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

Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2 / A. Moriconi, M.C. Cesta, M.N. Cervellera, A. Aramini, S. Coniglio, S. Colagioia, A.R. Beccari, C. Bizzarri, M.R. Cavicchia, M. Locati, E. Galliera, P. Di Benedetto, P. Vigilante, R. Bertini, M. Allegretti. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 50:17(2007 Aug 23), pp. 3984-4002. [10.1021/jm061469t]

Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2

M. Locati;E. Galliera;
2007

Abstract

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
Chemokines ; receptor inhibitors ; inflammation ; leukocyte ; IL-8
Settore MED/04 - Patologia Generale
23-ago-2007
http://pubs.acs.org/cgi-bin/abstract.cgi/jmcmar/2007/50/i17/abs/jm061469t.html
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/33253
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