生物活性

• 描述CXC chemokines CXCL8 and CXCL1 play essential roles in the activation and recruitment of neutrophils. CXCR1 and CXCR2 are two membrane receptors that bind to CXCL8 with high affinity. Reparixin is a small-molecule, allosteric CXCR1 inhibitor. Reparixin at 0.1 μM led to an 80% inhibition on CXCL8 (10 nM)-induced wild-type CXCR1/L1.2 transfectants migration. The efficacy of reparixin in cells expressing CXCR1 WT and Ile43Val CXCR1 mutant were significantly different (IC₅₀ values of 5.6 and 80 nM, respectively)^[3]. In C57BL/6 mice, subcutaneous administration with reparixin (30 mg/kg) reduced neutrophil activity in the brain after middle cerebral artery occlusion/reperfusion. Reparixin treatment also decreased the levels of interleukin-1β in the brain compared to the vehicle-treated group^[4].
• 作用机制Reparixin is a non-competitive allosteric CXCR1 inhibitor that binds to the transmembrane region of CXCR1, thereby effectively blocking agonist-induced receptor signaling in the intracellular compartment. However, reparixin does not directly affect the expressions of receptors or the CXCL8 binding affinity.
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00224406	Ischemia-Reperfusion Injury ... more >> Lung Transplantation Collapse <<	Phase 2	Completed	-	United States, California ... more >> University of South California, Department of Cardiothoracic Surgery Los Angeles, California, United States, 90033 United States, Colorado University of Colorado, Health Sciences Centre Denver, Colorado, United States, 80262 United States, Missouri Washington University School of Medicine St. Louis, Missouri, United States, 63110 United States, North Carolina Duke University Medical Center Durham, North Carolina, United States, 27710 United States, Ohio The Cleveland Clinic Foundation Cleveland, Ohio, United States, 44195 Collapse <<
  NCT01817959	Islet Transplantation in Diabe... more >>tes Mellitus Type 1 Collapse <<	Phase 3	Completed	-	United States, Illinois ... more >> The University of Chicago Medical Center, Department of Surgery, Division of Abdominal Organ Transplantation Chicago, Illinois, United States, 60637 Czechia Institute for Clinical and Experimental Medicine (IKEM), Diabetes Centre; Department of Diabetes. Praha, Czechia, 14021 Italy Dipartimento di Medicina Interna e Specialistica; IRCCS Ospedale San Raffaele Milan, Italy, 20132 S.S.D. Diabetologia, Azienda Ospedaliera Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore 3 Milan, Italy, 20162 Sweden Transplant Institute - Sahlgrenska University Hospital Göteborg, Sweden, 41345 Department of Nephrology and Transplantation; Skane University Hospital Malmö, Sweden, 20502 Department of Transplantation Surgery; The Karolinska University Hospital Stockholm, Sweden, 14186 Division for Transplantation and Liver Surgery; Department of Surgery; Uppsala University Hospital Uppsala, Sweden, 75185 United Kingdom Institute of Transplantation, Newcastle upon Tyne Hospitals - NHS Foundation Trust, Freeman Hospital Newcastle upon Tyne, United Kingdom, NE7 7DN Collapse <<
  NCT00248040	Ischemia-Reperfusion Injury ... more >> Kidney Diseases Collapse <<	Phase 2	Completed	-	United States, Minnesota ... more >> Transplant Center, University of Minnesota Medical School Minneapolis, Minnesota, United States, 55455 United States, Pennsylvania Division of Transplantation, Drexel University College of Medicine Philadelphia, Pennsylvania, United States, 19102 France Service de Nephrologie et Transplantation, Hopital Lapeyronie, Centre Hospitalier Universitaire Montpellier Montpellier, France, 34295 Cedex 5 Service de Transplantation et Soins Intensifs Nephrologiques, Hopital Necker Paris, France, 75743 Cedex 15 Italy Divisione di Nefrologia e Dialisi, Ospedali Riuniti di Bergamo Bergamo, Italy, 24128 Divisione di Nefrologia e Dialisi, Azienda Ospedaliera Spedali Civili di Brescia Brescia, Italy, 25123 Università degli Studi di Padova, Clinica Chirurgica III Padova, Italy, 35128 Spain Renal Transplant Unit, Hopital Clinic i Provincial de Barcelona Barcelona, Spain, 08036 Division of Nephrology, Institut Catala de la Salut, Ciutat Sanitaria i Universitaria de Bellvitge Barcelona, Spain, 08907 Collapse <<

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• 参考文献

• [1] Bertini R, Barcelos LS, et al. Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor. Br J Pharmacol. 2012 Jan;165(2):436-54.

  [2] Moriconi A, Cesta MC, et al. Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2. J Med Chem. 2007 Aug 23;50(17):3984-4002.

  [3] Moriconi A, Cesta MC, Cervellera MN, Aramini A, Coniglio S, Colagioia S, Beccari AR, Bizzarri C, Cavicchia MR, Locati M, Galliera E, Di Benedetto P, Vigilante P, Bertini R, Allegretti M. Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2. J Med Chem. 2007 Aug 23;50(17):3984-4002. doi: 10.1021/jm061469t. Epub 2007 Aug 1. PMID: 17665889.

  [4] Sousa LF, Coelho FM, Rodrigues DH, Campos AC, Barcelos Lda S, Teixeira MM, Rachid MA, Teixeira AL. Blockade of CXCR1/2 chemokine receptors protects against brain damage in ischemic stroke in mice. Clinics (Sao Paulo). 2013;68(3):391-4. doi: 10.6061/clinics/2013(03)oa17. PMID: 23644861; PMCID: PMC3611745.