Inhibitors of factor Xa

Sheehan and coworkers [47] have also prepared a novel isocyanide derivative, which was used in an Ugi-4CR to prepare noncovalent inhibitors of factor Xa, a key element in the coagulation process [48]. 

Cyclic ureas incorporating a 1,3-diazepinone skeleton continue to be of pharmacological interest. The Ai V-disubstituted system 89 has been prepared and shown to be a potent inhibitor of factor Xa in vitro and to have an improved pharmacokinetic profile in the rabbit. The binding model for this series of compounds was confirmed by an X-ray crystallographic analysis of one analogue in the series <00BMCL301>. 

Preliminary reports have appeared describing a pentapeptide that is a potent (K =3 nM) and selective inhibitor of Factor Xa (SEL2711) [70,71]. 

Considerably more is known about anticoagulants from the blood-feeding hookworm, Ancylostoma caninum. Several families of small, anti-clotting peptides have been described in A. caninum. AcAP, an 8.7 kDa peptide secreted by adult worms that does not exhibit homology to other anticoagulants, but is a potent inhibitor of Factor Xa, was described by Cappello et at. (1995). A family of related peptides, one of which uniquely inhibited a complex of blood coagulation factor VIIA and tissue factor, was also reported (Stanssens et al., 1996). 

Andersen JC. Advances in anticoagulation therapy the role of selective inhibitors of factor Xa and thrombin in thromboprophylaxis after major orthopedic surgery. Semin Thromb Hemost. 2004 30 609-618. 

Abendschein DR, Baum PK, Martin DJ, et al. Effects of ZK-807834, a novel inhibitor of factor Xa, on arterial and... 

Abendschein DR, Baum PK, Verhallen R et al. A novel synthetic inhibitor of factor Xa decreases early reocclusion and improves 24-h patency after coronary fibrinolysis in dogs. J Pharmacol Exp Ther 2001 296 567-572. 

Fondaparinux is a pure inhibitor of factor Xa, which exerts its effect through antithrombin. This compares with UFH and LMWH both of which have additional activity against thrombin to a greater and lesser degree, respectively. To date one trial has been published investigating fondaparinux use... 

The preparation of simple, cyclic 7-9 membered lactams via RCM was also reported <01SL37> (Figure 3). Organ and co-workers reported the preparation of some 8-membered lactams in their enantiospecific synthesis of inhibitors of factor Xa <02TL8177>. 

Lyle EM, Fujita T, Conner MW et al. (1995) Effect of inhibitors of factor Xa or platelet adhesion, heparin, and aspirin on platelet deposition in an atherosclerotic rabbit model of angioplasty injury. J Pharmacol Toxicol Meth 33 53-61 Meng K (1975) Tierexperimentelle Untersuchungen zur an-tithrombotischen Wirkung von Acetylsalicylsaure. Therap Ber 47 69-79... 

Hara T, Yokoyama A, Tanabe K et al. (1995) DX-9065a, an orally active, specific inhibitor of factor Xa, inhibits thrombosis without affecting bleeding time in rats. Thromb Haemost 74 635-639... 

Herbert JM, Bernat A, Dol F et al. (1996) DX 9065A, a novel, synthetic selective and orally active inhibitor of factor Xa in vitro and in vivo studies. J Pharmacol Exp Therapeutics 276 1030-1038... 

Sato K, Kawasaki T, Hisamichi N et al. (1998) Antithrombotic effects of YM-60828, a newly synthesized factor Xa inhibitor, in rat thrombosis models and its effects on bleeding time. Br J Pharmacol 123 92-96 Yamazaki M, Asakura H, Aoshima K et al. (1994) Effects of DX-9065a, an orally active, newly synthesized and specific inhibitor of factor Xa, against experimental disseminated intravascular coagulation in rats. Thromb Haemostasis 72 393-396... 

The azepinyl and 1,4-diazepinyl (homopiperazine) moieties were frequently reported in 2007 by medicinal chemistry groups for exploration of SAR around cyclic amino or cyclic diamino residues, respectively. Examples where the azepinyl substituent yielded optimal activity include l-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 antagonists <07JMC3651> the 1,4-diazepinyl-substituent yielded optimal activity for anthranilimide derivatives as potent inhibitors of factor Xa and displayed in vitro... 

J.L Seymour, R.N. Lindquist, M.S. Dennis, B. Moffat, D. Yansura, D. Reiix M.E. Wessinger R.A. Lazarus, Ecotin is a potent anticoagulant and reversible tight-binding inhibitor of factor-Xa. Biochemistry 1994, 33, 3949-3958. 

New approaches to design inhibitors of Factor Xa as potential anticoagulants have been reviewed (173), and important type III mimetics have been described (Fig. 15.42). All inhibitors contain amidine or basic groups that bind in the enzyme s site none of the inhibitors contains a classical electrophilic center of the type employed in TSA inhibitors (174-180). 

Inhibitors of Factor Xa activity offer potential as anticoagulants and several irreversible inhibitors of Factor Xa have been developed. One of the few tight-binding reversible inhibitors of Factor Xa is BnSOg-D-Arg-Gly-Arg-ke-tothiazole (19). 

Figure 7. Factor Xa targeting in the devdopment of new antithrombotic agents. Both the direct and indirect inhibitors of factor Xa is explored. Ihese agents are also potent inhibitors of thrombin generation at both the plasmatic and cellular sites.

In the last several years, it has become known and more appreciated that the in vivo role of heparin as an anticoagulant may be less important as an inhibitor of thrombin and more important as an inhibitor of Factor Xa.8B Actually heparin is not an anticoagulant, but a cofactor for a protein (a8 globulin - antithrombin III) in the plasma that neutralizes Factor Xa or thrombin by molecular combination. Without heparin this neutralization, which is concentration dependent, is slow. In the presence of heparin, it is greatly accelerated. Heparin has no effect on thrombin... 

Inhibitors of factor Xa (FXa), a serine protease involved in the cascade coagnlation, would allow to control the coagulation process and bleeding problems. Discovery of orally... 

Idraparinux is a polymethylated derivative of fondaparinux that may soon be marketed. Like fondaparinux, this drug is an indireot inhibitor of factor Xa, whioh binds to antithrombin with high affinity (62). The drug has a plasma half-life of 80 hours and oan be administered once a week. Idraparinux is administered subcutaneously, is 100% bioavailable, and does not bind to other plasma proteins. 

Bauer KA. Fondaparinux a new synthetic and selective inhibitor of factor Xa. Best Pract... 

Heparin and the closely related molecule heparan sulfate act as cofactors in AT III inhibition process by affording a 1000-fold increase in the rate at which AT III inhibits coagulation enzymes (9). In the absence of heparin, AT III is a relatively ineffective inhibitor of factor Xa and thrombin (kgssoc [factor Xa] = 2.6 x 10 ... 

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