Target Validation Information
TTD ID T17758
Target Name Urokinase-type plasminogen activator (PLAU)
Type of Target
Successful
Drug Potency against Target Amediplase Drug Info IC50 < 1000 nM [7]
(3,4-dichlorophenyl)(1H-pyrazol-1-yl)methanone Drug Info IC50 = 2600 nM [5]
(3-nitro-1H-pyrazol-1-yl)(p-tolyl)methanone Drug Info IC50 = 3100 nM [5]
(4-bromo-1H-pyrazol-1-yl)(p-tolyl)methanone Drug Info IC50 = 1700 nM [5]
(4-guanidino-benzyl)-carbamic acid benzyl ester Drug Info Ki = 16000 nM [6]
(4-nitro-1H-pyrazol-1-yl)(o-tolyl)methanone Drug Info IC50 = 1300 nM [5]
(4-nitro-1H-pyrazol-1-yl)(phenyl)methanone Drug Info IC50 = 18200 nM [5]
1-benzoyl-N-phenyl-1H-pyrazole-3-carboxamide Drug Info IC50 = 1500 nM [5]
1-guanidino-7-isoquinolinesulphonamide Drug Info Ki = 280 nM [4]
1-guanidino-N-phenyl-7-isoquinolinesulphonamide Drug Info Ki = 160 nM [4]
2-(2-Hydroxy-phenyl)-1H-indole-5-carboxamidine Drug Info Ki = 2400 nM [1]
2-nas-phe(3-am)-4-(2-guanidinoethyl)piperidine Drug Info Ki = 1300 nM [3]
4-chloro-1-guanidino-7-isoquinolinesulphonamide Drug Info Ki = 140 nM [4]
4-iodobenzo[b]thiophene 2-carboxamidine Drug Info Ki = 320 nM [2]
4-methoxy-N'-(2-phenylacetyl)benzohydrazide Drug Info IC50 = 2500 nM [5]
5-Methylsulfanyl-thiophene-2-carboxamidine Drug Info Ki = 6000 nM [2]
Action against Disease Model Amediplase Drug Info 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 [7]
References
REF 1 Development of serine protease inhibitors displaying a multicentered short (&lt;2.3 A) hydrogen bond binding mode: inhibitors of urokinase-type plasmi... J Med Chem. 2001 Aug 16;44(17):2753-71.
REF 2 Design and synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors. Bioorg Med Chem Lett. 2002 Feb 11;12(3):491-5.
REF 3 Secondary amides of sulfonylated 3-amidinophenylalanine. New potent and selective inhibitors of matriptase. J Med Chem. 2006 Jul 13;49(14):4116-26.
REF 4 Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines. J Med Chem. 2007 May 17;50(10):2341-51.
REF 5 N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase. J Med Chem. 2007 Oct 4;50(20):4928-38.
REF 6 Small, potent, and selective diaryl phosphonate inhibitors for urokinase-type plasminogen activator with in vivo antimetastatic properties. J Med Chem. 2007 Dec 27;50(26):6638-46.
REF 7 Fibrinolytic 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.

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