Factor Xa inhibitor

Ostrovsky, D. Udier-Blagovic, M. Jorgensen, W.L., Analyses of activity for factor Xa inhibitors based on Monte Carlo simulations, J. Med. Chem. 2003, 46, 5691-5699... 

A. Sokolowski, R. Rai, W. Young, and B. Sjostrom. In vitro intestinal permeability of factor Xa inhibitors influence of chemical structure on passive transport and susceptibility to efflux, Pharm. Res. 2001, 38, 1735— 1741... 

Antitrombotics and Anticoagulants (warfarin, heparin, LMWH, Factor Xa inhibitors, direct trombin inhibitors, thrombolytics, and glycoprotein... 

Liebeschuetz, J.W., Jones, S.D., Morgan, P.J., Murray, C.W., and Rimmer, A.D. PROSELECT combining stmcture-based drug design and array-based chemistry for rapid lead discovery. 2. The development of a series of highly potent and selective factor Xa inhibitors. /. Med. Chem. 2002, 45, 1221-1232. 

A major focus of drug development has been to develop orally active anticoagulants that do not require monitoring. Rivaroxiban is the first oral factor Xa inhibitor to reach phase III clinical trials. The safety and efficacy of rivaroxiban appears to be at least equivalent, and possibly superior, to LMW heparins for prevention of deep vein thrombosis no routine monitoring is required. This drug is also in clinical trials for treatment of deep vein thrombosis and prevention of stroke in atrial fibrillation. 

Table 1 Factor Xa Inhibitors (TAP, Antistasin) in Experimental Models of Thrombosis Rat and rabbit models of venous thrombosis [25]...

Recently, compounds based on a bisamidine motif (e.g., DX-9065a) have been reported as potent and selective Factor Xa inhibitors (1, DX-9065a) [60-63]. 

The initial discovery of bisamidine structures as potential Factor Xa inhibitors was actually made much earlier with the finding that compounds such as 4 showed an almost 300-fold preference for Factor Xa over thrombin with a K of 13 nM(FXa) [67],... 

In an effort to compare the relative efficacy of thrombin versus Factor Xa inhibitors, Markwardt et al. [67] synthesized a set of amidinoaryl compounds with moderate potency as Factor Xa inhibitors (5). 

VIII. Positional Requirements of Factor Xa Inhibitors (Table 6)... 

Hauptmann J, Kaiser B, Vowak G, Struzebecher J, Markwardt F. Comparison of the anticoagulant and antithrombotic effects of synthetic thrombin and factor Xa inhibitors. Throm Haemostas 1990 63 220-223. 

Jacobs JW, Cupp EW, Sardana M, Friedman PA. Isolation and characterization of a coagulation factor Xa inhibitor from black fly salivary glands. Thromb Haemost (GERMANY) 1990 64 235-238. 

Dunwiddie CT, Nutt EM, Vlasuk GP, Siegel PDS, Schaffer LW. Anticoagulant efficacy and immunogenicity of the selective factor Xa inhibitor antistasin following subcutaneous administration in the rhesus monkey. Thromb Haemostas 1992 67 371-376. 

Hofmann KJ, Nutt EM, Dunwiddie CT. Site-directed mutagenesis of the leechderived factor Xa inhibitor antistasin. Biochem J 1992 287 943. 

A remarkable example of this approach is the synthesis of the prolyl endopepti-dase inhibitor eurystatin A 39 reported by Semple et al. (Scheme 2.16) [31]. Another application of this methodology to the synthesis of a family of potent Factor Xa inhibitors was recently reported by the same group [25b],... 

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