Thrombininhibitoren

Zusammenfassung

Thrombin ist nicht nur das Schlüsselenzym der Blutgerinnung sondern ist auch in der Lage, vielfältige hormonähnliche, rezeptorvermittelte Reaktionen an verschiedenen Zellen und Geweben auszulösen. Thrombin aktiviert den G-Proteingekoppelten Rezeptor, indem es vom extrazellulären N-Terminus ein Peptid abspaltet und der neugebildete N-Terminus als Ligand den Plättchenrezeptor aktiviert. In der Folge wird eine intrazelluläre Signalkaskade ausgelöst, die zur Formveränderung, Sekretion, Aggregation, Expression von GPIIb/llla und anderen Adhäsionsmolekülen führt. Die rezeptorvermittelten Thrombineffekte an den Plättchen können im Prinzip durch Hemmung der Bindung des Thrombins am Rezeptor über eine Blockade der »Anion-binding-exosite« des Thrombins oder der entsprechenden Bindungsstelle am Rezeptor verhindert werden. Triabin, ein rekombinantes Protein aus der Raubwanze Triatoma pallidipennis, ist ein hochwirksamer »Anion-binding-exosite«-lnhibitor, der in nanomolaren Konzentrationen die Thrombin-Pättchenreaktionen verhindert. Thrombinrezeptorantagonisten sind in der Entwicklung; sie blockieren die Aktivierung des Rezeptors durch Thrombin und Rezeptor-aktivierende Peptide (TRAP). Die derzeit verfügbaren Rezeptorantagonisten sind Peptide mit relativ geringer inhibitorischer Aktivität. Da die proteolytische Aktivität des Enzyms für die Plättchenaktivierung erforderlich ist, können direkte Inhibitoren des Thrombins, die die katalytische Aktivität blockieren, die thrombinbedingte Plättchenaktivierung unterbrechen. Neben dem stärksten selektiven Thrombinhemmstoff Hirudin und dem synthetischen Hirulog sind es kleinmolekulare irreversible oder reversibel wirkende kompetitive Inhibitoren wie PPACK, Tripeptide, Argininund Benzamidinderivate, die gleichfalls zu einer Hemmung der thrombinbedingten Plättchenaktivierung führen. Größere klinische Studien liegen nur mit Hirudin (Refludan®, Revasc®), Hirulog (Bivalirudin®) und Argatroban (Novastan®) bei Patienten mit instabiler Angina pectoris, Myokardinfarkt, Angioplastie, aortokoronarem Bypass, Hämodialyse und heparininduzierter Thrombozytopenie und Thrombose-Syndrom (HITTS II) vor. Eine Verbesserung der therapeutischen Maßnahmen bei akuten und chronischen thromboembolischen Komplikationen könnte durch eine Kombination von Thrombininhibitoren und anderen Plättchenfunktionshemmstoffen erreicht werden.

Schlüsselwörter

Blutplättchen - Thrombinrezeptor - Thrombininhibitoren - Thrombinrezeptorantagonisten

• LITERATUR

• 1 Antman EM. The TIMI 9B investigators. Hirudin in acute myocardial infarction. Thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9B trial. Circulation 1996; 94: 911-21.
• 2 Badimon JJ, Weng D, Chesebro JH, Fuster V, Badimon L. Platelet deposition induced by severely damaged vessel wall is inhibited by a boroarginine synthetic peptide with antithrombin activity. Thromb Haemost 1994; 71: 511-6.
• 3 Bagdy D, Barabas E, Bajusz S, Szell E. In vitro inhibition of blood coagulation by tripeptide aldehydes a retrospective screening study focused on the stable D-Me Phe-Pro-Arg-H-H2S04. Thromb Haemost 1992; 67: 325-30.
• 4 Bagdy B, Barabas E, Szabo G, Bajusz S, Szell E. In vivo anticoagulant and antiplatelet effect of D-Phe-Pro-Arg-H and DMePhe-Pro-Arg-H. Thromb Haemost 1992; 67: 357-65.
• 5 Bates ER. Clinical trial results with hirudin and bivalirudin for acute coronary artery syndromes. Semin Thromb Hemost 1997; 23: 575-81.
• 6 Bernatowicz MS, Klimas CE, Hartl KS, Peluso M, Allegretto NJ, Seiler SM. Development of potent thrombin receptor antagonist peptides. J Med Chem 1996; 39: 4879-87.
• 7 Blackhart BD, Cuenco G, Toda T, Scarborough RM, Wolf DL, Ramakrishnan V. The anion-binding exosite is critical for the high affinity binding of thrombin to the human thrombin receptor. Growth Factors 1994; 11: 17-28.
• 8 Bounamex H, Ehringer H, Hulting J, Rasche H, Rapold HJ, Zultak M. ADVENT Investigators. An exploratory trial of two dosages of a novel synthetic thrombin inhibitor (Nagsagatran, Ro 46-6240) compared with heparin for treatment of proximal deep-vein thrombosis. Thromb Haemost 1997; 78: 997-1002.
• 9 Bracht F, Schrör K. Isolation and identification of aptamers from defibrotide that act as thrombin antagonists in vitro. Biochem Biophys Res Commun 1994; 200: 933-7.
• 10 Brass LF, Vassalo Jr. RR, Belmonte E, Ahuja M, Cichowski K, Hoxie JA. Structure and function of the human platelet thrombin receptor: studies using monoclonal antibodies against a defined domain within the receptor N-terminus. J Biol Chem 1992; 267: 13795-8.
• 11 Bretschneider E, Wittpoth M, Weber AA, Glusa E, Schrör K. Thrombin but not thrombin receptor activating peptide is mitogenic for coronary artery smooth muscle cells. Thromb Res 1997; 87: 493-7.
• 12 Bretschneider E, Wittpoth M, Weber AA, Glusa E, Schrör K. Activation of NFkB is essential but not sufficient to stimulate mitogenesis of vascular smooth muscle cells. Biochem Biophys Res Commun 1997; 235: 365-8.
• 13 Connolly AJ, Ishihara H, Kahn ML, Farese Jr. RV, Coughlin SR. Role of the thrombin receptor in development and evidence for a second receptor. Nature 1996; 381: 516-9.
• 14 Connolly TM, Condra C, Feng DM, Cook JJ, Stranieri MT, Reilly CF, Nutt RF, Gould RJ. Species variability in platelet and other cellular responsiveness to thrombin receptor-derived peptides. Thromb Haemost 1994; 72: 627-33.
• 15 Cousins GR, Friedrichs GS, Sudo Y, Rebello SS, Rote WE, Vlasuk GP, Nolan TG. Orally effective CVS-1123 prevents coronary artery thrombosis in the conscious dog. Circulation 1996; 94: 1705-12.
• 16 Eriksson BI, Wille-Jorgensen P, Kalebo P, Mouret P, Rosencher N, Bosch P, Baur M, Ekman S, Bach D, Lindbratt S, Close P. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997; 337: 1329-1335.
• 17 Fuchs J, Cannon CP. The TIMI 7 Investigators. Hirulog in the treatment of unstable angina. Results of the thrombin inhibition in myocardial ischemia (TIMI) 7 trial. Circulation 1995; 92: 727-33.
• 18 Fuentes-Prior P, Noeske-Jingblut C, Donner P, Schleuning WD, Hube R, Bode W. Structure of the thrombin complex with triabin, a lipocalin-like exosite-binding inhibitor derived from a triatomine bug. Proc Natl Acad Sci USA 1997; 94: 11845-50.
• 19 Gast A, Tschopp TB, Baumgartner HR. Thrombin plays a key role in late platelet thrombus growth and/or stability. Effect of a specific thrombin inhibitor on thrombogenesis induced by aortic subendothelium exposed to flowing rabbit blood. Arterioscler Thromb 1994; 14: 1466-74.
• 20 Gast A, Tschopp TB, Schmid G, Hilpert K, Ackermann J. Inhibition of clot-bound and free (fluid-phase thrombin) by a novel synthetic thrombin inhibitor (Ro 46-6240), recombinant hirudin and heparin in human plasma. Blood Coag Fibrinol 1994; 05: 879-87.
• 21 Glusa E. Blutplättchen und Hirudin. Hämostaseologie 1991; 11: 163-6.
• 22 Glusa E. Vascular effects of thrombin. Semin Thromb Hemost 1992; 18: 296-304.
• 23 Glusa E, Paintz M, Zucker T-H, Schrör K. Thrombin receptor activating peptideinduced cellular effects: Comparative studies in human platelet activation and endothelium-dependent relaxation of porcine pulmonary arteries. Agents Actions Suppl. 1995; 45: 303-7.
• 24 Glusa E, Bretschneider E, Daum J, NoeskeJungblut C. Inhibition of thrombin-mediated cellular effects by triabin, a highly potent anionbinding exosite thrombin inhibitor. Thromb Haemost 1997; 77: 1196-200.
• 25 Glusa E, Gräbner D, Koch H. Influence of a »high affinity« thrombin receptor-activating peptide (haTRAP) on platelets and vascular endothelium. Ann Hematol Suppl. I 1998; 76: A13.
• 26 Glusa E. Inhibition of thrombin-induced platelet functions by direct thrombin inhibitors. Unpublished Results.
• 27 Grand RJA, Turnell AS, Grabham PW. Cellular consequences of thrombin receptor activation. Biochem J 1996; 313: 353-68.
• 28 Grip L. (Investigators of the TRIM study group). A low molecular weight, selective thrombin inhibitor, inogatran, vs heparin, in unstable coronary artery disease inl209 patients. Eur Heart J 1997; 18: 1416-25.
• 29 Gustafsson D, Antonsson T, Bylund R, Eriksson U, Gyzander E, Nilsson I, Elg M, Mattsson C, Deinum J, Pehrsson S, Karlsson O, Nilsson A, Sörensen H. Effects of Melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes. Thromb Haemost 1998; 79: 110-8.
• 30 Hanson SR, Harker LA. Interruption of acute platelet-dependent thrombosis by the synthetic antithrombin D-phenylalanyl-Lprolyl-L-arginyl chloromethyl ketone. Proc Natl Acad Sci USA 1988; 85: 3184-8.
• 31 Harker LA. Strategies for inhibiting the effects of thrombin. Blood Coag Fibrinol 1994; 05: S47-S58.
• 32 Hauptmann J, Markwardt F. Pharmacological aspects of the development of selective synthetic thrombin inhibitors as anticoagulants. Semin Thromb Hemost 1992; 18: 200-17.
• 33 Heras M, Chesebro JH, Webster MWI. Effects of thrombin inhibition on the development of acute platelet-thrombus deposition during angioplasty in pigs: heparin versus recombinant hirudin, a specific thrombin inhibitor. Circulation 1989; 79: 657-65.
• 34 Hung DT, Wong YH, Vu T-K H, Coughlin SR. The cloned platelet thrombin receptor couples to at least two distinct effectors to stimulate phosphoinositide hydrolysis and inhibit adenylyl cyclase. J Biol Chem 1992; 267: 20831-4.
• 35 Imura Y, Stassen J-M, Vreys I, Lesaffre E, Gold HK, Collen D. Synergistic antithrombotic properties of G4120, a RGD-containing synthetic peptide, and argatroban, a synthetic thrombin inhibitor, in a hamster femoral vein platelet-rich thrombosis model. Thromb Haemost 1992; 68: 336-40.
• 36 Ishihara H, Connolly AJ, Zeng D, Kahn ML, Zheng YW, Timmons C, Tram T, Coughlin SR. Protease-activated receptor 3 is a second thrombin receptor in humans. Nature 1997; 386: 502-6.
• 37 Jackson CV, Crowe VG, Frank JD, Wilson HC, Coffman WJ, Utterback BG, Jakubowski JA, Smith GF. Pharmacological assessment of the antithrombotic activity of the peptide thrombin inhibitor, D-methyl-phenylalanylprolyl-arginal (GYKI-14766), in a canine model of coronary artery thrombosis. J Pharmacol Exp Ther 1992; 261: 546-52.
• 38 Jakubowski JA, Maraganore JM. Inhibition of coagulation and thrombin-induced platelet activities by a synthetic dodecapeptide modeled on the carboxy-terminus of hirudin. Blood 1990; 75: 399-406.
• 39 Jandrot-Perrus M, Huisse MG, Krstenansky JL, Bezeaud A, Guillin MC. Effect of the hirudin carboxy-terminal peptide 54-65 on the interaction of thrombin with platelets. Thromb Haemost 1991; 66: 300-5.
• 40 Kaiser B, Fareed J, Walenga JM, Hoppenstedt D, Markwardt F. In vitro studies on thrombin generation in citrated, r-hirudinized and heparinized whole blood. Thromb Res 1991; 64: 589-96.
• 41 Kaiser B, Koza M, Walenga JM, Fareed J. Flow cytometric evaluation of the effect of various thrombin inhibitors on platelet activation in whole blood. Thromb Res 1996; 82: 257-63.
• 42 Kaiser B, Hauptmann J. Pharmacology of synthetic thrombin inhibitors of the tripeptide type. Cardiovasc Drug Rev 1992; 10: 71-87.
• 43 Kettner C, Mersinger L, Knabb R. The selective inhibition of thrombin by peptides of boroarginine. J Biol Chem 1990; 265: 18289-97.
• 44 Lau L-F, Pumiglia K, Cote YP, Feinstein B. Thrombin-receptor agonist peptides, in contrast to thrombin itself, are not full agonists for activation and signal transduction in human platelets in the absence of plateletderived secondary mediators. Biochem J 1994; 303: 391-400.
• 45 Liu L, Freedman J, Hornstein A, Fenton II JW, Song Y, Ofosu FA. Binding of thrombin to the G-protein-linked receptor, and not to glycoprotein Ib, precedes thrombin-mediated platelet activation. J Biol Chem 1997; 272: 1997-2004.
• 46 Lefkovits J, Topol EJ. Direct thrombin inhibitors in cardiovascular medicine. Circulation 1994; 90: 1522-36.
• 47 Maraganore JM, Bourdon P, Jablonski J, Ramachandran KL, Fenton II JW. Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochemistry 1990; 29: 7095-101.
• 48 Markwardt F. The development of hirudin as an antithrombotic drug. Thromb Res 1994; 74: 1-23.
• 49 Matsuo T, Koide M, Kario K. Development of argatroban, a direct thrombin inhibitor, and its clinical application. Semin Thromb Hemost 1997; 23: 517-22.
• 50 McNicol A, Gerrard JM. Post-receptor events associated with thrombin-induced platelet activation. Blood Coagul Fibrinol 1993; 04: 975-91.
• 51 Molino M, Bainton DF, Hoxie JA, Coughlin SR, Brass LF. Thrombin receptors on human platelets. J Biol Chem 1997; 272: 6011-7.
• 52 Noeske-Jungblut C, Haendler B, Donner P, Alagon A, Possani L, Schleuning W-D. Triabin: a highly potent exosite inhibitor of thrombin. J Biol Chem 1995; 270: 28629-34.
• 53 Paborsky LR, McCurdy SN, Griffin LC, Toole JJ, Leung LK. The single-stranded DNA aptamer-binding site of human thrombin. J Biol Chem 1993; 355: 20808-11.
• 54 Pratico D, Murphy NP, Fitzgerald DJ. Interaction of a thrombin inhibitor and a platelet GP IIb/IIIa antagonist in vivo: Evidence that thrombin mediates platelet aggregation and subsequent thromboxane A2 formation during coronary thrombolysis. J Pharmacol Exp Ther 1997; 281: 1178-85.
• 55 Ray A, Hegde LG, Gupta JB. Thrombin receptor: A novel target for antiplatelet drug development. Thromb Res 1997; 87: 37-50.
• 56 Rasmussen UB, Vouret-Craviari V, Jallat S, Schlesinger Y, Pages G, Pavirani A, Lecocq JP, Pouyssegur J, Van Obberghen-Schilling E. cDNA cloning and expression of a hamster a-thrombin receptor coupled to Ca²⁺ mobilization. FEBS Lett 1991; 228: 123-8.
• 57 Rebello SS, Miller BV, Basler GC, Lucchesi BR. CVS-1123, a direct thrombin inhibitor, prevents occlusive arterial and venous thrombosis. J Cardiovasc Pharmacol 1997; 29: 240-9.
• 58 Reilly TM. Knabb RM, Hassell SM, Bozarth JM, Forsythe MS, Mayo MC, Racanelli AL, Mousa SA: Effect of thrombin inhibitors on platelet functions: comparative analysis of DuP 714 and hirudin. Blood Coagul Fibrinol 1992; 03: 513-7.
• 59 Schwarz RP, Becker JCP, Brooks RL, Hursting MJ, Joffrion JL, Knappenberger GD, Kogan TP, Kogan PW, McKinney AA. The preclinical and clinical pharmacology of novastan (argatroban): A small-molecule, direct thrombin inhibitor. Clin Appl Thrombos Hemost 1997; 03: 1-15.
• 60 Seiler SM. Thrombin receptor antagonists. Sem Thromb Hemost 1996; 22: 223-32.
• 61 Shetler TJ, Crowe VG, Bailey BD, Jackson CV. Antithrombotic assessment of the effects of combination therapy with the anticoagulants efegatran and heparin and the glycoprotein IIb-IIIa platelet receptor antagonist 7E3 in a canine model of coronary artery thrombosis. Circulation 1996; 94: 1719-25.
• 62 Simoons ML, van Miltenburg A, Scheffer MG, Werner H, Leenders CM, Remme WJ, Stoel I, de Milliano P, Stibbe J, Roberts E. Anticoagulant properties of efegatran, a direct thrombin inhibitor in patients with unstable angina. Eur Heart J 1994; 15: 120.
• 63 Stürzebecher J, Markwardt F, Voigt B, Wagner G, Walsmann P. Cyclic amides of N a-arylsulfonylaminoacylated 4 amidinophenylalanine tight binding inhibitors of thrombin. Pharmazie 1983; 29: 635-42.
• 64 Tapparelli C, Metternich R, Ehrhardt C, Cook NS. Synthetic low-molecular weight thrombin inhibitors: molecular design and pharmacological profile. Trends Pharmacol Sci 1993; 14: 366-76.
• 65 Tapparelli C, Metternich R, Gfeller P, Gafner B, Powling M. Antithrombotic activity in vivo of SDZ 217-766, a low-molecular weight thrombin inhibitor in comparison to heparin. Thromb Haemost 1995; 73: 641-7.
• 66 Tapparelli C, Metternich R, Gafner B, Gfeller P. Anti-thrombotic and anti-thrombolytic effects of low molecular weight thrombin inhibitors and heparin in rat arterio-venous shunt models. Thromb Haemost 1995; 73: 1323.
• 67 Teger-Nilsson AC, Gustafsson D, Eriksson U, Mattsson C, Held P, Nilsson JE, Grip L, Wallentin L. Experimental and clinical experience of the thrombin inhibitor inogatran. Haemostasis 1996; 26 (Suppl. 03) 129.
• 68 Tschopp TB, Ackermann J, Gast A, Hilpert K, Kirchhofer D, Roux S, Schmid G, Soukup M. Napsagatran. Drugs of the Future 1995; 20: 476-9.
• 69 Uriuda Y, Wang Q-D, Grip L, Ryden L, Sjöquist P-O, Mattson C. Antithrombotic activity of inogatran, a new low-molecularweight inhibitor of thrombin, in a closedchest porcine model of coronary artery thrombosis. Cardiovasc Res 1996; 32: 320-7.
• 70 Verstraete M. Direct thrombin inhibitors: Appraisal of the antithrombotic/hemorrhagic balance. Thromb Haemost 1997; 78: 357-63.
• 71 Vu TKH, Hung DT, Wheaton VI, Coughlin SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991; 64: 1057-68.
• 72 Walsmann P, Kaiser B. Biochemical and pharmacological properties of recombinant hirudin. Drugs today 1989; 25: 473-85.
• 73 Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385-91.
• 74 Zingali RB, Jandrot-Perrus M, Guillin MC, Bon C. Bothrojaracin, a new thrombin inhibitor isolated from Bothrops jararaca venom: characterization and mechanism of thrombin inhibition. Biochemistry 1993; 32: 10794-802.
• 75 Yusuf S. The Investigators of the OASIS trial. Comparison of the effects of two doses of recombinant hirudin compared with heparin in patients with acute myocardial ischemia without ST elevation. Circulation 1997; 96: 769-77.