Multitarget antithrombotic drugs

Current Topics in Medicinal Chemistry

Volumn 11, Issue 22, 2011, Pages 2834-2848

  Ilić, Miloš ^a   Kikelj, Danijel ^a   Ilaš, Janez ^a  

^a UNIVERSITY OF LJUBLJANA   (Slovenia)

Author keywords

Anticoagulants; Antiplatelet; Antithrombotics; Dual inhibitors; Multitarget drugs

Indexed keywords

3,4 DIHYDRO 2H 1,4 BENZOXAZINE DERIVATIVE; ACETYLSALICYLIC ACID; ANTICOAGULANT AGENT; ANTITHROMBOCYTIC AGENT; ARGATROBAN; BENZOFURAN 7 YLOXYACETIC ACID DERIVATIVE; BLOOD CLOTTING FACTOR 10A INHIBITOR; FIBRINOGEN RECEPTOR ANTAGONIST; FONDAPARINUX; GALACTAN; GALACTANE SULFATE; HEPARIN; HIRULOG; ILOPROST; PHOSPHODIESTERASE INHIBITOR; PICOTAMIDE; PROSTACYCLIN RECEPTOR AGONIST; PROTEINASE ACTIVATED RECEPTOR 1; PURINERGIC P2Y RECEPTOR ANTAGONIST; PURINERGIC P2Y12 RECEPTOR ANTAGONIST; RIDOGREL; SULOTROBAN; TERBOGREL; THROMBIN INHIBITOR; THROMBOXANE A2 RECEPTOR BLOCKING AGENT; THROMBOXANE RECEPTOR BLOCKING AGENT; THROMBOXANE SYNTHASE INHIBITOR; TICLOPIDINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; WARFARIN;

BLEEDING; BLOOD CLOTTING; CARDIOVASCULAR DISEASE; DEEP VEIN THROMBOSIS; DRUG BINDING; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG EFFICACY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; HEART INFARCTION; HUMAN; IC 50; LUNG EMBOLISM; NONHUMAN; REVIEW; STROKE; THROMBOCYTE; THROMBOCYTE AGGREGATION; THROMBOEMBOLISM;

ANIMALS; ANTICOAGULANTS; ENZYME INHIBITORS; HUMANS; THROMBOEMBOLISM;

EID: 82055170359     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/156802611798184364     Document Type: Review

References (95)

1. Mackman, N.; Tilley, R.E.; Key, N.S. Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscler. Thromb. Vasc. Biol., 2007, 27, 1687-1693.
2. Labuzek, K.; Krysiak, R.; Okopien, B.; Herman, Z.S. Progress in pharmacotherapy of thrombosis. Pol. J. Pharmacol., 2003, 55, 523-533.
3. Mackman, N. Triggers, targets and treatments for thrombosis. Nature, 2008, 451, 914-918.
4. Moll, S.; Mackman, N. Venous thromboembolism: A need for more public awareness and research into mechanisms. Arterioscler. Thromb. Vasc. Biol., 2008, 28, 367-369.
5. Ansell, J.; Bergqvist, D. Current options in the prevention of thromboembolic disease. Drugs, 2004, 64, 1-5.
6. Ruef, J.; Katus, H.A. New antithrombotic drugs on the horizon. Expert. Opin. Investig. Drugs, 2003, 12, 781-797.
7. Bereznicki, L.R.; Peterson, G.M. New Antithrombotics for Atrial Fibrillation. Cardiovasc. Ther., 2010, 28, 278-286.
8. Schaden, E.; Kozek-Langenecker, S.A. Direct thrombin inhibitors: pharmacology and application in intensive care medicine. Intensive. Care. Med., 2010, 36, 1127-1137.
9. Weitz, J.I. New oral anticoagulants in development. Thromb. Haemost., 2010, 103, 62-70.
10. Piccini, J.P.; Lopes, R.D.; Mahaffey, K.W. Oral factor Xa inhibitors for the prevention of stroke in atrial fibrillation. Curr. Opin. Cardiol., 2010, 25, 312-320.
11. Shirk, R.A.; Vlasuk, G.P. Inhibitors of factor VIIa/Tissue factor. Arterioscler. Thromb. Vasc. Biol., 2007, 27, 1895-1900.
12. Howard, E.L.; Becker, K.C.D.; Rusconi, C.P.; Becker, R.C. Factor IXa inhibitors as novel anticoagulants. Arterioscler. Thromb. Vasc. Biol., 2007, 27, 722-727.
13. Gulseth, M.P.; Michaud, J.; Nutescu, E.A. Rivaroxaban: An oral direct inhibitor of factor Xa. Am. J. Health. Syst. Pharm., 2008, 65, 1520-1529.
14. Miura, M.; Seki, N.; Koike, T.; Ishihara, T.; Niimi, T.; Hirayama, F.; Shigenaga, T.; Sakai-Moritani, Y.; Tagawa, A.; Kawasaki, T.; Sakamoto, S.; Okada, M.; Ohta, M.; Tsukamoto, S. Design, synthesis and biological activity of selective and orally available TF/FVIIa complex inhibitors containing non-amidine P1 ligands. Bioorg. Med. Chem., 2007, 15, 160-173.
15. Miura, M.; Seki, N.; Koike, T.; Ishihara, T.; Niimi, T.; Hirayama, F.; Shigenaga, T.; Sakai-Moritani, Y.; Kawasaki, T.; Sakamoto, S.; Okada, M.; Ohta, M.; Tsukamoto, S.I. Potent and selective TF/FVIIa inhibitors containing a neutral P1 ligand. Bioorg. Med. Chem., 2006, 14, 7688-7705.
16. Kranjc, A.; Kikelj, D.; Peterlin-Masic, L. Recent advances in the discovery of tissue factor/factor VIIa inhibitors and dual inhibitors of factor VIIa/factor Xa. Curr. Pharm. Des., 2005, 11, 4207-4227.
17. Frederick, R.; Pochet, L.; Charlier, C.; Masereel, B. Modulators of the coagulation cascade: Focus and recent advances in inhibitors of tissue factor, factor VIIa and their complex. Curr. Med. Chem., 2005, 12, 397-417.
18. Lazarus, R.A.; Olivero, A.G.; Eigenbrot, C.; Kirchhofer, D. Inhibitors of tissue Factoro center dot Factor VIIa for anticoagulant therapy. Curr. Med. Chem., 2004, 11, 2275-2290.
19. Sellers, M. B.; Tricoci, P.; Harrington, R.A. A new generation of antiplatelet agents. Curr. Opin. Cardiol. 2009, 24, 307-312.
20. Michelson, A.D. Antiplatelet therapies for the treatment of cardiovascular disease. Nat. Rev. Drug. Discov., 2010, 9, 154-169.
21. Anderluh, P.S.; Anderluh, M.; Ilas, J.; Mravljak, J.; Dolenc, M.S.; Stegnar, M.; Kikelj, D. Toward a novel class of antithrombotic compounds with dual function. Discovery of 1,4-benzoxazin- 3(4H)-one derivatives possessing thrombin inhibitory and fibrinogen receptor antagonistic activities. J. Med. Chem., 2005, 48, 3110-3113.
22. Ilas, J.; Jakopin, Z.; Borstnar, T.; Stegnar, M.; Kikelj, D. 3,4- Dihydro-2H-1,4-benzoxazine derivatives combining thrombin inhibitory and glycoprotein IIb/IIIa receptor antagonistic activity as a novel class of antithrombotic compounds with dual function. J. Med. Chem., 2008, 51, 5617-5629.
23. Norris, L.A. Blood coagulation. Best. Pract. Res. Clin. Obstet. Gynaecol. 2003, 17, 369-383.
24. Alban, S. Pharmacological strategies for inhibition of thrombin activity. Curr. Pharm. Des., 2008, 14, 1152-1175.
25. Khrenov, A.V.; Ananyeva, N.M.; Griffin, J.H.; Saenko, E.L. Coagulation pathways in atherothrombosis. Trends Cardiovasc. Med., 2002, 12, 317-324.
26. Ruttmann, T. Coagulation for the clinician. S. Afr. J. Surg., 2006, 44, 22-26.
27. Bhopale, G.M.; Nanda, R.K. Blood coagulation factor VIII: An overview. J. Biosci., 2003, 28, 783-789.
28. Walsh, P.N. Platelet coagulation-protein interactions. Semin. Thromb. Hemost., 2004, 30, 461-471.
29. Furie, B.; Furie, B.C. Thrombus formation in vivo. J. Clin. Invest., 2005, 115, 3355-3362.
30. Van de Werf, F. New antithrombotic agents: are they needed and what can they offer to patients with a non-ST-elevation acute coronary syndrome? Eur. Heart J., 2009, 30, 1695-1702.
31. Gross, P.L.; Weitz, J.I. New Antithrombotic Drugs. Clin. Pharmacol. Ther., 2009, 86, 139-146.
32. Morphy, R.; Kay, C.; Rankovic, Z. From magic bullets to designed multiple ligands. Drug Discov. Today, 2004, 9, 641-651.
33. Morphy, R.; Rankovic, Z. Fragments, network biology and designing multiple ligands. Drug Discov. Today, 2007, 12, 156-160.
34. Morphy, R.; Rankovic, Z. Designing multiple ligands - Medicinal chemistry strategies and challenges. Curr. Pharm. Des., 2009, 15, 587-600.
35. Morphy, R.; Rankovic, Z. Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem., 2005, 48, 6523-6543.
36. Kranjc, A.; Kikelj, D. Dual inhibitors of the blood coagulation enzymes. Curr. Med. Chem., 2004, 11, 2535-2547.
37. Graefe-Mody, E.U.; Schuhly, U.; Rathgen, K.; Stahle, H.; Leitner, J. M.; Jilma, B. Pharmacokinetics and pharmacodynamics of BIBT 986, a novel small molecule dual inhibitor of thrombin and factor Xa. J. Thromb. Haemost., 2006, 4, 1502-1509.
38. Ries, U.J.; Priepke, H.W.M.; Hauel, N.H.; Handschuh, S.; Mihm, G.; Stassen, J.M.; Wienen, W.; Nar, H. Heterocyclic thrombin inhibitors. part 2: Quinoxalinone derivatives as novel, potent antithrombotic agents. Bioorg. Med. Chem. Lett., 2003, 13, 2297-2302.
39. Giardino, E.C.; Haertlein, B.J.; de Garavilla, L.; Costanzo, M.J.; Damiano, B.P.; Andrade-Gordon, P.; Maryanoff, B.E. Cooperative antithrombotic effect from the simultaneous inhibition of thrombin and factor Xa. Blood Coagulation & Fibrinolysis, 2010, 21, 128-134.
40. Young, R.J.; Brown, D.; Burns-Kurtis, C.L.; Chan, C.; Convery, M.A.; Hubbard, J.A.; Kelly, H.A.; Pateman, A.J.; Patikis, A.; Senger, S.; Shah, G.P.; Toomey, J.R.; Watson, N.S.; Zhou, P. Selective and dual action orally active inhibitors of thrombin and factor Xa. Bioorg. Med. Chem. Lett., 2007, 17, 2927-2930.
41. Donnecke, D.; Schweinitz, A.; Sturzebecher, A.; Steinmetzer, P.; Schuster, M.; Sturzebecher, U.; Nicklisch, S.; Sturzebecher, J.; Steinmetzer, T. From selective substrate analogue factor Xa inhibitors to dual inhibitors of thrombin and factor Xa. Part 3. Bioorg. Med. Chem. Lett., 2007, 17, 3322-3329.
42. Buijsman, R.C.; Basten, J.E.M.; van Dinther, T.G.; van der Marel, G.A.; van Boeckel, C.A.A.; van Boom, J.H. Design and synthesis of a novel synthetic NAPAP-pentasaccharide conjugate displaying a dual antithrombotic action. Bioorg. Med. Chem. Lett., 1999, 9, 2013-2018.
43. Tromp, C.; Basten, J.; Van Boeckel, C.; Buijsman, R. Antithrombotic compounds. US patent 6,486,129, Nov 26, 2002.
44. De Kort, M.; Van Boeckel, C. Antithrombotic Dual Inhibitors Comprising A Biotin Residue. US patent 2010/0004186, Jan 7, 2010.
45. Melo, F.R.; Mourao, P.A.S. An algal sulfated galactan has an unusual dual effect on venous thrombosis due to activation of factor XII and inhibition of the coagulation proteases. Thromb. Haemost., 2008, 99, 531-538.
46. Dogne, J.M.; de Leval, X.; Hanson, J.; Frederich, M.; Lambermont, B.; Ghuysen, A.; Casini, A.; Masereel, B.; Ruan, K.H.; Pirotte, B.; Kolh, P. New developments on thromboxane and prostacyclin modulators - Part I: Thromboxane modulators. Curr. Med. Chem., 2004, 11, 1223-1241.
47. Neri Serneri, G.G.; Coccheri, S.; Marubini, E.; Violi, F. Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study. Eur. Heart J., 2004, 25, 1845-1852.
48. Guth, B.D., Narjes, H., Schubert, H.-D., Tanswell, P., Riedel, A.; Nehmiz, G. Pharmacokinetics and pharmacodynamics of terbogrel, a combined thromboxane A2 receptor and synthase inhibitor, in healthy subjects. Br. J. Clin. Pharmacol., 2004, 58, 40-51.
49. 2/prostaglandin endoperoxide receptor antagonist, versus aspirin as adjunct to thrombolysis in patients with acute myocardial infarction. The Ridogrel Versus Aspirin Patency Trial (RAPT). Circulation,1994, 89, 588-595.
50. Ghuysen, A.; Lambermont, B.; Dogne, J.M.; Kolh, P.; Tchana- Sato, V.; Morimont, P.; Magis, D.; Hanson, J.; Segers, P.; D'Orio, V. Effect of BM-573 N-terbutyl-N'-2-(4'-methylphenylamino)-5- nitro-benzenesulfonyl urea, a dual thromboxane synthase inhibitor and thromboxane receptor antagonist, in a porcine model of acute pulmonary embolism. J. Pharmacol. Exp. Ther., 2004, 310, 964-972.
51. Ghuysen, A.; Dogne, J.M.; Chiap, P.; Rolin, S.; Masereel, B.; Lambermont, B.; Kolh, P.; Tchana-Sato, V.; Hanson, H.; D'Orio, V. Pharmacological profile and therapeutic potential of BM-573, a combined thromboxane receptor antagonist and synthase inhibitor. Cardiovasc. Drug. Rev., 2005, 23, 1-14.
52. Hanson, J.; Rolin, S.; Reynaud, D.; Qiao, N.; Kelley, L.P.; Reid, H.M.; Valentin, F.O.; Tippins, J.; Kinsella, B.T.; Masereel, B.; Pace-Asciak, C.; Pirotte, B.; Dogne, J.M. In vitro and in vivo pharmacological characterization of BM-613 N-n-pentyl-N'-2-(4'- methylphenylamino)-5-nitrobenzenesulfonyl urea, a novel dual thromboxane synthase inhibitor and thromboxane receptor antagonist. J. Pharmacol. Exp. Ther., 2005, 313, 293-301.
53. Kolh, P.; Rolin, S.; Tchana-Sato, V.; Petein, M.; Ghuysen, A.; Lambermont, B.; Hanson, J.; Magis, D.; Segers, P.; Masereel, B.; D'Orio, V.; Dogne, J.M. Evaluation of BM-573, a novel TXA(2) synthase inhibitor and receptor antagonist, in a porcine model of myocardial ischemia-reperfusion. Prostaglandins Other Lipid Mediat., 2006, 79, 53-73.
54. 2+ mobilization. J. Pharmacol. Exp. Ther., 2005, 312, 214-219.
55. Kuo, H.L.; Lien, J.C.; Chung, C.H.; Chang, C.H.; Lo, S.C.; Tsai, I.C.; Peng, H.C.; Kuo, S.C.; Huang, T.F. NP-184 2-(5-methyl-2- furyl) benzimidazole, a novel orally active antithrombotic agent with dual antiplatelet and anticoagulant activities. Naunyn Schmiedebergs Arch. Pharmacol., 2010, 381, 495-505.
56. Henriksson, P.; Edhag, O.; Vesterqvist, O.; Green, K. Generation of prostacyclin and tromboxane invivo during acute myocardialinfarction. Acta. Med. Scand., 1986, 110.
57. Tuleja, E.; Mejza, F.; Cmiel, A.; Szczeklik, A. Effects of cyclooxygenases inhibitors on vasoactive prostanoids and thrombin generation at the site of microvascular injury in healthy men. Arterioscler. Thromb. Vasc. Biol., 2003, 23, 1111-1115.
58. Sturzebecher, S.; Witt, W. The PGI2-analogue iloprost and the TXA2-receptor antagonist sulotroban synergistically inhibit TXA2- dependent platelet activation. Prostaglandins, 1988, 36, 751-760.
59. Klar, U.; Pletsch, K.; Rehwinkel, H.; Schreyer, R. An attempt to synthesize prostanoid thromboxane A(2) antagonists with an additional prostacyclin like quality. Bioorg. Med. Chem. Lett., 1995, 5, 1215-1218.
60. Ohno, M.; Miyamoto, M.; Hoshi, K.; Takeda, T.; Yamada, N.; Ohtake, A. Development of dual-acting benzofurans for thromboxane A(2) receptor antagonist and prostacyclin receptor agonist: Synthesis, structure-activity relationship, and evaluation of benzofuran derivatives. J. Med. Chem., 2005, 48, 5279-5294.
61. Ilas, J.; Anderluh, P.S.; Dolenc, M.S.; Kikelj, D. Recent advances in the synthesis of 2H-1,4-benzoxazin-3-(4H)-ones and 3,4- dihydro-2H-1,4-benzoxazines. Tetrahedron, 2005, 61, 7325-7348.
62. Ohno, M.; Tanaka, Y.; Miyamoto, M.; Takeda, T.; Hoshi, K.; Yamada, N.; Ohtake, A. Development of 3,4-dihydro-2H-benzo- 1,4-oxazine derivatives as dual thromboxane A(2) receptor antagonists and prostacyclin receptor agonists. Bioorg. Med. Chem., 2006, 14, 2005-2021.
63. Zhang, S.; Hu, L.A.; Du, H.G.; Guo, Y.; Zhang, Y.; Niu, H.X.; Jin, J.G.; Zhang, J.A.; Liu, J.L.; Zhang, X.H.; Kunapuli, S.P.; Ding, Z.R. BF0801, a novel adenine derivative, inhibits platelet activation via phosphodiesterase inhibition and P2Y(12) antagonism. Thromb. Haemost., 2010, 104, 845-857.
64. Holmes, D.R.; Kereiakes, D.J.; Kleiman, N.S.; Moliterno, D.J.; Patti, G.; Grines, C.L. Combining Antiplatelet and Anticoagulant Therapies. J. Am. Coll. Cardiol., 2009, 54, 95-109.
65. Maraganore, J.M.; Bourdon, P.; Jablonski, J.; Ramachandran, K.L.; Fenton, J.W. Design and characterization of hirulogs - A novel class of bivalent peptide inhibitors of thrombin. Biochemistry, 1990, 29, 7095-7101.
66. Broersma Jr, R.; Owen, T.; Krstenansky, J. Trifunctional antithrombin and antiplatelet peptides. US Patent 5, 681,925, Oct 28, 1997.
67. Church, F.C.; Phillips, J.E.; Woods, J.L. Chimeric antithrombin peptide - characterization of an Arg-Gly-Asp (RGD)-containing and hirudin carboxyl terminus-containing synthetic peptide. J. Chem. Biol., 1991, 266, 11975-11979.
68. Ilas, J.; Hudecz, F.; Suli-Vargha, H.; Kikelj, D. Peptides and pseudopeptides incorporating D-Phe-Pro-Arg and Arg-Gly-Asp lead sequences as potential antithrombotic agents. J. Pept. Sci., 2008, 14, 946-953.
69. Krishnamurthi, S.; Westwick, J.; Kakkar, V.V. Effect of pyridoxal 5'-phosphate (PALP) on human-platelet aggregation, dense granule release and thromboxane-B2 generation - role of Schiff-base formation. Thromb. Haemost., 1982, 48, 136-141.
70. Chang, S.J.; Chuang, H.J.; Chen, H.H. Vitamin B-6 down-regulates the expression of human GPIIb gene. J. Nutr. Sci. Vitaminol., 1999, 45, 471-479.
71. Zhang, W.L.; Yao, J.; Pham, V.; Whitney, T.; Froese, D.; Friesen, A.D.; Stang, L.; Xu, C.; Shuaib, A.; Diakur, J.M.; Haque, W. Pyridoxine as a template for the design of antiplatelet agents. Bioorg. Med. Chem. Lett., 2004, 14, 4747-4750.
72. Haque, W. Pyridoxine and Pyridoxal Analogues: Cardiovascular Therapeutics. US 6, 417,204, Jul 9, 2002.
73. Haque, W.; Diakur, J.; Pham, V.; Rehman, A.; Whitney, T.; Omar, M.; Yi, S.; Khan, A. Dual antiplatelet/anticoagulant pyridoxine analogs. US Patents 7, 812,037, Oct 12, 2010.
74. Haque, W. Pyridoxine and Pyridoxal Analogues: New Uses. US Patent 11/016,737, Sept 16, 2008.
75. Medicure Int. Inc. A Unique Dual Acting Inhibitor for Thrombosis: Combining Anticoagulant & Antiplatelet Effects into a Single Molecule, Non-Confidential Dossier, May 2009. http://www.medicure.com/pdfs/Nonconfidential_Antithrombotic.pdf (Accesed jan. 2011).
76. Husted, S. Benefits and risks with antiplatelet therapy: how great a problem is bleeding? Eur. Heart. J. Suppl., 2008, 10, 19-24.
77. Iqbal, Z.; Cohen, M. Emerging antithrombotic agents: what does the intensivist need to know? Curr. Opin. Crit. Care, 2010, 16, 419-425.
78. Buijsman, R.; De Kort, M.; Meuleman, D.; Van Boeckel, C. Antithrombotic compound. US Patent 7, 576, 071, Aug 18, 2009.
79. De Kort, M.; Van Boeckel, A.; Nicholson, D. Anticoagulant Antithrombotic Dual Inhibitors Comprising a Biotin Label. US Patent 2010/0029582, Feb 4. 2010.
80. Gollamudi, R.; Thompson, W.B.; Zheng, X. Mechanism of action of antiplatelet nipecotamides, and design of dual-function analogs. Thromb. Haemost., 1997, P2822-P2822.
81. Zheng, X.Z.; Gollamudi, R. Design and synthesis of antiplatelet nipecotamides with a dual mechanism of action. Med. Chem. Res., 1997, 7, 219-227.
82. de Candia, M.; Summo, L.; Carrieri, A.; Altomare, C.; Nardecchia, A.; Cellamare, S.; Carotti, A. Investigation of platelet aggregation inhibitory activity by phenyl amides and esters of piperidinecarboxylic acids. Bioorg. Med. Chem., 2003, 11, 1439-1450.
83. De Marco, A.; de Candia, M.; Carotti, A.; Cellamare, S.; De Candia, E.; Altomare, C. Lipophilicity-related inhibition of blood platelet aggregation by nipecotic acid anilides. Eur. J. Pharm. Sci., 2004, 22, 153-164.
84. Feng, Z.X.; Gollamudi, R.; Dillingham, E.O.; Bond, S.E.; Lyman, B.A.; Purcell, W.P.; Hill, R.J.; Korfmacher, W.A. Molecular determinants of the platelet-aggregation inhibitory activity of carbamoylpiperidines. J. Med. Chem., 1992, 35, 2952-2958.
85. Zheng, X.Z.; Salgia, S.R.; Thompson, W.B.; Dillingham, E.O.; Bond, S.E.; Feng, Z.X.; Prasad, K.R.; Gollamudi, R. Design and synthesis of piperidine-3-carboxamides as human plateletaggregation inhibitors. J. Med. Chem., 1995, 38, 180-188.
86. Guo, Z.M.; Zheng, X.Z.; Thompson, W.; Dugdale, M.; Gollamudi, R. New carbamoylpiperidines as human platelet aggregation inhibitors. Bioorg. Med. Chem., 2000, 8, 1041-1058.
87. de Candia, M.; Liantonio, F.; Carotti, A.; De Cristofaro, R.; Altomare, C. Fluorinated Benzyloxyphenyl Piperidine-4- carboxamides with Dual Function against Thrombosis: Inhibitors of Factor Xa and Platelet Aggregation. J. Med. Chem., 2009, 52, 1018-1028.
88. Bohm, H.J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Muller, K.; Obst-Sander, U.; Stahl, M. Fluorine in medicinal chemistry. Chembiochem, 2004, 5, 637-643.
89. Olsen, J.A.; Banner, D.W.; Seiler, P.; Wagner, B.; Tschopp, T.; Obst-Sander, U.; Kansy, M.; Muller, K.; Diederich, F. Fluorine interactions at the thrombin active site: Protein backbone fragments H-C-alpha-C = O comprise a favorable C-F environment and interactions of C-F with electrophiles. Chembiochem, 2004, 5, 666-675.
90. Levi, M.; van der Poll, T.; Buller, H.R. Bidirectional relation between inflammation and coagulation. Circulation, 2004, 109, 2698-2704.
91. Thalassitis, A.; Hadjipavlou-Litina, D. J.; Litinas, K.E.; Miltiadou, P. Synthesis of modified homo-N-nucleosides from the reactions of mesityl nitrile oxide with 9-allylpurines and their influence on lipid peroxidation and thrombin inhibition. Bioorg. Med. Chem. Lett., 2009, 19, 6433-6436.
92. Herráiz, T.; Galisteo, J. Tetrahydro-beta-carboline alkaloids occur in fruits and fruit juices. Activity as antioxidants and radical scavengers. J. Agric. Food Chem., 2003, 51, 7156-7161.
93. Andronati, S.A.; Karaseva, T.L.; Krysko, A.A. Peptidomimetics - Antagonists of the fibrinogen receptors: Molecular design, structures, properties and therapeutic applications. Curr. Med. Chem., 2004, 11, 1183-1211.
94. Bi, W.; Bi, L.R.; Cai, J.H.; Liu, S.G.; Peng, S.Q.; Fischer, N.O.; Tok, J.B.H.; Wang, G.H. Dual-acting agents that possess free radical scavenging and antithrombotic activities: Design, synthesis, and evaluation of phenolic tetrahydro-beta-carboline RGD peptide conjugates. Bioorg. Med. Chem. Lett., 2006, 16, 4523-4527.
95. Bi, W.; Cai, J.H.; Liu, S.G.; Baudy-Floc'h, M.; Bi, L.R. Design, synthesis and cardioprotective effect of a new class of dual-acting agents: Phenolic tetrahydro-beta-carboline RGD peptidomimetic conjugates. Bioorg. Med. Chem., 2007, 15, 6909-6919.