Target Validation Information
Target ID T56923
Target Name High affinity interleukin-8 receptor B
Target Type
Successful
Drug Potency against Target Reparixin Drug Info IC50 = 1 nM [552901]
5-(pentylthio)thiazolo[4,5-d]pyrimidin-7-ol Drug Info IC50 = 10000 nM [527875]
1-(2-Hydroxy-3-nitro-phenyl)-3-phenyl-urea Drug Info IC50 = 860 nM [526980]
R-KETOPROFEN Drug Info IC50 = 34 nM [527602]
(R)-2-(4-Isobutyl-phenyl)-N-methoxy-propionamide Drug Info IC50 = 1.8 nM [527602]
1-(3-cyano-2-hydroxyphenyl)-3-phenylurea Drug Info IC50 = 276 nM [528628]
1-(2-bromophenyl)-3-(4-cyano-2-hydroxyphenyl)urea Drug Info IC50 = 25 nM [528628]
IBUPROPHEN Drug Info IC50 = 110 nM [527602]
SB-656933 Drug Info IC50 = 5.1 nM [552889]
1-(2-hydroxy-4-nitrophenyl)-3-phenylurea Drug Info IC50 = 320 nM [528628]
SCH-527123 Drug Info Ki = 2.6 nM [552662]
1-(2-Hydroxy-5-nitro-phenyl)-3-phenyl-urea Drug Info IC50 = 10900 nM [526980]
1-(4-cyano-2-hydroxyphenyl)-3-phenylurea Drug Info IC50 = 200 nM [528628]
1-(5-chloro-2-hydroxy-4-nitrophenyl)-3-phenylurea Drug Info IC50 = 950 nM [528628]
RAPARIXIN Drug Info IC50 = 5.3 nM [527602]
Action against Disease Model SCH-527123 In a h uMan neutrophil (hPMN) chemotaxis assay, SCH 527123 displayed superior inhibition of chemotaxis in vitro induced by CXCL1 or CXCL8. SCH 527123 demonstrated complete inhibition of CXCL1-mediated neutrophil chemotaxis at 2 nM, while inhibition of CXCL8-mediated chemotaxis was less potent [552662] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations In marked contrast, neutrophil recruitment to the corneas of CXCR2(-/-) mice was significantly impaired (p < 0.0001 compared with control, BALB/c mice) with only occasional neutrophils detected in the central cornea. Furthermore, CXCR2(-/-) mice developed only mild corneal opacification compared with BALB/c mice. These differences were not due to impaired KC and MIP-2 production in the corneal stroma of CXCR2(-/-) mice, which was similar to BALB/c mice. Furthermore, although MIP-1 alpha production was lower in CXCR2(-/-) mice than BALB/c mice, eosinophil recruitment to the cornea was not impaired. These observations demonstrate the critical role for CXCR2 expression in neutrophil infiltration to the cornea and may indicate a target for immune intervention in neutrophil-mediated corneal inflammation [552901]
References
Ref 552901Chemokine receptor antagonists: overcoming developmental hurdles. Nat Rev Drug Discov. 2009 Jan;8(1):23-33. doi: 10.1038/nrd2734. Epub 2008 Dec 12.
Ref 527875Bioorg Med Chem Lett. 2006 Feb 15;16(4):960-3. Epub 2005 Nov 15.Hit-to-Lead studies: the discovery of potent, orally bioavailable thiazolopyrimidine CXCR2 receptor antagonists.
Ref 526980J Med Chem. 2004 Mar 11;47(6):1319-21.Evaluation of potent and selective small-molecule antagonists for the CXCR2 chemokine receptor.
Ref 527602J Med Chem. 2005 Jun 30;48(13):4312-31.2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors.
Ref 527602J Med Chem. 2005 Jun 30;48(13):4312-31.2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors.
Ref 528628Bioorg Med Chem Lett. 2007 Mar 15;17(6):1713-7. Epub 2006 Dec 23.Comparison of N,N'-diarylsquaramides and N,N'-diarylureas as antagonists of the CXCR2 chemokine receptor.
Ref 528628Bioorg Med Chem Lett. 2007 Mar 15;17(6):1713-7. Epub 2006 Dec 23.Comparison of N,N'-diarylsquaramides and N,N'-diarylureas as antagonists of the CXCR2 chemokine receptor.
Ref 527602J Med Chem. 2005 Jun 30;48(13):4312-31.2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors.
Ref 552889CXCR2 antagonists for the treatment of pulmonary disease. Pharmacol Ther. 2009 Jan;121(1):55-68. doi: 10.1016/j.pharmthera.2008.10.005. Epub 2008 Oct 31.
Ref 552662Discovery of 2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5- methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobut-1-enylamino}benzamide (SCH 527123): a potent, orally bioavailable CXCR2/CXCR1 receptor antagonist. J Med Chem. 2006 Dec 28;49(26):7603-6.
Ref 528628Bioorg Med Chem Lett. 2007 Mar 15;17(6):1713-7. Epub 2006 Dec 23.Comparison of N,N'-diarylsquaramides and N,N'-diarylureas as antagonists of the CXCR2 chemokine receptor.
Ref 552662Discovery of 2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5- methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobut-1-enylamino}benzamide (SCH 527123): a potent, orally bioavailable CXCR2/CXCR1 receptor antagonist. J Med Chem. 2006 Dec 28;49(26):7603-6.
Ref 526980J Med Chem. 2004 Mar 11;47(6):1319-21.Evaluation of potent and selective small-molecule antagonists for the CXCR2 chemokine receptor.
Ref 528628Bioorg Med Chem Lett. 2007 Mar 15;17(6):1713-7. Epub 2006 Dec 23.Comparison of N,N'-diarylsquaramides and N,N'-diarylureas as antagonists of the CXCR2 chemokine receptor.
Ref 528628Bioorg Med Chem Lett. 2007 Mar 15;17(6):1713-7. Epub 2006 Dec 23.Comparison of N,N'-diarylsquaramides and N,N'-diarylureas as antagonists of the CXCR2 chemokine receptor.
Ref 527602J Med Chem. 2005 Jun 30;48(13):4312-31.2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors.

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