Factor Vila inhibitors

Amino-bicyclic pyrazinone, (V), and pyridinone derivatives prepared by Zhang (5) were effective as factor Vila inhibitors and as selective inhibitors of serine protease enzymes associated with the coagulation cascade. 

Kranjc, A., Kikelj, D. and Peterlin-Masic, L. (2005) Recent advances in the discovery of tissue factor/factor, Vila inhibitors and dual inhibitors of factor, VIIa/Factor, Xa. Curr. Pharm. Des., 11, 4207 1227. 

Parlow, J. J., Stevens, A. M., Stegeman, R. A., et al. (2003) Synthesis and crystal structures of substituted benzenes and benzoquinones as tissue factor Vila inhibitors. Journal of Medicinal Chemistry, 46(20), 4297 1312. 

There are examples of the use of supported carbodiimide 2 (R = Cy) for the formation of N-hydroxybenzotriazole (HOBt)-derived active esters from N-Boc-protected amino acids (see below), which have been subsequently employed in coupling reactions for the synthesis of dipeptide p-nitroanilides and dipeptide diphenyl phosphonates [12, 13]. Such HOBt-active esters have also been generated from pyrazinone-derived acids using 2 (R = Cy) [14], as well as from difluorophenyl acetic acids [15] for further amidation reactions in the parallel synthesis of tissue factor Vila inhibitors. 

L. Weber, Bioorg. Med Chem. Lett. 2005,15,817-822. Design of selective phenylglycine amide tissue factor/factor Vila inhibitors. 

M. A. Riederer, M. Stahl, T. B. Tschopp, U. Obst-Sander, Bioorg. Med. Chem. 2006, 14, 5357-5369. Dose-dependent antithrombotic activity of an orally active tissue factor/factor Vila inhibitor without concomitant enhancement of bleeding propensity. 

Dennis, M.S., Lazarus, R.A. Kunitz domain inhibitors of tissue factor-factor Vila. 1. Potent inhibitors selected from libraries by phage display. /. Biol. Chem. 269 22129-22136, 1994. 

The marine natural product dynosin A (92) is a new member of the aerugi-nosin family and a novel inhibitor of thrombin and Factor Vila. In Hanessian s total synthesis of 92 [66], both the dihydroxyoctahydroindole 88 and the A3 pyrroline moiety 91 were prepared by RCM-based routes (Scheme 17). 

PCCs contain the vitamin K-dependent factors II, VII, IX, and X. These agents represent another attempt to bypass the factor at which the antibody is directed (see Fig. 64-2). However, PCCs carry the risk of serious thrombotic complications. Porcine factor VIII is most useful when the inhibitor titer is less than 50 BU (see Fig. 64-2 for dose and frequency). Owing to its similarity to human factor VIII, porcine factor VIII participates in the coagulation cascade. However, most inhibitors have very weak neutralizing activity against it. Porcine factor VIII is a third-line agent (only after factor Vila and a PCC have failed) owing to a 15% incidence of cross-reactivity.15... 

Tissue factor pathway inhibitor (TFPI), a 42-kDa protein with three Kunitz domains, is a potent inhibitor of coagulation. It inhibits tissue factor-factor Vila complex upon binding to the active site of Kunitz domain one. Factor Xa is inhibited upon binding to the active site of the second Kunitz domain of TFPI (27). 

HO " T COjH H Sponge -Lamellodysidea chlorea Dysinosins A, C, and D -inhibitors of factor Vila and thrombin 266, 268, 272... 

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. 

A number of 1-substituted 2(l//)-pyrazinone derivatives show antithrombotic activity as selective inhibitors of the tissue Factor Vila complex <2003BML23I9> and were examined as mast cell tryptase inhibitors <2004BML48I9>. As a curious effect, dihydropyrazines proved to show DNA strand-breakage activity <2005CPB1359>. 

Predicted secondary structure of tissue factor pathway inhibitor (TFPI) showing the Factor Xa and Factor Vila inhibitory domains. The arrows point to the PI sites. 

In another example of combinatorial parallel chemistry, we have recently used the Ugi three-component reactions (Ugi 3-CR) to construct a library of 16,840 protease inhibitors (25). It has been demonstrated previously that the Ugi-3CR reaction provides a useful chemical scaffold for the design of serine protease inhibitors N-substituted 2-substituted-glycine /V-ary 1/alky 1 -amidcs have been identified that are potent factor Xa, factor Vila, or thrombin inhibitors. The three variable substituents of this scaffold, provided by the amine, aldehyde, and isonitrile starting materials, span a favorable pyramidal pharma-cophoric scaffold that can fill the S1, S2, and S3 pockets of the respective protease. This library was screened against five proteases (factor Xa, trypsin, uro-... 

Lusher, J. M. (1996). Recombinant factor Vila (NovoSeven) in the treatment of internal bleeding in patients with factor VIII and IX inhibitors. 

TFPI, when administered to rabbits, has been shown to have an antithrombotic effect when thromboplastin was used as a thrombogenic challenge (I 10). TFPI was also shown to be an effective inhibitor when thrombosis was induced in rabbit jugular veins by endothelial destruction and restricted blood flow. The antithrombotic and antiprotease actions of TFPI have been tested in several other animal models. Warn-Cramer et al. investigated the effect of immunodepletion of TFPI in factor Vila and Xa induced coagulation in rabbits (III). These rabbits were observed to be sensitized to the procoagulant effects of factor Vila, but not factor Xa in the absence of factor Vila. Two studies have indicated that TFPI administration reduces the lethal effects of . coli administration in a septic shock model in baboons (I 12). These studies also indicated that TFPI may have an anti-inflammatory effect, as an attenuation of the IL-6 response was also observed. Administration of TFPI has been observed to prevent... 

Sultan Y Loyer F In vitro evaluation of factor VI11-bypassing activity of activated prothrombin complex concentrates and factor Vila in the plasma of patients with factor VIII inhibitors thrombin generation test in the presence of collagen-activated platelets. J Lab Clin Med 1993 121 444-452. 

V-Guanidinoal kvI amides analogs of the current invention, (n), prepared by Klingler (2) were effective as reversible inhibitors of the blood clotting enzymes factor Xa and/or factor Vila and used in the treatment of thromboembolic diseases or restenosis. 

Peptide derivatives, (III), prepared by Shiraishi (3) selectively inhibited extrinsic blood coagulation by inhibiting factor Vila. a-Ketoamide peptides, (IV), while those prepared by Chatterjee (4) were effective as cysteine and serine proteases inhibitors and used in treating coagulation disorders associated with thrombophlebitis and... 

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