| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T82739 | ||||
| Target Name | Plasma kallikrein | ||||
| Target Type | Successful |
||||
| Drug Potency against Target | D-Pro-Phe-Arg chloromethyl ketone | Drug Info | IC50 = 31 nM | [529454] | |
| ZK-810388 | Drug Info | Ki = 37 nM | [528872] | ||
| (3-nitro-1H-pyrazol-1-yl)(p-tolyl)methanone | Drug Info | IC50 = 6100 nM | [529037] | ||
| (3-nitro-1H-pyrazol-1-yl)(phenyl)methanone | Drug Info | IC50 = 18800 nM | [529037] | ||
| 1-benzoyl-N-phenyl-1H-pyrazole-3-carboxamide | Drug Info | IC50 = 12300 nM | [529037] | ||
| (3,4-dichlorophenyl)(1H-pyrazol-1-yl)methanone | Drug Info | IC50 = 5700 nM | [529037] | ||
| (4-bromo-1H-pyrazol-1-yl)(p-tolyl)methanone | Drug Info | IC50 = 6200 nM | [529037] | ||
| ZK-814048 | Drug Info | Ki = 1000 nM | [528872] | ||
| The Effect of Target Knockout, Knockdown or Genetic Variations | Tissue kallikrein is the main kinin-forming enzyme in mammals, and differences in kinin levels are thought to be a contributing factor to diabetic nephropathy. Here, we determined the role of the kallikrein-kinin system in the pathogenesis of streptozotocin-induced diabetic nephropathy in wild-type and tissue kallikrein-knockout mice. All diabetic mice developed similar hyperglycemia, but the knockout mice had a significant two-fold increase in alb uMinuria compared to the wild-type mice before and after blood pressure elevation. Ezrin mRNA, a podocyte protein potentially implicated in alb uMinuria, was downregulated in the kidney of knockout mice. One month after induction of diabetes, the mRNAs of kininogen, tissue kallikrein, kinin B1, and B2 receptors were all increased up to two-fold in the kidney in both genotypes. Diabetes caused a 50% decrease in renal angiotensin-converting enzyme expression and a 20-fold increase in kidney injury molecule-1 reflecting tubular dysfunction, but there was no genotype difference. | [529454] | |||
| References | |||||
| Ref 529454 | J Med Chem. 2008 Jun 12;51(11):3077-80. Epub 2008 May 7.Novel 3-carboxamide-coumarins as potent and selective FXIIa inhibitors. | ||||
| Ref 528872 | J Med Chem. 2007 Jun 28;50(13):2967-80. Epub 2007 May 31.Thiophene-anthranilamides as highly potent and orally available factor Xa inhibitors. | ||||
| Ref 529037 | J 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 529037 | J 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 529037 | J 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 529037 | J 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 529037 | J 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 528872 | J Med Chem. 2007 Jun 28;50(13):2967-80. Epub 2007 May 31.Thiophene-anthranilamides as highly potent and orally available factor Xa inhibitors. | ||||
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