Journal of Medicinal Chemistry 2005-06-30

2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors.

Marcello Allegretti, Riccardo Bertini, Maria Candida Cesta, Cinzia Bizzarri, Rosa Di Bitondo, Vito Di Cioccio, Emanuela Galliera, Valerio Berdini, Alessandra Topai, Giuseppe Zampella, Vincenzo Russo, Nicoletta Di Bello, Giuseppe Nano, Luca Nicolini, Massimo Locati, Piercarlo Fantucci, Saverio Florio, Francesco Colotta

Index: J. Med. Chem. 48 , 4312-31, (2005)

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Abstract

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.