Design of Noncompetitive Interleukin-8 Inhibitors Acting on CXCR1 and CXCR2

• Published in: Journal of medicinal chemistry Vol. 50; no. 17; pp. 3984 - 4002
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 23-08-2007
• Subjects: Allosteric Regulation; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Chemotaxis, Leukocyte; Dinoprostone - biosynthesis; Humans; Interleukin-8 - antagonists & inhibitors; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - physiology; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - metabolism; Mesylates - chemical synthesis; Mesylates - chemistry; Mesylates - pharmacology; Mice; Models, Molecular; Mutation; Phenylpropionates - chemical synthesis; Phenylpropionates - chemistry; Phenylpropionates - pharmacology; Propionates - chemical synthesis; Propionates - pharmacokinetics; Propionates - pharmacology; Receptors, Interleukin-8A - antagonists & inhibitors; Receptors, Interleukin-8A - genetics; Receptors, Interleukin-8B - antagonists & inhibitors; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061469t

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.