo, Vincenzo,Di Bello, Nicoletta,Nano, Giuseppe,Nicolini, Luca,Locati, Massimo,Fantucci, Piercarlo,Florio, Saverio,Colotta, Francesco
, p. 4312 - 4331 (2007/10/03)
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 CXCLS-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.
