Target Validation Information
Target ID T83369
Target Name Coagulation factor IX
Target Type
Clinical Trial
Drug Potency against Target TTP889 Drug Info IC50 = 1500 nM [536572]
4-Phenyl-benzo[b]thiophene-2-carboxamidine Drug Info Ki = 1600 nM [530682]
5-Benzyloxy-benzo[b]thiophene-2-carboxamidine Drug Info Ki = 1900 nM [530682]
2-amidino-4-iodobenzothiophene Drug Info Ki = 950 nM [530682]
RAZAXABAN Drug Info Ki = 9000 nM [527987]
6-Benzyloxybenzo[b]thiophene-2-carboxamidine Drug Info Ki = 3800 nM [530682]
4-Benzyloxybenzo[b]thiophene-2-carboxamidine Drug Info Ki = 1500 nM [530682]
Action against Disease Model TTP889 In vitro models show dose-dependent inhibition of FIX/FIXa activity with TTP889 to a maxim uM of about 90% (IC50 ??? 1.5 |?m). TTP889 does not appear to accelerate clotting induced by exogenous FXIa or Fxa. The antithrombotic potential of TTP889 has been demonstrated in animal models of venous and arterial thrombosis by inhibiting clotting in two a/v shunt models without prolonging bleeding times [536572] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations A murine model of factor IX (F. IX) deficiency was generated to develop gene therapy strategies for hemophilia B. A targeting vector was created by replacing a 3.2-kb segment ofthe gene encompassing the catalytic domain with a phosphoglycerokinase promoter-driven neomycin resistant (neor) gene cassette. The transfected embryonic stem cell clones generated chimeric male mice, and germ line transmission of the inactivated F. IX gene was observed in their offsprings. Southern analysis confirmed the mutant genotype in hemizygous male and carrier female mice. F. IX transcripts were not detected in liver RNA isolated from hemizygous mice, and lower levels of F. IX mRNA were noted in carrier female mice when compared with those of normal litter mates. As expected, the meanF. IX coagulant titer of affected male mice was 2.8 U/dL (n = 10), while the mean F. IX titer of carrier female mice was 35 U/dL (n = 14), compared with 69 U/dL (n = 9) for the normal female mice and92 U/dL (n = 22) for normal male and female litter mates. Further, the tail bleeding time of hemizygous mice was markedly prolonged (>3 hours) compared with those of normal and carrier female litter mates (15 to 20 minutes). Seven of 19 affected male mice died of exsanguination after tail snipping, and two affected mice died of uMbilical cord bleeding. Currently, there are 10 affected mice surviving at 4 months of age. Aside from the factor IX defect, the carrier female and hemizygous male mice had no liver pathology by histologic examination, were fertile, and transmitted the F. IX gene mutation in the expected Mendelian frequency. Taken together, we have generated a F. IX knockout mouse for evaluation of novel gene therapy strategies for hemophilia B. [536572]
References
Ref 536572Partial factor IXa inhibition with TTP889 for prevention of venous thromboembolism: an exploratory study. J Thromb Haemost. 2008 Mar;6(3):457-63. Epub 2007 Dec 12.
Ref 530682J Med Chem. 2010 Feb 25;53(4):1465-72.Studies of benzothiophene template as potent factor IXa (FIXa) inhibitors in thrombosis.
Ref 530682J Med Chem. 2010 Feb 25;53(4):1465-72.Studies of benzothiophene template as potent factor IXa (FIXa) inhibitors in thrombosis.
Ref 530682J Med Chem. 2010 Feb 25;53(4):1465-72.Studies of benzothiophene template as potent factor IXa (FIXa) inhibitors in thrombosis.
Ref 527987Bioorg Med Chem Lett. 2006 Apr 1;16(7):1795-8. Epub 2006 Jan 24.Aminobenzisoxazoles with biaryl P4 moieties as potent, selective, and orally bioavailable factor Xa inhibitors.
Ref 536572Partial factor IXa inhibition with TTP889 for prevention of venous thromboembolism: an exploratory study. J Thromb Haemost. 2008 Mar;6(3):457-63. Epub 2007 Dec 12.
Ref 530682J Med Chem. 2010 Feb 25;53(4):1465-72.Studies of benzothiophene template as potent factor IXa (FIXa) inhibitors in thrombosis.
Ref 530682J Med Chem. 2010 Feb 25;53(4):1465-72.Studies of benzothiophene template as potent factor IXa (FIXa) inhibitors in thrombosis.

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