Target Validation Information
Target ID T17758
Target Name Urokinase-type plasminogen activator
Target Type
Successful
Drug Potency against Target (4-guanidino-benzyl)-carbamic acid benzyl ester Drug Info Ki = 16000 nM [529189]
2-nas-phe(3-am)-4-(2-guanidinoethyl)piperidine Drug Info Ki = 1300 nM [528292]
2-amidino-4-iodobenzothiophene Drug Info Ki = 320 nM [526259]
5-Methylsulfanyl-thiophene-2-carboxamidine Drug Info Ki = 6000 nM [526259]
1-guanidino-N-phenyl-7-isoquinolinesulphonamide Drug Info Ki = 160 nM [528796]
(3,4-dichlorophenyl)(1H-pyrazol-1-yl)methanone Drug Info IC50 = 2600 nM [529037]
2-(2-Hydroxy-phenyl)-1H-indole-5-carboxamidine Drug Info Ki = 2400 nM [526118]
1-guanidino-7-isoquinolinesulphonamide Drug Info Ki = 280 nM [528796]
(3-nitro-1H-pyrazol-1-yl)(p-tolyl)methanone Drug Info IC50 = 3100 nM [529037]
(4-bromo-1H-pyrazol-1-yl)(p-tolyl)methanone Drug Info IC50 = 1700 nM [529037]
4-chloro-1-guanidino-7-isoquinolinesulphonamide Drug Info Ki = 140 nM [528796]
(4-nitro-1H-pyrazol-1-yl)(o-tolyl)methanone Drug Info IC50 = 1300 nM [529037]
1-benzoyl-N-phenyl-1H-pyrazole-3-carboxamide Drug Info IC50 = 1500 nM [529037]
4-methoxy-N'-(2-phenylacetyl)benzohydrazide Drug Info IC50 = 2500 nM [529037]
(4-nitro-1H-pyrazol-1-yl)(phenyl)methanone Drug Info IC50 = 18200 nM [529037]
Amediplase Drug Info IC50 < 1000 nM [552637]
Action against Disease Model Amediplase The in-vitro fibrinolytic efficacy of Tenecteplase, Amediplase (a recombinant chimeric plasminogen activator) and scu-PA was investigated in different external lysis models by measuring the lysis of h uMan plasma clots after the addition of the plasminogen activators (PAs) to the surrounding plasma. The effect of TAFI was examined for each PA by neutralising TAFIa with potato carboxypeptidase inhibitor (PCI). The lytic efficacy of Amediplase was lower than that of Tenecteplase at low PA concentrations but slightly higher at therapeutic concentrations. The activity of scu-PA was clearly lower than that of either Tenecteplase or Amediplase. The TAFI system inhibited external clot lysis mediated by all the PAs when thrombomodulin was present in the model. In the therapeutic range (5-10 m ug/ml) however, the TAFIa effect was negligible for both Amediplase and Tenecteplase. At lower PA concentrations the effect of TAFI on Amediplase was slightly stronger than that on Tenecteplase. Under static conditions the lysis rates were lower than with stirring. The role of TAFI was similar under both conditions. In conclusion, at therapeutic concentrations Amediplase was slightly more active than Tenecteplase and scu-PA under all conditions used. Therefore, Amediplase might possibly be a more potent thrombolytic agent at these concentrations and increase the efficacy of thrombolysis [552637] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations In vivo t uMor progression in mice with targeted deficiencies in urokinase-type plasminogen activator (UPA-/-) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1-/-), was studied using a fibrosarcoma t uMor model. Murine T241 fibrosarcoma cells were s.c. implanted into three groups of mice with the following genotypes, wild-type (WT), UPA-/-, and PAI-1-/-. A significantly diminished primary t uMor growth in UPA-/- and PAI-1-/- mice occurred, relative to WT mice. T uMors in UPA-/- and PAI-1-/- mice displayed lower proliferative and higher apoptotic indices and displayed a different neovascular morphology, as compared with WT mice. These results are consistent with the decreased growth rates of this t uMor in these gene-deleted mice. Immunohistochemical analyses of the t uMors revealed a decrease in vascularity and vascular endothelial growth factor expression only in t uMors in PAI-1-/- mice. Analyses of the relative extents of corneal angiogenesis in these same animals, induced by basic fibroblast growth factor, corroborated the resistance of PAI-1-/- mice to neovascularization. The results obtained suggest that the host fibrinolytic system plays an important role in t uMor growth in this model. Alterations in host expression of components of this system may alter t uMor growth and dissemination by affecting the balance between t uMor cell death and proliferation, as well as extracellular matrix changes needed for invasiveness and angiogenesis. [529189]
References
Ref 529189J Med Chem. 2007 Dec 27;50(26):6638-46. Epub 2007 Dec 1.Small, potent, and selective diaryl phosphonate inhibitors for urokinase-type plasminogen activator with in vivo antimetastatic properties.
Ref 528292J Med Chem. 2006 Jul 13;49(14):4116-26.Secondary amides of sulfonylated 3-amidinophenylalanine. New potent and selective inhibitors of matriptase.
Ref 526259Bioorg Med Chem Lett. 2002 Feb 11;12(3):491-5.Design and synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors.
Ref 526259Bioorg Med Chem Lett. 2002 Feb 11;12(3):491-5.Design and synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors.
Ref 528796J Med Chem. 2007 May 17;50(10):2341-51. Epub 2007 Apr 21.Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines.
Ref 529037J Med Chem. 2007 Oct 4;50(20):4928-38. Epub 2007 Sep 12.N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase.
Ref 526118J Med Chem. 2001 Aug 16;44(17):2753-71.Development of serine protease inhibitors displaying a multicentered short (&lt;2.3 A) hydrogen bond binding mode: inhibitors of urokinase-type plasminogen activator and factor Xa.
Ref 528796J Med Chem. 2007 May 17;50(10):2341-51. Epub 2007 Apr 21.Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines.
Ref 529037J Med Chem. 2007 Oct 4;50(20):4928-38. Epub 2007 Sep 12.N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase.
Ref 529037J Med Chem. 2007 Oct 4;50(20):4928-38. Epub 2007 Sep 12.N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase.
Ref 528796J Med Chem. 2007 May 17;50(10):2341-51. Epub 2007 Apr 21.Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines.
Ref 552637Fibrinolytic efficacy of Amediplase, Tenecteplase and scu-PA in different external plasma clot lysis models: sensitivity to the inhibitory action of thrombin activatable fibrinolysis inhibitor (TAFI). Thromb Haemost. 2006 Sep;96(3):325-30.
Ref 529037J Med Chem. 2007 Oct 4;50(20):4928-38. Epub 2007 Sep 12.N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase.
Ref 529037J Med Chem. 2007 Oct 4;50(20):4928-38. Epub 2007 Sep 12.N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase.
Ref 529037J Med Chem. 2007 Oct 4;50(20):4928-38. Epub 2007 Sep 12.N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase.
Ref 529037J Med Chem. 2007 Oct 4;50(20):4928-38. Epub 2007 Sep 12.N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase.
Ref 552637Fibrinolytic efficacy of Amediplase, Tenecteplase and scu-PA in different external plasma clot lysis models: sensitivity to the inhibitory action of thrombin activatable fibrinolysis inhibitor (TAFI). Thromb Haemost. 2006 Sep;96(3):325-30.

If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.