Design of Noncompetitive Interleukin-8 Inhibitors Acting on CXCR1 and CXCR2
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- 作者：Alessio Moriconi ; Maria Candida Cesta ; Maria Neve Cervellera ; Andrea Aramini ; Silvia Coniglio ; Sandro Colagioia ; Andrea Rosario Beccari ; Cinzia Bizzarri ; Michela Rita Cavicchia ; Massimo Locati ; Emanue
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：August 23, 2007
- 年：2007
- 卷：50
- 期：17
- 页码：3984 - 4002
- 全文大小：504K
- 年卷期：v.50,no.17(August 23, 2007)
- ISSN：1520-4804
文摘
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 forCXCR2. In the past decade, the physiopathological role of CXCL8 and CXCL1 has been investigated. Anovel class of small molecular weight allosteric CXCR1 inhibitors was identified, and reparixin, the firstdrug candidate, is currently under clinical investigation in the prevention of ischemia/reperfusion injury inorgan transplantation. Reparixin binding mode to CXCR1 has been studied and used for a computer-assisteddesign 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 optimizedpharmacokinetic characteristics.