New thrombin inhibitors in cardiovascular disease

Current Opinion in Chemical Biology

Volumn 1, Issue 2, 1997, Pages 242-253

  Ripka, William C ^a  

^a Dendreon   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTICOAGULANT AGENT; ANTITHROMBIN; THROMBIN;

BLOOD; CORONARY ARTERY THROMBOSIS; DRUG ANTAGONISM; HUMAN; REVIEW;

ANTICOAGULANTS; ANTITHROMBINS; CORONARY THROMBOSIS; HUMANS; THROMBIN;

EID: 0031197125     PISSN: 13675931     EISSN: None     Source Type: Journal    
DOI: 10.1016/S1367-5931(97)80016-6     Document Type: Article

References (73)

1. Hirsh J, Salzman EW, Marder VJ, Colman RW: Therapeutic agents and their practical use in thrombotic disorders: approach to the thrombophilic patient for hemostasis and thrombosis. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice. edn 3. Edited by Colman RW, Hirsh J, Marder VJ, Salzman EW. Philadelphia: JB Lippincott; 1994.
2. Coughlin SR: Thrombin receptor function and cardiovascular disease. Trends Cardiovasc Med 1994, 4:77-83.
3. Weitz J: New anticoagulant strategies. Current status and future potential. Drugs 1994, 48:485-497.
4. Bouton MC, Jandrot-Perrus M, Bezeaud A, Guillin MC: Late fibrin(ogen) fragment E modulates human α-thrombin specificity. Eur J Biochem 1993, 215:143-149.
5. Guillin MC, Bezeaud A, Bouton MC, Jandrot-Perrus M: Thrombin specificity. Thromb Haemost 1995, 74:129-133.
6. 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 Coagul Fibrinolysis 1994, 5:879-887.
7. Hirsh J: Oral anticoagulant drugs. N Engl J Med 1991, 324:1865-1875.
8. Hennekens CH, O'Donnell CJ, Ridker PM: Current and future perspectives on antithrombotic therapy of myocardial infarction. Eur Heart J 1995, 16:2-9.
9. Turpie AGG, Weitz JI, Hirsh J: Advances in antithrombotic therapy: novel agents. Thromb Haemost 1995, 74:565-571.
10. Harker LA, Hanson SR, Kelly AB: Antithrombotic benefits and hemorrhagic risks of direct thrombin antagonists. Thromb Haemost 1995, 74:464-472.
11. Vermylen J: Clinical trials of primary and secondary prevention of thrombosis and restenosis. Thromb Haemost 1995, 74:377-381.
12. Colman RW, Hirsh J, Marder VJ, Salzman EW (Eds): Hemostasis and Thrombosis: Basic Principles and Clinical Practice. edn 3. Philadelphia: JB Lippicott; 1994.
13. Stone SR: Thrombin inhibitors. A new generation of antithrombotics. Trends Cardiovasc Med 1995, 5:135-140.
14. Kimball SD: Thrombin site inhibitors. Curr Pharm Drugs 1995, 1:441-468.
15. Weber PC, Lee SL, Lewandowski FA, Schadt MC, Chang CH, Kettner CA: Kinetic and cristallographic studies of thrombin with Ac-(D)-Phe-Pro-boroArg-OH and its lysine, amidine, homolysine, and ornithine analogs. Biochemistry 1995, 34:3750-3757.
16. Gold HK, Torres FW, Garabedian HD, Werner W, Jang IK, Khan A, Hagstrom JN, Yasuda T, Leinbach RC, Newwell JB et al.: Evidence for a rebound coagulation phenomenon after cessation of a 4-hour infusion of a specific thrombin inhibitor in patients with unstable angina pectoris. J Am Coll Cardiol 1993, 21:1039-1047.
17. Eckhardt U, Stuber W, Dicknate G, Deers M, Petzinger E: First-pass elimination of a peptidomimetic thrombin inhibitor is due to carrier-mediated uptake by the liver. Biochem Pharmacol 1996, 52:85-96. A very important study for the reasons behind the lack of oral bioavailability of one of the major classes of inhibitors (reversible). The work suggests the involvement of an active transporter into hepatocytes and could potentially give guidance to solving the lack of oral bioavailability in this class.
18. Stubbs MT, Bode W: The clot thickens: clues provided by thrombin structure. Trends Biochem Sci 1995, 20:23-28.
19. Klein SI, Dener JM, Molino BF, Gardner CJ, D'Alisa R, Dunwiddie CT, Kasiewski C, Leadley RJ: O-Benzyl hydroxyproline as a bioisostere for Phe-Pro: novel dipeptide thrombin inhibitors. Bioorg Med Chem Letts 1996, 18:2225-2230.
20. Rezaie A, Esmon CT: Conversion of glutamic acid 192 to glutamine in activated protein C changes the substrate specificity and increases reactivity toward macromolecular inhibitors. J Biol Chem 1993, 268:19943-19948.
21. LeBonniec BF, Esmon CT: Glu-192-→GIn substitution in thrombin mimics the catalytic switch induced by thrombomodulin. Proc Natl Acad Sci USA 1991, 88:7371-7375.
22. Markwardt F: Hirudin and derivatives as anticoagulant agents. Thromb Haemost 1991, 66:141-152.
23. Sharp KA: Electrostatic interactions in hirudin-thrombin binding. Biophys Chem 1996, 61:37-49.
24. Cheng Y, Slon-Usakiewicz J, Wang J, Purisimia EO, Konishi Y: Nonpolar interactions of thrombin and its inhibitors at the fibrinogen recognition exosite: thermodynamic analysis. Biochemistry 1996, 35:13021-13029.
25. Cacciola J, Fevig JM, Alexander RS, Brittelli DR, Kettner CA, Knabb RM, Weber PC: Synthesis of conformationally-restricted boropeptide thrombin inhibitors. Bioorg Med Chem Lett 1996, 6:301-306.
26. •]). An extensive structure-activity relationship study raises several interesting questions.
27. Schacht AL, Wiley MR, Chirgadze N, Clawson D, Craft TJ, Coffman WJ, Jones ND, Gifford-Moore D, Olkowski J, Shuman RT et al.: N-Substituted glycines as replacements for proline in tripeptide aldehyde thrombin inhibitors. Bioorg Med Chem Lett 1995, 5:2529-2534.
28. Matthews JH, Krishnan R, Costanzo MJ, Maryanoff BE, Tulinsky A: Crystal structures of thrombin with thiazole-containing inhibitors: probes of the S1′ binding site. Biophys J 1996, 71:2830-2839. An interesting foray into development of inhibitors into the relatively unexplored S′ regions supported by detailed crystal structure analysis.
29. Engh RA, Brandstetter H, Sucher G, Eichinger A, Baumann U, Bode W, Huber R, Poll T, Rudolph R, von der Saal W: Enzyme flexibility, solvent and 'weak' interactions characterized thrombin-ligand interactions: implications for drug design. Structure 1996, 4:1353-1361. An interesting crystallographic paper discussing a number of issues relevant for the design of thrombin inhibitors.
30. Malley MF, Tabernero L, Chiehying YC, Ohringer SL, Roberts DGM, Jagabandhu D, Sack JS: Crystallographic determination of the structures of human α-thrombin complexed with BMS-186282 and BMS-189090. Protein Sci 1996, 5:221-228.
31. Semple JE, Rowley DC, Brunck TK, Ha-Uong T, Minami N, Owens TD, Tamura SY, Goldman EA, Siev DV, Ardecky RJ et al.: Design, synthesis, and evolution of a novel, selective, and orally bioavailable class of thrombin inhibitors: P1-argininal derivatives incorporating P3-P4 lactam sulfonamide moieties. J Med Chem 1996, 39:4531-4536. A clear demonstration that selectivity can be obtained in transition state inhibitors with appropriate molecular alterations. Noteworthy is the report in this paper of substantial oral bioavailability for these tripeptide inhibitors.
32. Levy OE, Semple JE, Lim ML, Reiner J, Rote WE, Dempsey E, Richard BM, Zhang E, Tulinsky A, Ripka WC, Nutt RF: Potent and selective thrombin inhibitors incorporating the constrained arginine mimic L-3-piperidyl(N-guanidino)alanine at P1. J Med Chem 1996, 39:4527-4530. Although always hoped for, a rare example where two independent selectivity-enhancing features were combined into a single molecule resulting in an additive effect to produce transition state inhibitors with extraordinary selectivity.
33. Fevig JM, Abelman MM, Brittelli DR, Kettner CA, Knabb RM, Weber PC: Design and synthesis of ring-constrained boropeptide thrombin inhibitors. Bioorg Med Chem Lett 1996, 6:295-300.
34. Rehse PH, Steinmetzer T, Li Y, Konishi Y, Cygler M: Crystal structure of a peptidyl pyridinium methyl ketone inhibitor with thrombin. Biochemistry 1995, 34:11537-11544.
35. Bajusz S, Szell E, Horvath G, Barabas E, Bagdy D: Interaction of peptidyl arginine aldehydes with thrombin. In Peptides 1990. Edited by Giralt E, Andreu D. ESCOM Science Publishers BV; 1991:779-780.
36. Tamura SY, Goldman EA, Brunck TK, Ripka WC, Semple JE: Rational design, synthesis, and serine protease inhibitory activity of a novel P1-argininal derivative featuring a conformationally constrained P2-P3 bicyclic lactam moiety. Bioorg Med Chem Lett 1997, 7:331-336.
37. Deadman JJ, Elgendy S, Goodwin CA, Green D, Baban JA, Patel G, Skordalakes E, Chino N, Claeson G, Kakkar VV, Scully MF: Characterization of a class of peptide boronates with neutral P1 side chains as highly selective inhibitors of thrombin. J Med Chem 1995, 38:1511-1522.
38. Marsh HC, Meinwald YC, Thannhauser TW, Scheraga HA: Mechanism of action of thrombin on fibrinogen. Kinetic evidence for involvement of aspartic acid at position P10. Biochemistry 1983, 22:4170-4174.
39. Qui X, Padmanabhan KP, Carperos VE, Tulinsky A, Kline T, Maragonore JM, Fenton JW II: Structure of the hirulog 3-thrombin complex and nature of the S′ subsites of substrates and inhibitors. Biochemistry 1992, 31:11689-11697.
40. Brady SF, Lewis SD, Colton CD, Stauffer KJ, Sisko JT, Ng AS, Homnick CF, Bogusky MJ, Shafer JA, Veber DF, Nutt RF: Development of highly potent and selective α-keto carbonyl thrombin inhibitors with novel P1 side chains: synthesis and biological profile of L-370,518. In Peptides: Chemistry, Structure and Biology. Edited by Kaumaya PTP, Hodges RS. Kingswinford, UK: Mayflower Scientific Ltd; 1996:331-333.
41. Cutrona KJ, Sanderson PEJ: The synthesis of thrombin inhibitor L-370,518 via an α-hydroxy-β-lactam. Tetrahedron Lett 1996, 37:5045-5048.
42. Costanzo MJ, Maryanoff BE, Hecker LR, Schott MR, Yabut SC, Zhang HC, Andrade-Gordon P, Kauffman JA, Lewis JM, Krishnan R, Tulinsky A: Potent thrombin inhibitors that probe the S1′ subsite: tripeptide transition state analogues based on a heterocycle-activated carbonyl group. J Med Chem 1996, 39:3039-3043.
43. Steinmetzer T, Konishi Y: Tripeptidyl pyridinium methyl ketones as potent active site inhibitors of thrombin. Bioorg Med Chem Lett 1996, 6:1677-1682.
44. Kikumoto R, Tamao Y, Tezuka T, Tonomura S, Hara H, Ninomiya K, Hijikata A, Okamoto S: Selective inhibition of thrombin by (2R,4R)-4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quino linyl)-sulfonyl]-L-arginyl]-2-piperidine carboxylic acid. Biochemistry 1984, 23:85-90.
45. Wiley MR, Chirgadze NY, Clawson DK, Craft TJ, Gifford-Moore DS, Jones ND, Olkowski JL, Schacht AL, Weir LC, Smith GF: Serine protease selectivity of the thrombin inhibitor D-Phe-Pro-Agmatine and its homologs. Bioorg Med Chem Lett 1995, 5:2835-2840.
46. Wiley MR, Chirgadze NY, Clawson DK, Craft TJ, Gifford-Moore DS, Jones ND, Olkowski JL, Weir LC, Smith GF: D-Phe-pro-p-amidinobenzylamine: a potent and highly selective thrombin inhibitor. Bioorg Med Chem Lett 1996, 6:2387-2392.
47. Tucker TJ, Lumma WC, Mulichak AM, Zhonggua C, Naylor-Olsen AM, Lewis DS, Lucas R, Freidinger RM, Kuo LC: Design of highly potent noncovalent thrombin inhibitors that utilize a novel lipophilic binding pocket in the thrombin active site. J Med Chem 1997, 40:830-832
48. Markwardt F: Hirudin as an inhibitor of thrombin. In Methods Enzymol. Edited by Perlmann GE, Lorand L. 1970, 19:924-932.
49. Stone SR, Hofsteenge J: Kinetics of the inhibition of thrombin by hirudin. Biochemistry 1986, 25:4622-4628.
50. Lombardi A, Nastri F, Morte RD, Rossi A, DeRosa A, Staiano N, Pedone C, Pavone V: Rational design of true hirudin mimetics: synthesis and characterization of multisite-directed α-thrombin inhibitors. J Med Chem 1996, 39:2008-2017.
51. Cappiello M, Vilardo PG, Lippi A, Criscuoli M, Del Corso A, Mura U: Kinetics of human thrombin inhibition by two novel peptide inhibitors (Hirunorm IV and Hirunorm V). Biochem Pharmacol 1996, 52:1141-1146.
52. Cirillo R, Lippi A, Subissi A, Agnelli G, Criscuoli M: Experimental pharmacology of hirunorm: a novel synthetic peptide thrombin inhibitor. Thromb Haemost 1996, 76:384-392.
53. Fethiere J, Tsuda Y, Coulombe R, Konishi Y, Cygler M: Crystal structure of two new bifunctional nonsubstrate type thrombin inhibitors complexed with human α-thrombin. Protein Sci 1996, 5:1174-1183.
54. Krstenansky JL, Broersma RJ, Owen TJ, Payne MH, Yates MT, Mao SJT: Development of MDL 28,050, a small stable antithrombin agent based on a functional domain of the leech protein, hirudin. Thromb Haemost 1990, 63:208-214.
55. Kelly AB, Maraganore JM, Bourdon P, Hanson SR, Harker LA: Antithrombotic effects of synthetic petpides targeting various functional domains of thrombin. Proc Natl Acad Sci USA 1992, 89:6040-6044.
56. Arocas V, Zingali RB, Guillin MC, Bon C, Jandrot-Perrus M: Bothrojaracin: a potent two-site-directed thrombin inhibitor. Biochemistry 1996, 35:9083-9089. A very interesting finding suggesting possible alternate approaches to active site inhibitors for the inhibition of thrombin.
57. Bock LC, Griffin LC, Latham JA, Vermaas EH, Toole JJ: Selection of single-stranded DNA molecules that bind and inhibit human thrombin. Nature 1992, 355:564-566.
58. Padmanabhan K, Padmanabhan KP, Ferrara JD, Sadler JE, Tulinsky A: The structure of α-thrombin inhibited by a 15-mer single-stranded DNA aptamer. J Biol Chem 1993, 268:17651-17654.
59. Lee WA, Fishback JA, Shaw JP, Bock LC, Griffin LC, Cundy KC: A novel oligodeoxynucleotide inhibitor of thrombin. II. Pharmacokinetics in the cynomolgus monkey. Pharm Res 1995, 12:1943-1947.
60. Shuman RT, Rothernberger RB, Jackson CV, Roberts EW, Singer B, Lucas RA, Kurz KD: Oral activity of tripeptide aldehyde thrombin inhibitors. In Peptides: Chemistry, Structure and Biology. Edited by Kaumaya PTP, Hodges RS. Kingswinford, UK: Mayflower Scientific Ltd; 1996:215-216.
61. Simoons M, Lenderink T, Scheffer M, Stoel I, de Milliano P, Remme W, Werner H, Leenders C, Molhoek G, Arnold A: Efegatran, a new direct thrombin inhibitor [abstract]. Lecture 1241 at the 67th Scientific Session, American Heart Association. Circulation 1994:I-231.
62. Teger-Nilsson AC: at Antithrombotic drugs: from current knowledge and therapeutic uses to future avenues. Lecture at Institute Pasteur Euroconferences, 1997 March 6-7, Paris.
63. Tschopp TB, Ackermann J, Gast A, Hilpert K, Kirchofer S, Roux G, Schmid M: Napasagatran. Drugs Future. 1995, 20:476-479.
64. Vlasuk GP: CVS1123, an orally bioavailable direct inhibitor of thrombin [abstract]. American Society for Pharmacology and Experimental Therapeutics, 'Experimental Biology '96', 1996 April 17, Washington.
65. Ruterbories KJ, Hanssen BR, Lindstrom TD: Efegatran (GYKI-14766) [abstract, p 204]. Presented at ISSX proceedings, Fourth North American ISSX meeting 1992, Boll Harbor, Florida.
66. Eriksson VG, Renberg L, Vedin C, Strimfors M: Pharmacokinetics of Inogatran, a new low molecular weight thrombin inhibitor, in rats and dogs [abstract]. Throm Haemost 1995, 73:1605.
67. Uriuda Y, Wang Q-d, Grip L, Ryden L, Sjoequist PO, Mattsson C: Antithrombotic activity of inogatran, a new low-molecular weight inhibitor of thrombin in a closed-chest porcine model of coronary artery thrombosis. Swed Cardiovasc Res 1996, 32:320-327.
68. 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, 94:1719-1725.
69. Roux S, Tschopp T, Baumgartner HR: Effects of napsagatran (Ro 46-6240), a new synthetic thrombin inhibitor and of heparin in a canine model of coronary artery thrombosis: Comparison with an ex vivo annular perfusion chamber model. J Pharmacol Exp Ther 1996, 277:71-78.
70. Carteaux JP, Gast A, Tschopp TB, Roux S: Activated clotting time as an appropriate test to compare heparin and direct thrombin inhibitors such as hiruding or Ro 46-6240 in experimental arterial thrombosis. Circulation 1995, 91:1568-1574. This paper discusses an extremely important issue concerning the appropriateness of using the standard aPTT test to evaluate antithrombotic levels of direct thrombin inhibitors.
71. Chen L, Nichols WW, Mattsson C, Teger-Nilsson A-C, Saldeen TGP, Mehta JL: Inogatran, a novel direct low molecular weight thrombin inhibitor, given with, but not after, tissue-plasminogen activator, improves thrombolysis. J Pharmacol Exp Ther 1996, 277:1276-1283.
72. Cousins GR, Friedrichs GS, Sudo Y, Rebello SS, Rote WE, Vlasuk VP, Nolan TG, Mendoza C, Lucchesi BR: Orally effective CVS-1123 prevents coronary artery thrombosis in the conscious dog. Circulation 1996, 94:1705-1712. This paper demonstrates in a conscious canine model of arterial thrombosis substantial efficacy after oral administration of a transition-state thrombin inhibitor.
73. Rote WR, Dempsey EM, Oldeschulte GL, Ardecky RJ, Tamura SY, Nutt RG, Bergum PN, Tran HS, Anderson SM, Vlasuk GP: Evaluation of a novel orally active direct inhibitor of thrombin in animal models of thrombosis. Circulation 1994, 90:I-344.