Factor X inhibitors

Compound 165 and its derivatives inhibit serine protease enzymes such as TF/factor Vila and Xa (tissue factor) <2004USP0235852>. Benzofurans 166 and 167, which have transposed functional groups, are both TF/factor X inhibitors. Tissue factors are involved in the release of thrombin, so these compounds are applied to the treatment of clotting disorders <2003W003082847, 2005JPP2005120080>. Diarylbenzofuran 168 is used to inhibit bone loss <1996USP5489587>. 

Heparin and X Activates antithrombin III, inhibitor of thrombin and factor X... 

Vlasuk GP, Bradbury A, Lopes-Kinninger L, Colon S, Bergum PW, Maki S, Rote WE. Pharmacokinetics and anticoagulant properties of the factor Vila - tissue factor inhibitor recombinant nematode anticoagulant protein c2 following subcutaneous administration in man dependence on the stoichiometric binding to circulating factor X. Thromb Haemost 2003 90 803-12. 

V,/V-Dimethylaminomethyl-2,3,3 ,12 -tetrahydrodibenzo[A/]furo[2,3- /]oxepine derivatives, for example, 145 (X = F, Cl, Br, OMe, etc.), are described as potent anxiolytic agents <2004CPB262, 2005BML2898, 2005FA241>, dibenzo[A/]thieno[2,3- /]oxepine derivatives are claimed as inhibitors of tumor necrosis factor-cr and interleukin-1 production for the treatment of inflammatory diseases <2004W02004078763>. 8-Oxa-l,2-diazadibenzo[i , ]azulene derivatives (dibenzo[/>,/]pyrazolo[3,4- /]oxepines) were synthesized as inhibitors of tumor necrosis factor-x and interleukin-1 production <2003W02003099822>. 

Enjyoji K, Miyaya X Kamikubo Y Kato H, Effect of heparin on the inhibition of factor Xa by tissue factor pathway inhibitor a segment, Gly 212-Phe 243, of the third Kunitz domain is a heparin binding site. Biochemistry 1995 34 5725-5735,... 

Protein structures determined by X-ray or neutron diffraction or NMR which may include co-factors, substrates, inhibitors, or other ligands... 

Heterocyclic aromatics, (I), prepared by Pruitt (1), where ring A consists of isoxazole, oxazole or thiazine and where X is either N or CH, were effective as factor Xa inhibitors. Additional ring A derivatives were prepared by Quan (2). 

Tissue factor pathway inhibitor. This limits the action of TF. It also inhibits excessive TF-mediated activation of factor IX and X. 

Tissue factor pathway inhibitor (TFPI) is a Kunitz type inhibitor composed of three Kunitz domains. The N-terminal Kunitz domain binds to and inhibits the VHa-TF complex that activates factor X (Fig. 11.6a), whereas the downstream Kunitz domain binds directly to factor Xa and inhibits it strongly and permanently. No function has yet been demonstrated for the third Kunitz domain. The C-terminal region of TFPI is basic and remains attached to endothelial cell surfaces where it inhibits inadvertent factor Xa activation. Studies in mice indicate that knocking out the gene for TFPI stops fetal development. Indeed, clotting diseases such as a stroke and heart attacks are associated with mutations of AITH, HCII and ZPI, but not of TFPI. Like TF (Sect. 11.3.1), diminished TFPI activity may be incompatible with life. 

---