Direct thrombin inhibitors: Patents 2002-2012 (Review)

Kong,Yi; Chen,Hao; Wang,Yong-Qing; Meng,Ling; Wei,Ji-Fu

doi:10.3892/mmr.2014.2025

Direct thrombin inhibitors: Patents 2002-2012 (Review)

Authors:
- Yi Kong
- Hao Chen
- Yong-Qing Wang
- Ling Meng
- Ji-Fu Wei
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Affiliations: School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China, Research Division of Clinical Pharmacology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
Published online on: March 6, 2014 https://doi.org/10.3892/mmr.2014.2025
Pages: 1506-1514

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Abstract

Acute vascular diseases and other thromboses of the blood system constitute major health risks in developing countries. Thrombin plays a central role in blood coagulation, which is a crucial process involved in thrombosis. Direct thrombin inhibitors (DTIs) such as argatroban, dabigatran, dabigatran etexilate, lepirudin, desirudin and bivalirudin, which bind to thrombin and block its enzymatic activity, are widely and effectively used in the treatment of thromboembolic diseases. DTIs appear to overcome the disadvantages of indirect thrombin inhibitors such as unfractionated heparins (UFH). Although these DTIs show specific advantages over indirect inhibitors, they still present limitations, such as a narrow therapeutic window, and bleeding and anaphylaxis as side-effects. Novel anticoagulant drugs need thus to be developed to overcome these limitations. In the search for additional candidate agents with improved efficacy, safety and high bioavailability in oral administration, a high number of compounds has been identified, such as those derived from the tripeptide template D-Phe-Pro-Arg, aptamers and peptides isolated from blood-sucking animals. These candidates may prove the new agents of choice for the treatment of cardiovascular diseases.

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1	Baldo L, Plent S, Skerjanec S and Meanwell C: Novel use of bivalirudin in the treatment of acute coronary syndrome US Patent 20090247465 A1. Filed March 27, 2009; issued October 1, 2009.
2	Di Cera E: Thrombin. Mol Aspects Med. 29:203–254. 2008.
3	Nar H: The role of structural information in the discovery of direct thrombin and factor Xa inhibitors. Trends Pharmacol Sci. 33:279–288. 2012. View Article : Google Scholar : PubMed/NCBI
4	Bock PE, Panizzi P and Verhamme I: Exosites in the substrate specificity of blood coagulation reactions. J Thromb Haemost. 5:81–94. 2007. View Article : Google Scholar : PubMed/NCBI
5	Gustafsson D: Combinations comprising a low molecular weight thrombin inhibitor and a prodrug of a low molecular weight thrombin inhibitor US Patent 20080113960 A1. Filed November 9, 2007; issued May 15, 2008.
6	Robert S, Ghiotto J, Pirotte B, et al: Is thrombin generation the new rapid, reliable and relevant pharmacological tool for the development of anticoagulant drugs? Pharmacol Res. 59:160–166. 2009. View Article : Google Scholar : PubMed/NCBI
7	Lee CJ and Ansell JE: Direct thrombin inhibitors. Br J Clin Pharmacol. 72:581–592. 2011. View Article : Google Scholar
8	Harenberg J, Marx S, Krejczy M and Wehling M: New anticoagulants-promising and failed developments. Br J Pharmacol. 165:363–372. 2012. View Article : Google Scholar : PubMed/NCBI
9	Nutescu EA and Wittkowsky AK: Direct thrombin inhibitors for anticoagulation. Ann Pharmacother. 38:99–109. 2004.PubMed/NCBI
10	Fareed J and Jeske WP: Small-molecule direct antithrombins: argatroban. Best Pract Res Clin Haematol. 17:127–138. 2004. View Article : Google Scholar : PubMed/NCBI
11	Owoo G and Burgos RA: Argatroban formulations and methods for making and using same US Patent 7915290 B2. Filed February 29, 2008; issued March 29, 2011.
12	Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J and Roth W: The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos. 36:386–399. 2008. View Article : Google Scholar : PubMed/NCBI
13	Fugate JE, Rabinstein AA, McBane RD and Lanzino G: Dabigatran: a primer for neurosurgeons. World Neurosurg. 79:154–158. 2013. View Article : Google Scholar : PubMed/NCBI
14	Franchini M and Mannucci PM: A new era for anticoagulants. Eur J Intern Med. 20:562–568. 2009. View Article : Google Scholar : PubMed/NCBI
15	Eriksson BI, Smith H, Yasothan U and Kirkpatrick P: Dabigatran etexilate. Nat Rev Drug Discov. 7:557–558. 2008. View Article : Google Scholar : PubMed/NCBI
16	Greinacher A and Lubenow N: Recombinant hirudin in clinical practice: focus on lepirudin. Circulation. 103:1479–1484. 2001. View Article : Google Scholar : PubMed/NCBI
17	Frame JN, Rice L, Bartholomew JR and Whelton A: Rationale and design of the PREVENT-HIT study: a randomized, open-label pilot study to compare desirudin and argatroban in patients with suspected heparin-induced thrombocytopenia with or without thrombosis. Clin Ther. 32:626–636. 2010. View Article : Google Scholar
18	Gosselin RC, Dager WE, King JH, et al: Effect of direct thrombin inhibitors, bivalirudin, lepirudin, and argatroban, on prothrombin time and INR values. Am J Clin Pathol. 121:593–599. 2004. View Article : Google Scholar : PubMed/NCBI
19	Warkentin TE: Bivalent direct thrombin inhibitors: hirudin and bivalirudin. Best Pract Res Clin Haematol. 17:105–125. 2004. View Article : Google Scholar : PubMed/NCBI
20	Gross PL and Weitz JI: New anticoagulants for treatment of venous thromboembolism. Arterioscler Thromb Vasc Biol. 28:380–386. 2008. View Article : Google Scholar : PubMed/NCBI
21	Greinacher A, Lubenow N and Eichler P: Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation. 108:2062–2065. 2003. View Article : Google Scholar : PubMed/NCBI
22	Lewis CM and Deschler DG: Desirudin reduces the rate of microvenous thrombosis in a rat model. Laryngoscope. 118:1149–1152. 2008. View Article : Google Scholar : PubMed/NCBI
23	Blombäck B, Blombäck M, Olsson P, Svendsen L and Aberg G: Synthetic peptides with anticoagulant and vasodilating activity. Scand J Clin Lab Invest Suppl. 107:59–61. 1969.PubMed/NCBI
24	Costanzo MJ, Maryanoff BE, Hecker LR, et al: Potent thrombin inhibitors that probe the S1 subsite: tripeptide transition state analogues based on a heterocycle-activated carbonyl group. J Med Chem. 39:3039–3043. 1996. View Article : Google Scholar
25	Kudryavtsev K, Shulga D, Chupakhin V, et al: Design of small-molecule thrombin inhibitors based on the cis-5-phenylproline scaffold. Russ Chem Bull Int Ed. 60:685–693. 2011. View Article : Google Scholar
26	Isaacs RC, Solinsky MG, Cutrona KJ, et al: Structure-based design of novel groups for use in the P1 position of thrombin inhibitor scaffolds. Part 1: Weakly basic azoles. Bioorg Med Chem Lett. 16:338–342. 2006. View Article : Google Scholar : PubMed/NCBI
27	Inghardt T and Nystrm JE: Amidinobenzylamine derivatives and their use as thrombin inhibitors US Patent 6599894. PCT Pub No. WO00/42059. Filed January 13, 2000; issued July 29, 2003.
28	Inghardt T, Karlsson O, Linschoten M and Nystrom JE: New amidino derivatives and their use as thrombin inhibitors US Patent 20070249578 A1. Filed June 6, 2007; issued October 25, 2007.
29	Inghardt T, Johansson A and Svensson A: New mandelic acid derivatives and their use as thrombin inhibitors US Patent 20100087651 Al. Filed June 25, 2009; issued April 8, 2010.
30	Kreutter KD, Lu T, Lee L, et al: Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif. Bioorg Med Chem Lett. 18:2865–2870. 2008. View Article : Google Scholar : PubMed/NCBI
31	Zega A, Mlinšek G, Šolmajer T, Trampuš-Bakija A, Stegnar M and Urleb U: Thrombin inhibitors built on an azaphenylalanine scaffold. Bioorg Med Chem Lett. 14:1563–1567. 2004. View Article : Google Scholar : PubMed/NCBI
32	Urleb U, Zega A, Stegnar M, Trampus BA, Solmajer T and Mlinsek G: Amidinophenylalanine derivatives as thrombin inhibitors US Patent 20080004256 A1. Filed September 12, 2007; issued January 3, 2008.
33	Isaacs RC, Solinsky MG, Cutrona KJ, et al: Structure-based design of novel groups for use in the P1 position of thrombin inhibitor scaffolds. Part 2: N-acetamidoimidazoles Bioorg Med Chem Lett. 18:2062–2066. 2008.
34	Staas DD, Savage KL, Sherman VL, et al: Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability. Bioorg Med Chem Lett. 14:6900–6916. 2006. View Article : Google Scholar : PubMed/NCBI
35	Brånalt J, Gustafsson D, Nilsson I and Polla M: Compounds 148 US Patent 8119673 B2. Filed June 23, 2009; issued February 21, 2012.
36	Lange UE, Baucke D, Hornberger W, Mack H, Seitz W and Höffken HW: Orally active thrombin inhibitors. Part 2: Optimization of the P2-moiety. Bioorg Med Chem Lett. 16:2648–2653. 2006. View Article : Google Scholar : PubMed/NCBI
37	Young MB, Barrow JC, Kristen L, et al: Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors. J Med Chem. 47:2995–3008. 2004. View Article : Google Scholar : PubMed/NCBI
38	Burgey CS, Robinson KA, Williams PD, Coburn C, Lyle TA and Sanderson PE: Pyrazinone thrombin inhibitors US Patent 6455532 B1. Filed June 1, 2000; issued September 24, 2002.
39	Nantermet PG, Burgey CS, Robinson KA, et al: P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold. Bioorg Med Chem Lett. 15:2771–2775. 2005. View Article : Google Scholar : PubMed/NCBI
40	Wang S: Boronic acid thrombin inhibitors US Patent 20070185060 A1. Filed March 9, 2005; issued August 9, 2007.
41	Ilaš J, Tomašić T and Kikelj D: Novel potent and selective thrombin inhibitors based on a central 1,4-benzoxazin-3(4H)-one scaffold. J Med Chem. 51:2863–2867. 2008.PubMed/NCBI
42	Xu Y, Yang X, Gong G, Yang W, He G and Li F: Oral thrombin inhibitor and preparation method and medical use thereof WIPO Patent 2012174856 A1. Filed June 15, 2012; issued December 27, 2012.
43	Poyarkov AA, Poyarkova SA, Smirnova IV and Kukhar VP: Liporetro-D-peptides-a novel class of highly selective thrombin inhibitors. Thromb Res. 129:97–105. 2012. View Article : Google Scholar : PubMed/NCBI
44	Burke JM and Berzal-Herranz A: In vitro selection and evolution of RNA: applications for catalytic RNA, molecular recognition, and drug discovery. FASEB J. 7:106–112. 1993.PubMed/NCBI
45	Bock LC, Griffin LC, Latham JA, Vermaas EH and Toole JJ: Selection of single-stranded DNA molecules that bind and inhibit human thrombin. Nature. 355:564–566. 1992. View Article : Google Scholar : PubMed/NCBI
46	Lancellotti S and De Cristofaro R: Nucleotide-derived thrombin inhibitors: a new tool for an old issue. Cardiovasc Hematol Agents Med Chem. 7:19–28. 2009. View Article : Google Scholar : PubMed/NCBI
47	White R, Rusconi C, Scardino E, et al: Generation of species cross-reactive aptamers using ‘toggle’ SELEX. Mol Ther. 4:567–573. 2001.PubMed/NCBI
48	Mazurov AV, Titaeva EV, Khaspekova SG, et al: Characteristics of a new DNA aptamer, direct inhibitor of thrombin. Bull Exp Biol Med. 150:422–425. 2011. View Article : Google Scholar : PubMed/NCBI
49	Tasset DM, Kubik MF and Steiner W: Oligonucleotide inhibitors of human thrombin that bind distinct epitopes. J Mol Biol. 272:688–698. 1997. View Article : Google Scholar : PubMed/NCBI
50	Bompiani KM, Monroe DM, Church FC and Sullenger BA: A high affinity, antidote-controllable prothrombin and thrombin-binding RNA aptamer inhibits thrombin generation and thrombin activity. J Thromb Haemost. 10:870–880. 2012. View Article : Google Scholar : PubMed/NCBI
51	Nimjee SM, Rusconi CP, Harrington RA and Sullenger BA: The potential of aptamers as anticoagulants. Trends Cardiovasc Med. 15:41–45. 2005. View Article : Google Scholar : PubMed/NCBI
52	van de Locht A, Lamba D, Bauer M, et al: Two heads are better than one: crystal structure of the insect derived double domain Kazal inhibitor rhodniin in complex with thrombin. EMBO J. 14:5149–5157. 1995.PubMed/NCBI
53	Markwardt F: The comeback of hirudin - an old-established anticoagulant agent. Folia Haematol Int Mag Klin Morphol Blutforsch. 115:10–23. 1988.PubMed/NCBI
54	Salzet M: Leech thrombin inhibitors. Curr Pharm Des. 8:493–503. 2002. View Article : Google Scholar : PubMed/NCBI
55	Strube KH, Kröger B, Bialojan S, Otte M and Dodt J: Isolation, sequence analysis and cloning of haemadin. An anticoagulant peptide from the Indian leech. J Biol Chem. 268:8590–8595. 1993.PubMed/NCBI
56	Markwardt F: State-of-the-Art Review: antithrombotic agents from hematophagous animals. Clin Appl Thromb Hemost. 2:75–82. 1996. View Article : Google Scholar
57	Salzet M, Chopin V, Baert J, Matias I and Malecha J: Theromin, a novel leech thrombin inhibitor. J Biol Chem. 275:30774–30780. 2000. View Article : Google Scholar : PubMed/NCBI
58	Francischetti IM, Valenzuela JG and Ribeiro JM: Anophelin: kinetics and mechanism of thrombin inhibition. Biochemistry. 38:16678–16685. 1999. View Article : Google Scholar : PubMed/NCBI
59	Waidhet-Kouadio P, Yuda M, Ando K and Chinzei Y: Purification and characterization of a thrombin inhibitor from the salivary glands of a malarial vector mosquito, Anopheles stephensi. Biochim Biophys Acta. 1381:227–233. 1998. View Article : Google Scholar : PubMed/NCBI
60	Watanabe RM, Soares TS, Morais-Zani K, et al: A novel trypsin Kazal-type inhibitor from Aedes aegypti with thrombin coagulant inhibitory activity. Biochimie. 92:933–939. 2010. View Article : Google Scholar : PubMed/NCBI
61	Soares TS, Watanabe RM, Tanaka-Azevedo AM, et al: Expression and functional characterization of boophilin, a thrombin inhibitor from Rhipicephalus (Boophilus) microplus midgut. Vet Parasitol. 521–528. 2012. View Article : Google Scholar : PubMed/NCBI
62	Macedo-Ribeiro S, Almeida C, Calisto BM, et al: Isolation, cloning and structural characterisation of boophilin, a multifunctional Kunitz-type proteinase inhibitor from the cattle tick. PLoS One. 3:e16242008. View Article : Google Scholar : PubMed/NCBI
63	Ciprandi A, de Oliveira SK, Masuda A, Horn F and Termignoni C: Boophilus microplus: Its saliva contains microphilin, a small thrombin inhibitor. Exp Parasitol. 114:40–46. 2006. View Article : Google Scholar
64	Liao M, Zhou J, Gong H, et al: Hemalin, a thrombin inhibitor isolated from a midgut cDNA library from the hard tick Haemaphysalis longicornis. J Insect Physiol. 55:165–173. 2009. View Article : Google Scholar : PubMed/NCBI
65	Iwanaga S, Okada M, Isawa H, Morita A, Yuda M and Chinzei Y: Identification and characterization of novel salivary thrombin inhibitors from the ixodidae tick, Haemaphysalis longicornis. Eur J Biochem. 270:1926–1934. 2003. View Article : Google Scholar : PubMed/NCBI
66	Noeske-Jungblut C, Haendler B, Donner P, Alagon A, Possani L and Schleuning WD: Triabin, a highly potent exosite inhibitor of thrombin. J Biol Chem. 270:28629–28634. 1995. View Article : Google Scholar : PubMed/NCBI
67	Campos I, Amino R, Sampaio C, et al: Infestin, a thrombin inhibitor present in Triatoma infestans midgut, a Chagas’ disease vector: gene cloning, expression and characterization of the inhibitor. Insect Biochem Mol Biol. 32:991–997. 2002.PubMed/NCBI
68	Araujo R, Campos I, Tanaka A, et al: Brasiliensin: a novel intestinal thrombin inhibitor from Triatoma brasiliensis (Hemiptera: Reduviidae) with an important role in blood intake. Int J Parasitol. 37:1351–1358. 2007. View Article : Google Scholar : PubMed/NCBI
69	Mende K, Petoukhova O, Koulitchkova V, et al: Dipetalogastin, a potent thrombin inhibitor from the blood-sucking insect Dipetalogaster maximus. Eur J Biochem. 266:583–590. 1999. View Article : Google Scholar : PubMed/NCBI
70	Osipov AV, Filkin SY, Makarova YV, Tsetlin VI and Utkin YN: A new type of thrombin inhibitor, noncytotoxic phospholipase A2, from the Naja haje cobra venom. Toxicon. 55:186–194. 2010. View Article : Google Scholar : PubMed/NCBI
71	Arocas V, Zingali RB, Guillin MC, Bon C and Jandrot-Perrus M: Bothrojaracin: a potent two-site-directed thrombin inhibitor. Biochemistry. 35:9083–9089. 1996. View Article : Google Scholar : PubMed/NCBI
72	Yang X, Wang Y, Lu Z, et al: A novel serine protease inhibitor from the venom of Vespa bicolor Fabricius. Comp Biochem Physiol B Biochem Mol Biol. 153:116–120. 2009. View Article : Google Scholar : PubMed/NCBI
73	Lu X, Ma Y, Wu J and Lai R: Two serine protease inhibitors from the skin secretions of the toad, Bombina microdeladigitora. Comp Biochem Physiol B Biochem Mol Biol. 149:608–612. 2008. View Article : Google Scholar : PubMed/NCBI
74	Liu L, Ma H, Yang N, et al: A series of natural flavonoids as thrombin inhibitors: structure-activity relationships. Thromb Res. 126:e365–e378. 2010. View Article : Google Scholar : PubMed/NCBI
75	Doljak B, Cateni F, Anderluh M, Procida G, Zilic J and Zacchigna M: Glycerolipids as selective thrombin inhibitors from the fungus Stereum hirsutum. Drug Dev Ind Pharm. 32:635–643. 2006. View Article : Google Scholar : PubMed/NCBI
76	Li NG, Song SL, Shen MZ, et al: Mannich bases of scutellarein as thrombin-inhibitors: design, synthesis, biological activity and solubility. Bioorg Med Chem. 20:6919–1923. 2012. View Article : Google Scholar : PubMed/NCBI
77	Anas AR, Kisugi T, Umezawa T, et al: Thrombin inhibitors from the freshwater cyanobacterium Anabaena compacta. J Nat Prod. 75:1546–1552. 2012. View Article : Google Scholar : PubMed/NCBI
78	Hanessian S, Therrien E, Zhang J, et al: From natural products to achiral drug prototypes: potent thrombin inhibitors based on P2/P3 dihydropyrid-2-one core motifs. Bioorg Med Chem Lett. 19:5429–5432. 2009. View Article : Google Scholar : PubMed/NCBI
79	Martin JA, Parekh P, Kim Y, et al: Selection of an aptamer antidote to the anticoagulant drug bivalirudin. PLoS One. 8:e573412013. View Article : Google Scholar : PubMed/NCBI
80	Hon SF, Li HL and Cheng PW: Use of direct thrombin inhibitor for treatment of cerebral venous thrombosis. J Stroke Cerebrovasc Dis. 21:e11–e15. 2012.PubMed/NCBI
81	Moshfeghi AA and Puliafito CA: Pegaptanib sodium for the treatment of neovascular age-related macular degeneration. Expert Opin Investig Drugs. 14:671–682. 2005. View Article : Google Scholar : PubMed/NCBI
82	Ku SK, Kim TH and Bae JS: Anticoagulant activities of persicarin and isorhamnetin. Vascul Pharmacol. 58:272–279. 2013. View Article : Google Scholar : PubMed/NCBI
83	Robert S, Baccelli C, Devel P, Dogné JM and Quetin-Leclercq J: Effects of leaf extracts from Croton zambesicus Müell. Arg on hemostasis. J Ethnopharmacol. 128:641–648. 2010.