Design of Noncompetitive Interleukin-8 Inhibitors Acting on CXCR1 and CXCR2
| Autor: | Paolo Vigilante, Maria Neve Cervellera, Andrea Aramini, Silvia Coniglio, Andrea R. Beccari, Sandro Colagioia, Marcello Allegretti, Alessio Moriconi, Paola Di Benedetto, Riccardo Bertini, Michela Rita Cavicchia, Maria Candida Cesta, Emanuela Galliera, Massimo Locati, Cinzia Bizzarri |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Chemokine Anti-Inflammatory Agents Pharmacology Receptors Interleukin-8B Receptors Interleukin-8A Mice Models Receptors Drug Discovery Leukocytes CXC chemokine receptors Receptor Mesylates Phenylpropionates biology Chemistry Chemotaxis Anti-Inflammatory Agents Non-Steroidal Stereoisomerism respiratory system CXCL1 Chemotaxis Leukocyte Biochemistry Molecular Medicine Non-Steroidal musculoskeletal diseases Agonist medicine.drug_class Interleukin-8A Mononuclear Allosteric regulation Allosteric Regulation Animals Dinoprostone Humans Interleukin-8 Leukocytes Mononuclear Macrophages Peritoneal Mutation Propionates Structure-Activity Relationship Peritoneal medicine Structure–activity relationship Interleukin-8B Macrophages Molecular Leukocyte biology.protein |
| Zdroj: | Journal of Medicinal Chemistry. 50:3984-4002 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm061469t |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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