946073-01-4Relevant articles and documents
Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2
Moriconi, Alessio,Cesta, Maria Candida,Cervellera, Maria Neve,Aramini, Andrea,Coniglio, Silvia,Colagioia, Sandro,Beccari, Andrea Rosario,Bizzarri, Cinzia,Cavicchia, Michela Rita,Locati, Massimo,Galliera, Emanuela,Di Benedetto, Paola,Vigilante, Paolo,Bertini, Riccardo,Allegretti, Marcello
, p. 3984 - 4002 (2008/02/11)
Chemokines CXCL8 and CXCL1 play a key role in the recruitment of neutrophils at the site of inflammation. CXCL8 binds two membrane receptors, CXCR1 and CXCR2, whereas CXCL1 is a selective agonist for CXCR2. In the past decade, the physiopathological role of CXCL8 and CXCL1 has been investigated. A novel class of small molecular weight allosteric CXCR1 inhibitors was identified, and reparixin, the first drug candidate, is currently under clinical investigation in the prevention of ischemia/reperfusion injury in organ transplantation. Reparixin binding mode to CXCR1 has been studied and used for a computer-assisted design program of dual allosteric CXCR1 and CXCR2 inhibitors. In this paper, the results of modeling-driven SAR studies for the identification of potent dual inhibitors are discussed, and three new compounds (56, 67, and 79) sharing a common triflate moiety have been selected as potential leads with optimized pharmacokinetic characteristics.
