An update on recent patents on thrombin inhibitors (2010-2013)

Expert Opinion on Therapeutic Patents

Volumn 24, Issue 1, 2014, Pages 47-67

  Mehta, Akul Y ^a   Jin, Yingzi ^a   Desai, Umesh R ^a  

^a VIRGINIA COMMONWEALTH UNIVERSITY   (United States)

Author keywords

Allosteric inhibition; Anticoagulant; Coagulation enzyme; Drug design; Enzyme inhibition; Thrombosis

Indexed keywords

ARC 183; ARGATROBAN; ATECEGATRAN METOXIL; DABIGATRAN ETEXILATE; EP 217609; MELAGATRAN; THROMBIN; THROMBIN INHIBITOR; UNCLASSIFIED DRUG; WARFARIN; XIMELAGATRAN;

ABSENCE OF SIDE EFFECTS; ANTICOAGULANT THERAPY; BLEEDING; CRYSTAL STRUCTURE; DRUG BIOAVAILABILITY; DRUG FORMULATION; DRUG HALF LIFE; DRUG PURIFICATION; DRUG SOLUBILITY; DRUG SYNTHESIS; ENZYME STRUCTURE; HEART ATRIUM FIBRILLATION; HUMAN; KIDNEY FUNCTION; LIVER FUNCTION; LIVER TOXICITY; NONHUMAN; PATENT; PHARMACODYNAMICS; REVIEW; SIDE EFFECT; SYSTEMATIC REVIEW; THROMBOCYTE ACTIVATION; THROMBOSIS;

ANIMALS; ANTITHROMBINS; BLOOD COAGULATION; CHEMISTRY, PHARMACEUTICAL; DRUG DESIGN; HUMANS; LEGISLATION, DRUG; MOLECULAR STRUCTURE; PATENTS AS TOPIC; STRUCTURE-ACTIVITY RELATIONSHIP; THROMBIN; THROMBOEMBOLISM;

EID: 84890364489     PISSN: 13543776     EISSN: 17447674     Source Type: Journal    
DOI: 10.1517/13543776.2014.845169     Document Type: Review

References (163)

1. Chan AK, Paredes N. The coagulation system in humans. Methods Mol Biol 2013;992:3-12
2. Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008;451:914-18
3. Wardrop D, Keeling D. The story of the discovery of heparin and warfarin. Br J Haematol 2008;141:757-63
4. Francis CW. Warfarin: An historical perspective. Hematology Am Soc 2008:251. doi: 10.1182/ asheducation-2008.1.251
5. Henry BL, Desai UR. Anticoagulants. In: Abraham DJ, Rotella DP, editors. Burger's medicinal chemistry, drug discovery and development. 7th edition. John Wiley; Hoboken, NJ: 2010. p. 365-408
6. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133:160S-98S
7. Di Nisio M, Middeldorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med 2005;353:1028-40
8. Akwaa F, Spyropoulos AC. Novel oral anticoagulants: A review of the literature and considerations in special clinical situations. Hosp Pract 2013;41: 8-18
9. Green D. Coagulation cascade. Hemodial Int 2006;10(Suppl 2): S2-4
10. Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: Initiation, maintenance, and regulation. Biochemistry 1991;30:10363-70
11. Laki K, Gladner JA. Chemistry and physiology of the fibrinogen-fibrin transition. Physiol Rev 1964;44: 127-60
12. Versteeg HH, Heemskerk JW, Levi M, et al. New fundamentals in hemostasis. Physiol Rev 2013;93:327-58
13. von dem Borne PA, Meijers JC, Bouma BN. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood 1995;86:3035-42
14. De Candia E, Hall SW, Rutella S, et al. Binding of thrombin to glycoprotein Ib accelerates the hydrolysis of PAR-1 on intact platelets. J Biol Chem 2001; 276:4692-8
15. Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 1989; 264:4743-6
16. Olson ST, Bjork I. Regulation of thrombin activity by antithrombin and heparin. Semin Thromb Hemost 1994;20:373-409
17. Kraut J. Serine proteases: Structure and mechanism of catalysis. Annu Rev Biochem 1977;46:331-58
18. Bode W, Mayr I, Baumann U, et al. The refined 1.9 a crystal-structure of human alpha-Thrombin - interaction with D-Phe-Pro-Arg chloromethylketone and significance of the Tyr-Pro-Pro-Trp insertion segment. Embo J 1989;8:3467-75
19. Di Cera E, Guinto ER, Vindigni A, et al. The Na+ binding site of thrombin. J Biol Chem 1995;270:22089-92
20. Abrahams JP, Thomassen EA. Mechanism of thrombin's enigmatic sodium switch revealed. Structure 2003;11:363-4
21. Huntington JA, Esmon CT. The molecular basis of thrombin allostery revealed by a 1.8 A structure of the "slow" form. Structure 2003;11:469-79
22. Huntington JA. Thrombin plasticity. Biochim Biophys Acta 2012;1824:246-52
23. Guillin MC, Bezeaud A, Bouton MC, et al. Thrombin specificity. Thromb Haemost 1995;74:129-33
24. Lechtenberg BC, Johnson DJ, Freund SM, et al. NMR resonance assignments of thrombin reveal the conformational and dynamic effects of ligation. Proc Natl Acad Sc USA 2010;107:14087-92
25. Lechtenberg BC, Freund SM, Huntington JA. An ensemble view of thrombin allostery. Biol Chem 2012;393:889-98
26. Qureshi SH, Yang L, Manithody C, et al. Mutagenesis studies toward understanding allostery in thrombin. Biochemistry 2009;48:8261-70
27. Gandhi PS, Chen Z, Mathews FS, et al. Structural identification of the pathway of long-range communication in an allosteric enzyme. Proc Natl Acad Sc USA 2008;105:1832-7
28. Di Cera E, Page MJ, Bah A, et al. Thrombin allostery. Phys Chem Chem Phys 2007;9:1291-306
29. Malovichko MV, Sabo TM, Maurer MC. Ligand binding to anion-binding exosites regulates conformational properties of thrombin. J Biol Chem 2013;288:8667-78
30. Keisu M, Andersson TB. Drug-induced liver injury in humans: The case of ximelagatran. Handb Exp Pharmacol 2010;196:407-18
31. Miller JL. Argatroban approved for heparin-induced thrombocytopenia. Am J Health Syst Pharm 2000;57: 1650
32. Ahmed S, Levin V, Malacoff R, et al. Dabigatran: A new chapter in anticoagulation. Cardiovasc Hematol Agents Med Chem 2012;10:116-23
33. Sixma JJ, de Groot PG. The ideal anti-Thrombotic drug. Thromb Res 1992;68:507-12
34. Heidbuchel H, Verhamme P, Alings M, et al. EHRA Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: Executive summary. Eur Heart J 2013;34:2094-106
35. Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med 2013;368:1272-4
36. Attia JR, Pearce R. The use, misuse and abuse of dabigatran. Med J Aust 2013;198:356-7
37. Maddry JK, Amir MK, Sessions D, et al. Fatal dabigatran toxicity secondary to acute renal failure. Am J Emerg Med 2013;31:462; e1-2
38. Fountzilas C, George J, Levine R. Dabigatran overdose secondary to acute kidney injury and amiodarone use. NZ Med J 2013;126:110-12
39. Shanghai Inst. Pharm. Industry. Peptide compound and preparation method and application thereof. CN101724016; 2010
40. Shanghai Inst. Pharm. Industry. Prolinamide derivative as thrombin inhibitor, preparation method and application thereof. WO2012062187; 2012
41. Bajusz S, Szell E, Bagdy D, et al. Highly active and selective anticoagulants: DPhe- Pro-Arg-H, a free tripeptide aldehyde prone to spontaneous inactivation, and its stable N-methyl derivative, D-MePhe-Pro-Arg-H. J Med Chem 1990;33:1729-35
42. Brighton TA. The direct thrombin inhibitor melagatran/ximelagatran. Med J Aust 2004;181:432-7
43. Ahrens I, Peter K, Lip GY, et al. Development and clinical applications of novel oral anticoagulants. Part II. Drugs under clinical investigation. Discov Med 2012;13:445-50
44. Atrial fibrillation (AF) patients not taking vitamin-K antagonists (VKA). Clinical Trials.gov NIH Available from: Http://Clinical Trials.gov/show/ NCT00623779 [Last accessed 6 September 2013]
45. Prevention of stroke and systemic embolic events in patients with atrial fibrillation. Clinical Trials.gov NIH. Available from: Http://Clinical Trials.gov/ show/NCT00684307 [Last accessed 6 September 2013]
46. Deinum J, Mattsson C, Inghardt T, et al. Biochemical and pharmacological effects of the direct thrombin inhibitor AR-H067637. Thromb Haemost 2009;101:1051-9
47. Johansson S, Cullberg M, Eriksson UG, et al. Single-dose pharmacokinetics, pharmacodynamics and safety of AZD0837, a novel oral direct thrombin inhibitor, in young healthy male subjects. Int J Clin Pharmacol Ther 2011; 49:258-67
48. Lip GY, Rasmussen LH, Olsson SB, et al. Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: A randomized dose-guiding, safety, and tolerability study of four doses of AZD0837 vs. vitamin K antagonists. Eur Heart J 2009;30:2897-907
49. Lip GY, Rasmussen LH, Olsson SB, et al. Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: A Phase II study of AZD0837 in patients who are appropriate for but unable or unwilling to take vitamin K antagonist therapy. Thromb Res 2011;127:91-9
50. Pharmacokinetics of extended-release testand reference formulations of AZD0837. Clinical Trials.gov NIH. Available from: Http://Clinical Trials.gov/show/ NCT00878618 [Last accessed 6 September 2013]
51. Tianjin Jiahong Technology LLC. Aromatic amidine derivatives, and preparation method and pharmaceutical application thereof. CN102827053; 2012
52. Riester D, Wirsching F, Salinas G, et al. Thrombin inhibitors identified by computer-Assisted multiparameter design. Proc Natl Acad Sci USA 2005;102: 8597-602
53. Matrix Pharma, Inc. Thrombin inhibiting compositions. WO2011120040A2; 2011
54. Friedrich R, Riester D, Gottig P, et al. Structure of a novel thrombin inhibitor with an uncharged D-Amino acid as P1 residue. Eur J Med Chem 2008;43: 1330-5
55. Rocha ESM, Beraldo WT, Rosenfeld G. Bradykinin, a hypotensive and smooth muscle stimulating factor released from plasma globulin by snake venoms and by trypsin. Am J Physiol 1949;156:261-73
56. Meloni FJ, Schmaier AH. Low molecular weight kininogen binds to platelets to modulate thrombin-induced platelet activation. J Biol Chem 1991;266: 6786-94
57. Cleary DB, Ehringer WD, Maurer MC. Establishing the inhibitory effects of bradykinin on thrombin. Arch Biochem Biophys 2003;410:96-106
58. The Regents of the University of Michigan. Synthetic peptide inhibitors of thrombin and thrombin activation of protease activated receptors 1 and 4. US7879792B2; 2011
59. Nieman MT, Burke F, Warnock M, et al. Thrombostatin FM compounds: Direct thrombin inhibitors - mechanism of action in vitro and in vivo. J Thromb Haemost 2008;6:837-45
60. Cheng-Lai A. Cardiovascular drug highlight: Hirudin. Heart Dis 1999;1: 41-9
61. Koh CY, Kazimirova M, Trimnell A, et al. Variegin, a novel fast and tight binding thrombin inhibitor from the tropical bont tick. J Biol Chem 2007; 282:29101-13
62. Natural Environment Research Council. Method of modifying serine protease inhibitors. WO2010128285A2; 2010
63. Koh CY, Kumar S, Kazimirova M, et al. Crystal structure of thrombin in complex with S-variegin: Insights of a novel mechanism of inhibition and design of tunable thrombin inhibitors. PLoS One 2011;6:e26367
64. Stangier J, Stahle H, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment.J Clin Pharmacol 2008;48: 1411-19
65. Hauel NH, Nar H, Priepke H, et al. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002;45:1757-66
66. Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007; 64:292-303
67. Eisert WG, Hauel N, Stangier J, et al. Dabigatran: An oral novel potent reversible nonpeptide inhibitor of thrombin. Arterioscler Thromb Vasc Biol 2010;30:1885-9
68. Beijing Meibeita Pharmaceutical Res. Inst. Co. Ltd. Dabigatran ester derivatives as prodrug. CN102050815; 2011
69. Beijing Meibeita Pharmaceutical Res. Inst. Co. Ltd. Ester derivatives of dabigatran. CN102050814; 2011
70. Beijing Prelude Pharm. Tech. Co. Ltd. Dabigatran etexilate derivative and preparation method and application thereof. CN102766134; 2012
71. Tianjin Inst. Pharm. Res. Dabigatran derivatives and preparation method thereof. CN102875529; 2013
72. Tianjin Institute of Pharmaceutical Research. Preparation, method and application of dabigatran ester derivatives. CN102993175; 2013
73. Tianjin Institute of Pharmaceutical Research. Dabigatran ester derivatives as pro-drug. CN102993174; 2013
74. Suzhou Borui Pharmaceuticals, Inc. (benzimidazole-2-yl)pyridine derivative and application thereof to preparation of anticoagulant medicines. CN102649787; 2012
75. Hefei Yigong Medicin Co. Ltd, Univ. China. Pharm. Oral thrombin inhibitor and preparation method and medical use thereof. WO2012174856; 2012
76. Tsai CC, Lai TY, Huang WC, et al. Inhibitory effects of potassium channel blockers on tetramethylpyrazine-induced relaxation of rat aortic strip in vitro. Life Sci 2002;71:1321-30
77. Zhu XL, Xiong LZ, Wang Q, et al. Therapeutic time window and mechanism of tetramethylpyrazine on transient focal cerebral ischemia/ reperfusion injury in rats. Neurosci Lett 2009;449:24-7
78. Li M, Handa S, Ikeda Y, et al. Specific inhibiting characteristics of tetramethylpyrazine, one of the active ingredients of the Chinese herbal medicine 'Chuanxiong,' on platelet thrombus formation under high shear rates. Thromb Res 2001;104:15-28
79. Angelico M, Carli L, Piat C, et al. Effects of isosorbide-5-mononitrate compared with propranolol on first bleeding and long-Term survival in cirrhosis. Gastroenterology 1997;113:1632-9
80. Univ. China Pharma. Nitric oxide donor with thrombin inhibition effect, as well as preparation method and medical application thereof. CN102633780; 2012
81. Univ. China Pharma. Non-peptide thrombin inhibitors as well as preparation method and medical application thereof. CN102250099; 2011
82. Univ. Fudan. Thrombase inhibitor containing guanidyl heterocyclic compound and preparation method thereof. CN101665465; 2010
83. Xu X, Song F, Wang S, et al. Dibenzyl bromophenols with diverse dimerization patterns from the brown alga Leathesia nana. J Nat Prod 2004;67:1661-6
84. Inst. of Oceanology of Chinese Acadmey of Science. Chemical complete synthesis method of medicine used for treating thrombus heart cerebrovascular disease. CN102020621; 2011
85. Shi D LX, Li J, Guo S, et al. Antithrombotic effects of bromophenol, an alga-derived thrombin inhibitor. Chin J Oceanology Limnol 2010;28:96-8
86. Guo S LJ, Li T, Shi D, Han L. Synthesis of three bromophenols from red algae as PTP1B inhibitors. Clin J Oceanol Limnol 2011;29:68-74
87. Shi D, Li J, Jiang B, et al. Bromophenols as inhibitors of protein tyrosine phosphatase 1B with antidiabetic properties. Bioorg Med Chem Lett 2012; 22:2827-32
88. Shi DY, Li J, Guo SJ, et al. The antitumor effect of bromophenol derivatives in vitro and Leathesia nana extract in vivo. Chin J Oceanology Limnol 2009;27:277-82
89. Illig C, Eisennagel S, Bone R, et al. Expanding the envelope of structure-based drug design using chemical libraries: Application to small-molecule inhibitors of thrombin. Med Chem Res 1998;8:244-60
90. Lu TB, Tomczuk B, Illig CR, et al. In vitro evaluation and crystallographic analysis of a new class of selective, non-Amide-based thrombin inhibitors. Bioorg Med Chem Lett 1998;8: 1595-600
91. Soll RM, Lu T, Tomczuk B, et al. Amidinohydrazones as guanidine bioisosteres: Application to a new class of potent, selective and orally bioavailable, non-Amide-based small-molecule thrombin inhibitors. Bioorg Med Chem Lett 2000;10:1-4
92. Lu TB, Soll RM, Illig CR, et al. Structure-Activity and crystallographic analysis of a new class of non-Amide-based thrombin inhibitor. Bioorg Med Chem Lett 2000;10:79-82
93. Lu TB, Tomczuk B, Bone R, et al. Non-peptidic phenyl-based thrombin inhibitors: Exploring structural requirements of the S1 specificity pocket with amidines. Bioorg Med Chem Lett 2000;10:83-5
94. Tomczuk B, Lu TB, Soll RM, et al. Oxyguanidines: Application to non-peptidic phenyl-based thrombin inhibitors. Bioorg Med Chem Lett 2003;13:1495-8
95. Lu TB, Markotan T, Coppo F, et al. Oxyguanidines. Part 2: Discovery of a novel orally active thrombin inhibitor through structure-based drug design and parallel synthesis. Bioorg Med Chem Lett 2004;14:3727-31
96. Bionika LLC. Thrombin function compounds and pharmaceutical compositions based on them. US20100324058A1; 2010
97. Sinauridze EI, Romanov AN, Gribkova IV, et al. New synthetic thrombin inhibitors: Molecular design and experimental verification. PLoS One 2011;6(5):e19969
98. Stefanadis C, Diamantopoulos L, Vlachopoulos C, et al. Thermal heterogeneity within human atherosclerotic coronary arteries detected in vivo: A new method of detection by application of a special thermography catheter. Circulation 1999;99:1965-71
99. Madjid M, Naghavi M, Malik BA, et al. Thermal detection of vulnerable plaque. Am J Cardiol 2002;90:36L-9L 100. National Research Council of Canada. Locally-Active anticoagulants and anti-inflammatory agents. WO2012142696A1; 2012
100. Cochran AG, Skelton NJ, Starovasnik MA. Tryptophan zippers: Stable, monomeric beta -hairpins. Proc Natl Acad Sci USA 2001;98: 5578-83
101. Buijsman RC, Basten JE, van Dinther TG, et al. Design and synthesis of a novel synthetic NAPAP-penta-saccharide conjugate displaying a dual antithrombotic action. Bioorg Med Chem Lett 1999;9:2013-18
102. Akzo Nobel, Universiteit Liden. Antithrombotic compounds. WO9965934; 1999
103. Endotis Pharma. Oligosaccharide conjugates in the prevention of ischemia-reperfusion injury. WO2012146774; 2012
104. Olson ST, Swanson R, Petitou M. Specificity and selectivity profile of EP217609: A new neutralizable dual-Action anticoagulant that targets thrombin and factor Xa. Blood 2012;119:2187-95
105. Petitou M, Nancy-Portebois V, Dubreucq G, et al. From heparin to EP217609: The long way to a new pentasaccharide-based neutralisable anticoagulant with an unprecedented pharmacological profile. Thromb Haemost 2009;102:804-10
106. Gueret P, Krezel C, Van Giersbergen PLM, et al. First human study with EP217609, a new synthetic parenteral neutralizable dual action anticoagulant. 21st International Congress of Thrombosis; Milan, Italy; 2010
107. Endotis Pharma. Combination of an anticoagulant and avidin useful in surgical intervention and clinical procedure. WO2013007762; 2013
108. Verseon Corp. Multisubstituted aromatic compounds as inhibitors of thrombin. WO2011126903A2; 2011
109. Verseon Corp. Dual inhibitor compounds and methods of use thereof. WO2013049591A2; 2013
110. Musumeci D, Montesarchio D. Polyvalent nucleic acid aptamers and modulation of their activity: A focus on the thrombin binding aptamer. Pharmacol Ther 2012;136:202-15
111. Bock LC, Griffin LC, Latham JA, et al. Selection of single-stranded DNA molecules that bind and inhibit human thrombin. Nature 1992;355:564-6
112. Wu Q, Tsiang M, Sadler JE. Localization of the single-stranded DNA binding site in the thrombin anion-binding exosite. J Biol Chem 1992;267:24408-12
113. Paborsky LR, McCurdy SN, Griffin LC, et al. The single-stranded DNA aptamer-binding site of human thrombin. J Biol Chem 1993;268: 20808-11
114. Macaya RF, Schultze P, Smith FW, et al. Thrombin-binding DNA aptamer forms a unimolecular quadruplex structure in solution. Proc Natl Acad Sci USA 1993;90:3745-9
115. Padmanabhan K, Padmanabhan KP, Ferrara JD, et al. The structure of alpha-Thrombin inhibited by a 15-mer single-stranded DNA aptamer. J Biol Chem 1993;268:17651-4
116. Padmanabhan K, Tulinsky A. An ambiguous structure of a DNA 15-mer thrombin complex. Acta Crystallogr D, Biol Crystallogr 1996;52:272-82
117. Wang KY, McCurdy S, Shea RG, et al. A DNA aptamer which binds to and inhibits thrombin exhibits a new structural motif for DNA. Biochemistry 1993;32:1899-904
118. Schultze P, Macaya RF, Feigon J. Three-dimensional solution structure of the thrombin-binding DNA aptamer d (GGTTGGTGTGGTTGG). J Mol Biol 1994;235:1532-47
119. Kelly JA, Feigon J, Yeates TO. Reconciliation of the X-ray and NMR structures of the thrombin-binding aptamer d(GGTTGGTGTGGTTGG). J Mol Biol 1996;256:417-22
120. Avino A, Fabrega C, Tintore M, et al. Thrombin binding aptamer, more than a simple aptamer: Chemically modified derivatives and biomedical applications. Curr Pharm Des 2012;18:2036-47
121. Diener JL, Wagner-Whyte J, Fontana D; Archemix Corp. Aptamers that bind thrombin with high affinity. WO2007025049; 2007
122. Griffin LC, Tidmarsh GF, Bock LC, et al. In vivo anticoagulant properties of a novel nucleotide-based thrombin inhibitor and demonstration of regional anticoagulation in extracorporeal circuits. Blood 1993;81:3271-6
123. Apto-Farm. Anti-Thrombosis aptamers and method for stabilizing the structure thereof. EP2514822A1; 2012
124. Archemix Corp. Anti-Thrombin aptamer formulations and methods for use. WO2010033167A2; 2010
125. Study of NU172 as anticoagulation in patients undergoing off-pump CABG surgery (SNAP-CABG-OFF). Clinical Trials.gov NIH Available from: Http://Clinical Trials.gov/show/ NCT00808964 [Last accessed 6 September 2013]
126. Davin LB, Lewis NG. Lignin primary structures and dirigent sites. Curr Opin Biotechnol 2005;16:407-15
127. Virginia Commonwealth University. Cinnamic acid-based oligomers and uses thereof. US8491872B2; 2013
128. Henry BL, Thakkar JN, Liang A, et al. Sulfated, low molecular weight lignins inhibit a select group of heparin-binding serine proteases. Biochem Biophys Res Commun 2012;417:382-6
129. Henry BL, Monien BH, Bock PE, et al. A novel allosteric pathway of thrombin inhibition: Exosite II mediated potent inhibition of thrombin by chemo-enzymatic, sulfated dehydropolymers of 4-hydroxycinnamic acids. J Biol Chem 2007;282:31891-9
130. Monien BH, Henry BL, Raghuraman A, et al. Novel chemo-enzymatic oligomers of cinnamic acids as direct and indirect inhibitors of coagulation proteinases. Bioorg Med Chem 2006;14: 7988-98
131. Henry BL, Thakkar JN, Martin EJ, et al. Characterization of the plasma and blood anticoagulant potential of structurally and mechanistically novel oligomers of 4-hydroxycinnamic acids. Blood Coagul Fibrinolysis 2009;20:27-34
132. Rawson TE, VanGorp KA, Yang J, et al. Separation of 21-(R)- And 21-(S)- Argatroban: Solubility and activity of the individual diastereoisomers. J Pharm Sci 1993;82:672-3
133. Argatroban injection solution. Available from: Http://www.fda.gov/ downloads/ advisorycommittees/ committeesmeetingmaterials/ pediatricadvisorycommittee/ucm192057. pdf [Last accessed 10 July 2013]
134. Tianjin Weijie Technology LLC. 21(R) argatroban intravenous injection with alcohol as solubilizer. CN102228426; 2011
135. Baxter Healthcare. Argatroban formulation. US8034830B2; 2011
136. Eagle Pharmaceuticals. Alcohol free formulation of argatroban. US20130023559A1; 2013
137. Dorniani D, Hussein MZ, Kura AU, et al. Preparation of Fe3O4 magnetic nanoparticles coated with gallic acid for drug delivery. Int J Nanomedicine 2012; 7:5745-56
138. Mok H, Zhang M. Superparamagnetic iron oxide nanoparticle-based delivery systems for biotherapeutics. Expert Opin Drug Deliv 2013;10:73-87
139. Jiangsu Yeming Biomedical Technology Ltd. Thrombin inhibitor SSR182289A magnetic nanometer microsphere and preparation method thereof. CN102614128; 2012
140. Berry CN, Lassalle G, Lunven C, et al. SSR182289A, a novel, orally active thrombin inhibitor: In vitro profile and ex vivo anticoagulant activity. J Pharmacol Exp Ther 2002;303:1189-98
141. Boehringer Ingelheim. Method for manufacturing medicinal compounds containing dabigatran. WO2010007016; 2010
142. Boehringer Ingelheim. 3-[(2-{[4- (hexyloxycarbonylaminoiminomethyl) phenylamino]methyl}-1-methyl-1Hbenzimidazol- 5-carbonyl)pyridin-2- ylamino]propionic acid ethylester methansulfonate and its use as medicament. US20050234104A1; 2005
143. ConjuChem, Inc. Antibodies to argatroban derivatives and their use in therapeutic and diagnostic treatments. US6440417; 2002
144. Tianjin Weijie Technology Co. Ltd. Argatroban separation method. CN1951936; 2006
145. Hainan Kangling Pharmaceuticals. Argatroban compound and preparation method thereof. CN102408468; 2012
146. Boehringer Ingelheim Pharma. Disubstituted bicyclic heterocycles, their production and use as medicaments. WO9837075A1; 1998
147. Esteve Quimica, S. A. Process of preparing a thrombin specific inhibitor. WO2012004396A2; 2012
148. Zentiva K.S.A method for the preparation of dabigatran and its intermediates. WO2010045900A1; 2010
149. Zentiva K. S. Method for the preparation of dabigatran. US8394961B1; 2013
150. Boehringer Ingelheim. Process for the manufacture of dabigatran etexilate. US20130158270A1; 2013 Merck & Co.
151. Sanderson PE, Lyle TA, Dorsey BD. Pyrazinone thrombin inhibitors. WO9911267A1; 1999
152. Burgey CS, Robinson KA, Lyle TA, et al. Metabolism-directed optimization of 3-Aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines. J Med Chem 2003;46:461-73
153. Diakron Pharmaceuticals. Process for the preparation of pyrazinone thrombin inhibitor and its intermediates. US20110105753A1; 2010
154. Verstraete M, Zoldhelyi P. Novel antithrombotic drugs in development. Drugs 1995;49:856-84
155. Deangelis PL, Liu J, Linhardt RJ. Chemoenzymatic synthesis of glycosaminoglycans: Re-creating, re-modeling and re-designing nature's longest or most complex carbohydrate chains. Glycobiology 2013;23:764-77
156. King CS, Holley AB, Moores LK. Moving toward a more ideal anticoagulant: The oral direct thrombin and factor Xa inhibitors. Chest 2013; 143:1106-16
157. Roser-Jones C, Chan M, Howard EL, et al. Factor IXa as a target for pharmacologic inhibition in acute coronary syndrome. Cardiovasc Ther 2011;29:e22-35
158. Schumacher WA, Luettgen JM, Quan ML, et al. Inhibition of factor XIa as a new approach to anticoagulation. Arterioscler Thromb Vasc Biol 2010;30:388-92
159. Howard EL, Becker KC, Rusconi CP, et al. Factor IXa inhibitors as novel anticoagulants. Arterioscler Thromb Vasc Biol 2007;27:722-7
160. Factor IX inhibition in thrombosis prevention (The FIXIT Trial). Clinical Trials.gov NIH Available from: Http://Clinical Trials.gov/show/
161. Al-Horani RA, Ponnusamy P, Mehta AY, et al. Sulfated pentagalloylglucoside is a potent, allosteric, and selective inhibitor of factor XIa. J Med Chem 2013;56: 867-78
162. Wong PC, Crain EJ, Watson CA, et al. A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits. J Thromb Thrombolysis 2011; 32:129-37
163. Schumacher WA, Seiler SE, Steinbacher TE, et al. Antithrombotic and hemostatic effects of a small molecule factor XIa inhibitor in rats. Eur J Pharmacol 2007;570:167-74