Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

An Overview of Thrombin Inhibitors in the Perspective of Structureactivity Relationships

Author(s): Jiangming Wang, Xiaojing Sun, Na Li, Ruilong Sheng and Ruihua Guo*

Volume 30, Issue 25, 2023

Published on: 07 November, 2022

Page: [2864 - 2930] Pages: 67

DOI: 10.2174/0929867329666220906105200

Price: $65

Open Access Journals Promotions 2
Abstract

Thrombosis is one of the most important pathogenic factors related to cardiovascular diseases. Presently, thrombin inhibitors have gradually gained prominence in clinical practice due to their unique potential, such as dabigatran. Nevertheless, the risk of bleeding is not completely eliminated, and the threats of gastrointestinal bleeding are even increased in some cases. Therefore, developing new oral thrombin inhibitors with low side effects is urgent. In this paper, we summarized recent advances in the newly synthesized and isolated thrombin inhibitors from 2000 to 2019 and their structure-activity relationships (SARs) along with structure-dependent pharmacokinetic parameters, guiding the next generation of oral thrombin inhibitors.

Keywords: Antithrombotic, thrombin inhibitor, structure-activity relationship, pharmacokinetics.

« Previous
[1]
Benjamin, E.J.; Virani, S.S.; Callaway, C.W.; Chamberlain, A.M.; Chang, A.R.; Cheng, S.; Chiuve, S.E.; Cushman, M.; Delling, F.N.; Deo, R.; de Ferranti, S.D.; Ferguson, J.F.; Fornage, M.; Gillespie, C.; Isasi, C.R.; Jiménez, M.C.; Jordan, L.C.; Judd, S.E.; Lackland, D.; Lichtman, J.H.; Lisabeth, L.; Liu, S.; Longenecker, C.T.; Lutsey, P.L.; Mackey, J.S.; Matchar, D.B.; Matsushita, K.; Mussolino, M.E.; Nasir, K.; O’Flaherty, M.; Palaniappan, L.P.; Pandey, A.; Pandey, D.K.; Reeves, M.J.; Ritchey, M.D.; Rodriguez, C.J.; Roth, G.A.; Rosamond, W.D.; Sampson, U.K.A.; Satou, G.M.; Shah, S.H.; Spartano, N.L.; Tirschwell, D.L.; Tsao, C.W.; Voeks, J.H.; Willey, J.Z.; Wilkins, J.T.; Wu, J.H.; Alger, H.M.; Wong, S.S.; Muntner, P. Heart disease and stroke statistics-2018 Update: A report from the American Heart Association. Circulation, 2018, 137(12), e67-e492.
[http://dx.doi.org/10.1161/CIR.0000000000000558] [PMID: 29386200]
[2]
Quan, M.L.; Pinto, D.J.P.; Smallheer, J.M.; Ewing, W.R.; Rossi, K.A.; Luettgen, J.M.; Seiffert, D.A.; Wexler, R.R. Factor XIa inhibitors as new anticoagulants. J. Med. Chem., 2021, 61(17), 7425-7447.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00173] [PMID: 29775297];
(2a) Wang, Y.; Chen, H.; Sheng, R.; Fu, Z.; Fan, J.; Wu, W.; Tu, Q.; Guo, R. Synthesis and bioactivities of marine pyran-isoindolone derivatives as potential antithrombotic agents. Mar. Drugs, 2021, 19(4), 218.
[http://dx.doi.org/10.3390/md19040218] [PMID: 33921137]
[3]
World Health Organization. World Health Statistics. Monitoring Health for the SDGs, Sustainable Development Goals; World Health Organization: Genève, 2018.
[4]
Li, H.; Ge, J. Cardiovascular diseases in China: Current status and future perspectives. Int. J. Cardiol. Heart Vasc., 2014, 6, 25-31.
[http://dx.doi.org/10.1016/j.ijcha.2014.10.002] [PMID: 28785622]
[5]
Valavanidis, A.; Fiotakis, K.; Vlachogianni, T. Airborne particulate matter and human health: Toxicological assessment and importance of size and composition of particles for oxidative damage and carcinogenic mechanisms. J. Environ. Sci. Health Part C Environ. Carcinog. Ecotoxicol. Rev., 2008, 26(4), 339-362.
[http://dx.doi.org/10.1080/10590500802494538] [PMID: 19034792]
[6]
Wendelboe, A.M.; Raskob, G.E. Global burden of thrombosis: Epidemiologic aspects. Circ. Res., 2016, 118(9), 1340-1347.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.306841] [PMID: 27126645]
[7]
Steg, P.G.; James, S.K.; Atar, D.; Badano, L.P.; Blömstrom-Lundqvist, C.; Borger, M.A.; Di Mario, C.; Dickstein, K.; Ducrocq, G.; Fernandez-Aviles, F.; Gershlick, A.H.; Giannuzzi, P.; Halvorsen, S.; Huber, K.; Juni, P.; Kastrati, A.; Knuuti, J.; Lenzen, M.J.; Mahaffey, K.W.; Valgimigli, M.; van ’t Hof, A.; Widimsky, P.; Zahger, D. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur. Heart J., 2012, 33(20), 2569-2619.
[http://dx.doi.org/10.1093/eurheartj/ehs215] [PMID: 22922416]
[8]
Morrow, D.A.; Wiviott, S.D.; White, H.D.; Nicolau, J.C.; Bramucci, E.; Murphy, S.A.; Bonaca, M.P.; Ruff, C.T.; Scirica, B.M.; McCabe, C.H.; Antman, E.M.; Braunwald, E. Effect of the novel thienopyridine prasugrel compared with clopidogrel on spontaneous and procedural myocardial infarction in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38: An application of the classification system from the universal definition of myocardial infarction. Circulation, 2009, 119(21), 2758-2764.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.108.833665] [PMID: 19451347]
[9]
Kapoor, J.R. Platelet activation and atherothrombosis. N. Engl. J. Med., 2008, 358(15), 1638-1639.
[http://dx.doi.org/10.1056/NEJMc080056] [PMID: 18403776]
[10]
Ossovskaya, V.S.; Bunnett, N.W. Protease-activated receptors: Contribution to physiology and disease. Physiol. Rev., 2004, 84(2), 579-621.
[http://dx.doi.org/10.1152/physrev.00028.2003] [PMID: 15044683]
[11]
Mackman, N. Triggers, targets and treatments for thrombosis. Nature, 2008, 451(7181), 914-918.
[http://dx.doi.org/10.1038/nature06797] [PMID: 18288180]
[12]
Popov Aleksandrov, A.; Mirkov, I.; Ninkov, M.; Mileusnic, D.; Demenesku, J.; Subota, V.; Kataranovski, D.; Kataranovski, M. Effects of warfarin on biological processes other than haemostasis: A review. Food Chem. Toxicol., 2018, 113, 19-32.
[http://dx.doi.org/10.1016/j.fct.2018.01.019] [PMID: 29353071]
[13]
Harenberg, J.; Marx, S.; Krejczy, M.; Wehling, M. New anticoagulants - promising and failed developments. Br. J. Pharmacol., 2012, 165(2), 363-372.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01578.x] [PMID: 21740405]
[14]
Kong, Y.; Chen, H.; Wang, Y-Q.; Meng, L.; Wei, J-F. Direct thrombin inhibitors: Patents 2002-2012. Mol. Med. Rep., 2014, 9, 1506-1514.
[15]
Yeh, C.H.; Hogg, K.; Weitz, J.I. Overview of the new oral anticoagulants: Opportunities and challenges. Arterioscler. Thromb. Vasc. Biol., 2015, 35(5), 1056-1065.
[http://dx.doi.org/10.1161/ATVBAHA.115.303397] [PMID: 25792448]
[16]
Ruff, C.T.; Giugliano, R.P.; Braunwald, E.; Hoffman, E.B.; Deenadayalu, N.; Ezekowitz, M.D.; Camm, A.J.; Weitz, J.I.; Lewis, B.S.; Parkhomenko, A.; Yamashita, T.; Antman, E.M. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: A meta-analysis of randomised trials. Lancet, 2014, 383(9921), 955-962.
[http://dx.doi.org/10.1016/S0140-6736(13)62343-0] [PMID: 24315724]
[17]
McNamara, C.A.; Sarembock, I.J.; Gimple, L.W.; Fenton, J.W.D., II; Coughlin, S.R.; Owens, G.K. Thrombin stimulates proliferation of cultured rat aortic smooth muscle cells by a proteolytically activated receptor. J. Clin. Invest., 1993, 91(1), 94-98.
[http://dx.doi.org/10.1172/JCI116206] [PMID: 8380817]
[18]
Mhatre, M.; Nguyen, A.; Kashani, S.; Pham, T.; Adesina, A.; Grammas, P. Thrombin, a mediator of neurotoxicity and memory impairment. Neurobiol. Aging, 2004, 25(6), 783-793.
[http://dx.doi.org/10.1016/j.neurobiolaging.2003.07.007] [PMID: 15165703]
[19]
Gould, T.W.; Dominguez, B.; de Winter, F.; Yeo, G.W.; Liu, P.; Sundararaman, B.; Stark, T.; Vu, A.; Degen, J.L.; Lin, W.; Lee, K.F. Glial cells maintain synapses by inhibiting an activity-dependent retrograde protease signal. PLoS Genet., 2019, 15(3), e1007948.
[http://dx.doi.org/10.1371/journal.pgen.1007948] [PMID: 30870413]
[20]
Warkentin, T.E. Bivalent direct thrombin inhibitors: Hirudin and bivalirudin. Best Pract. Res. Clin. Haematol., 2004, 17(1), 105-125.
[http://dx.doi.org/10.1016/j.beha.2004.02.002] [PMID: 15171961]
[21]
Hankey, G.J.; Eikelboom, J.W. Dabigatran etexilate: A new oral thrombin inhibitor. Circulation, 2011, 123(13), 1436-1450.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.110.004424] [PMID: 21464059]
[22]
Nutescu, E.A.; Wittkowsky, A.K. Direct thrombin inhibitors for anticoagulation. Ann. Pharmacother., 2004, 38(1), 99-109.
[http://dx.doi.org/10.1345/aph.1D066] [PMID: 14742803]
[23]
Lee, C.J.; Ansell, J.E. Direct thrombin inhibitors. Br. J. Clin. Pharmacol., 2011, 72(4), 581-592.
[http://dx.doi.org/10.1111/j.1365-2125.2011.03916.x] [PMID: 21241354]
[24]
Kam, P.C.A.; Kaur, N.; Thong, C.L. Direct thrombin inhibitors: Pharmacology and clinical relevance. Anaesthesia, 2005, 60(6), 565-574.
[http://dx.doi.org/10.1111/j.1365-2044.2005.04192.x] [PMID: 15918828]
[25]
de Moerloose, P.; Boehlen, F. Two new antithrombotic agents (fondaparinux and ximelagatran) and their implications in anesthesia. Can. J. Anaesth., 2002, 49(6), S5-S10.
[PMID: 12557410]
[26]
Das, J.; Kimball, S.D. Thrombin active site inhibitors. Bioorg. Med. Chem., 1995, 3(8), 999-1007.
[http://dx.doi.org/10.1016/0968-0896(95)00104-O] [PMID: 7582987]
[27]
Steinmetzer, T.; Stürzebecher, J. Progress in the development of synthetic thrombin inhibitors as new orally active anticoagulants. Curr. Med. Chem., 2004, 11(17), 2297-2321.
[http://dx.doi.org/10.2174/0929867043364540] [PMID: 15379714]
[28]
Straub, A.; Roehrig, S.; Hillisch, A. Oral, direct thrombin and factor Xa inhibitors: The replacement for warfarin, leeches, and pig intestines? Angew. Chem. Int. Ed. Engl., 2011, 50(20), 4574-4590.
[http://dx.doi.org/10.1002/anie.201004575] [PMID: 21538731]
[29]
Mehta, A.Y.; Jin, Y.; Desai, U.R. An update on recent patents on thrombin inhibitors (2010 - 2013). Expert Opin. Ther. Pat., 2014, 24(1), 47-67.
[http://dx.doi.org/10.1517/13543776.2014.845169] [PMID: 24099091]
[30]
He, L.W.; Dai, W.C.; Li, N.G. Development of orally active thrombin inhibitors for the treatment of thrombotic disorder diseases. Molecules, 2015, 20(6), 11046-11062.
[http://dx.doi.org/10.3390/molecules200611046] [PMID: 26083038]
[31]
Xie, Z.; Tian, Y.; Lv, X.; Xiao, X.; Zhan, M.; Cheng, K.; Li, S.; Liao, C. The selectivity and bioavailability improvement of novel oral anticoagulants: An overview. Eur. J. Med. Chem., 2018, 146, 299-317.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.067] [PMID: 29407959]
[32]
Zhu, D. The composition and function of blood. In: Human anatomy and physiology, 7th Ed; Zhou, H.; Cui, H., Eds.; People’s Medical Publishing House: Beijing, 2017; p. 75.
[33]
Rachel, B.S. Protease-activated receptors. In: Encyclopedia of Cancer; Schwab, M., Ed.; Springer Berlin Heidelberg: Berlin, Heidelberg, 2015; pp. 1-4.
[34]
Kahn, M.L.; Nakanishi-Matsui, M.; Shapiro, M.J.; Ishihara, H.; Coughlin, S.R. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J. Clin. Invest., 1999, 103(6), 879-887.
[http://dx.doi.org/10.1172/JCI6042] [PMID: 10079109]
[35]
Antoniak, S.; Pawlinski, R.; Mackman, N. Protease-activated receptors and myocardial infarction. IUBMB Life, 2011, 63(6), 383-389.
[http://dx.doi.org/10.1002/iub.441] [PMID: 21438116]
[36]
Coughlin, S.R. Thrombin signalling and protease-activated receptors. Nature, 2000, 407(6801), 258-264.
[http://dx.doi.org/10.1038/35025229] [PMID: 11001069]
[37]
Vu, T.K.H.; Wheaton, V.I.; Hung, D.T.; Charo, I.; Coughlin, S.R. Domains specifying thrombin-receptor interaction. Nature, 1991, 353(6345), 674-677.
[http://dx.doi.org/10.1038/353674a0] [PMID: 1717851]
[38]
Aslan, J.E. Platelet Rho GTPase regulation in physiology and disease. Platelets, 2019, 30(1), 17-22.
[http://dx.doi.org/10.1080/09537104.2018.1475632] [PMID: 29799302]
[39]
Angiolillo, D.J.; Ueno, M. Optimizing platelet inhibition in clopidogrel poor metabolizers: Therapeutic options and practical considerations. JACC Cardiovasc. Interv., 2011, 4(4), 411-414.
[http://dx.doi.org/10.1016/j.jcin.2011.03.001] [PMID: 21511220]
[40]
Stenberg, P.E.; McEver, R.P.; Shuman, M.A.; Jacques, Y.V.; Bainton, D.F. A platelet alpha-granule membrane protein (GMP-140) is expressed on the plasma membrane after activation. J. Cell Biol., 1985, 101(3), 880-886.
[http://dx.doi.org/10.1083/jcb.101.3.880] [PMID: 2411738]
[41]
Henn, V.; Slupsky, J.R.; Gräfe, M.; Anagnostopoulos, I.; Förster, R.; Müller-Berghaus, G.; Kroczek, R.A. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature, 1998, 391(6667), 591-594.
[http://dx.doi.org/10.1038/35393] [PMID: 9468137]
[42]
Rohde, M.; Mayer, F.; Hicks, D.B.; Krulwich, T.A. Immunoelectron microscopic localization of the F1F0 ATPase (ATP synthase) on the cytoplasmic membrane of alkalophilic Bacillus firmus RAB. Biomembranes, 1989, 985, 233-235.
[43]
Angiolillo, D.J.; Capodanno, D.; Goto, S. Platelet thrombin receptor antagonism and atherothrombosis. Eur. Heart J., 2010, 31(1), 17-28.
[http://dx.doi.org/10.1093/eurheartj/ehp504] [PMID: 19948715]
[44]
Chen, Z.; Seiffert, D.; Hawes, B. Inhibition of Factor XI activity as a promising antithrombotic strategy. Drug Discov. Today, 2014, 19(9), 1435-1439.
[http://dx.doi.org/10.1016/j.drudis.2014.04.018] [PMID: 24794465]
[45]
Al-Horani, R.A.; Desai, U.R. Factor XIa inhibitors: A review of the patent literature. Expert Opin. Ther. Pat., 2016, 26(3), 323-345.
[http://dx.doi.org/10.1517/13543776.2016.1154045] [PMID: 26881476]
[46]
Bane, C.E., Jr; Gailani, D. Factor XI as a target for antithrombotic therapy. Drug Discov. Today, 2014, 19(9), 1454-1458.
[http://dx.doi.org/10.1016/j.drudis.2014.05.018] [PMID: 24886766]
[47]
Lee, Y.K.; Player, M.R. Developments in factor Xa inhibitors for the treatment of thromboembolic disorders. Med. Res. Rev., 2011, 31(2), 202-283.
[http://dx.doi.org/10.1002/med.20183] [PMID: 19967784]
[48]
(a) Al-Horani, R.A.; Afosah, D.K. Recent advances in the discovery and development of factor XI/XIa inhibitors. Med. Res. Rev., 2018, 38(6), 1974-2023.
[http://dx.doi.org/10.1002/med.21503] [PMID: 29727017]
[49]
Wood, J.P.; Ellery, P.E.R.; Maroney, S.A.; Mast, A.E. Biology of tissue factor pathway inhibitor. Blood, 2014, 123(19), 2934-2943.
[http://dx.doi.org/10.1182/blood-2013-11-512764] [PMID: 24620349];
(b) Guo, R.; Duan, D.; Hong, S.; Zhou, Y.; Wang, F.; Wang, S.; Wu, W.; Bao, B. A marine fibrinolytic compound FGFC1 stimulating enzymatic kinetic parameters of a reciprocal activation system based on a single chain urokinasetype plasminogen activator and plasminogen. Process Biochem., 2018, 68, 190-196.
[http://dx.doi.org/10.1016/j.procbio.2018.01.024];
(c) Guo, R.; Zhang, Y.; Duan, D.; Fu, Q.; Zhang, X.; Yu, X.; Wang, S.; Bao, B.; Wu, W. Fibrinolytic evaluation of compounds isolated from a marine fungus stachybotrys longispora FG216. Chin. J. Chem., 2016, 34, 1194-1198.
[http://dx.doi.org/10.1002/cjoc.201600623]
[50]
Griffin, J.H.; Fernández, J.A.; Gale, A.J.; Mosnier, L.O. Activated protein C. J. Thromb. Haemost., 2007, 5(Suppl. 1), 73-80.
[http://dx.doi.org/10.1111/j.1538-7836.2007.02491.x] [PMID: 17635713]
[51]
Corral, J.; de la Morena-Barrio, M.E.; Vicente, V. The genetics of antithrombin. Thromb. Res., 2018, 169, 23-29.
[http://dx.doi.org/10.1016/j.thromres.2018.07.008] [PMID: 30005274]
[52]
Gladysz, R.; Adriaenssens, Y.; De Winter, H.; Joossens, J.; Lambeir, A.M.; Augustyns, K.; Van der Veken, P. Discovery and SAR of novel and selective inhibitors of urokinase plasminogen activator (uPA) with an imidazo[1,2-a]pyridine scaffold. J. Med. Chem., 2015, 58(23), 9238-9257.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01171] [PMID: 26575094]
[53]
De Nanteuil, G.; Lila-Ambroise, C.; Rupin, A.; Vallez, M.O.; Verbeuren, T.J. New fibrinolytic agents: Benzothiophene derivatives as inhibitors of the t-PA-PAI-1 complex formation. Bioorg. Med. Chem. Lett., 2003, 13(10), 1705-1708.
[http://dx.doi.org/10.1016/S0960-894X(03)00233-6] [PMID: 12729646]
[54]
Esmon, C.T. Regulation of blood coagulation. Protein Struct. M, 2000, 1477, 349-360.
[55]
Krishnaswamy, S. The transition of prothrombin to thrombin. J. Thromb. Haemost., 2013, 11(Suppl. 1), 265-276.
[http://dx.doi.org/10.1111/jth.12217] [PMID: 23809130]
[56]
Boissel, J.P.; Le Bonniec, B.; Rabiet, M.J.; Labie, D.; Elion, J. Covalent structures of beta and gamma autolytic derivatives of human alpha-thrombin. J. Biol. Chem., 1984, 259(9), 5691-5697.
[http://dx.doi.org/10.1016/S0021-9258(18)91069-0] [PMID: 6715366]
[57]
De Cristofaro, R.; Akhavan, S.; Altomare, C.; Carotti, A.; Peyvandi, F.; Mannucci, P.M. A natural prothrombin mutant reveals an unexpected influence of A-chain structure on the activity of human alpha-thrombin. J. Biol. Chem., 2004, 279(13), 13035-13043.
[http://dx.doi.org/10.1074/jbc.M312430200] [PMID: 14722067]
[58]
Bode, W.; Mayr, I.; Baumann, U.; Huber, R.; Stone, S.R.; Hofsteenge, J. The refined 1.9 A crystal structure of human α-thrombin: Interaction with D-Phe-Pro-Arg chloromethylketone and significance of the Tyr-Pro-Pro-Trp insertion segment. EMBO J., 1989, 8(11), 3467-3475.
[http://dx.doi.org/10.1002/j.1460-2075.1989.tb08511.x] [PMID: 2583108]
[59]
Singh, R.R.; Chang, J.Y. Structural stability of human α-thrombin studied by disulfide reduction and scrambling. Proteins Proteom., 2003, 1651, 85-92.
[60]
Warshel, A.; Naray-Szabo, G.; Sussman, F.; Hwang, J.K. How do serine proteases really work? Biochemistry, 1989, 28(9), 3629-3637.
[http://dx.doi.org/10.1021/bi00435a001] [PMID: 2665806]
[61]
Di Cera, E.; Dang, Q.D.; Ayala, Y.M. Molecular mechanisms of thrombin function. Cell. Mol. Life Sci., 1997, 53(9), 701-730.
[http://dx.doi.org/10.1007/s000180050091] [PMID: 9368668]
[62]
Cera, E.D.; Gruber, A. Thrombin: Structure, functions, and regulation. In: Thrombin; Maragoudakis, M.E.; Tsopanoglou, N.E., Eds.; Springer New York: New York, NY, 2009.
[http://dx.doi.org/10.1007/978-0-387-09637-7_1]
[63]
Srivastava, S.; Goswami, L.N.; Dikshit, D.K. Progress in the design of low molecular weight thrombin inhibitors. Med. Res. Rev., 2005, 25(1), 66-92.
[http://dx.doi.org/10.1002/med.20016] [PMID: 15389730]
[64]
Nar, H. The role of structural information in the discovery of direct thrombin and factor Xa inhibitors. Trends Pharmacol. Sci., 2012, 33(5), 279-288.
[http://dx.doi.org/10.1016/j.tips.2012.03.004] [PMID: 22503439]
[65]
Bhunia, S.S.; Roy, K.K.; Saxena, A.K. Profiling the structural determinants for the selectivity of representative factor-Xa and thrombin inhibitors using combined ligand-based and structure-based approaches. J. Chem. Inf. Model., 2011, 51(8), 1966-1985.
[http://dx.doi.org/10.1021/ci200185q] [PMID: 21761917]
[66]
Schiele, F.; van Ryn, J.; Canada, K.; Newsome, C.; Sepulveda, E.; Park, J.; Nar, H.; Litzenburger, T. A specific antidote for dabigatran: Functional and structural characterization. Blood, 2013, 121(18), 3554-3562.
[http://dx.doi.org/10.1182/blood-2012-11-468207] [PMID: 23476049]
[67]
Sinauridze, E.I.; Romanov, A.N.; Gribkova, I.V.; Kondakova, O.A.; Surov, S.S.; Gorbatenko, A.S.; Butylin, A.A.; Monakov, M.Y.; Bogolyubov, A.A.; Kuznetsov, Y.V.; Sulimov, V.B.; Ataullakhanov, F.I. New synthetic thrombin inhibitors: Molecular design and experimental verification. PLoS One, 2011, 6(5), e19969.
[http://dx.doi.org/10.1371/journal.pone.0019969] [PMID: 21603576]
[68]
Gandhi, P.S.; Chen, Z.; Mathews, F.S.; Di Cera, E. Structural identification of the pathway of long-range communication in an allosteric enzyme. Proc. Natl. Acad. Sci. USA, 2008, 105(6), 1832-1837.
[http://dx.doi.org/10.1073/pnas.0710894105] [PMID: 18250335]
[69]
Myles, T.; Yun, T.H.; Leung, L.L.K. Structural requirements for the activation of human factor VIII by thrombin. Blood, 2002, 100(8), 2820-2826.
[http://dx.doi.org/10.1182/blood-2002-03-0843] [PMID: 12351390]
[70]
De Filippis, V.; Quarzago, D.; Vindigni, A.; Di Cera, E.; Fontana, A. Synthesis and characterization of more potent analogues of hirudin fragment 1-47 containing non-natural amino acids. Biochemistry, 1998, 37(39), 13507-13515.
[http://dx.doi.org/10.1021/bi980717n] [PMID: 9753436]
[71]
De Filippis, V.; Acquasaliente, L.; Pontarollo, G.; Peterle, D. Noncoded amino acids in protein engineering: Structure-activity relationship studies of hirudin-thrombin interaction. Biotechnol. Appl. Biochem., 2018, 65(1), 69-80.
[http://dx.doi.org/10.1002/bab.1632] [PMID: 29230873]
[72]
Lesk, A.M.; Fordham, W.D. Conservation and variability in the structures of serine proteinases of the chymotrypsin family. J. Mol. Biol., 1996, 258(3), 501-537.
[http://dx.doi.org/10.1006/jmbi.1996.0264] [PMID: 8642605]
[73]
Srinivasan, J.; Hu, S.; Hrabal, R.; Zhu, Y.; Komives, E.A.; Ni, F. Thrombin-bound structure of an EGF subdomain from human thrombomodulin determined by transferred nuclear Overhauser effects. Biochemistry, 1994, 33(46), 13553-13560.
[http://dx.doi.org/10.1021/bi00250a007] [PMID: 7947766]
[74]
Abdel Aziz, M.H.; Desai, U.R. Novel heparin mimetics reveal cooperativity between exosite 2 and sodium-binding site of thrombin. Thromb. Res., 2018, 165, 61-67.
[http://dx.doi.org/10.1016/j.thromres.2018.03.013] [PMID: 29573721]
[75]
Lechtenberg, B.C.; Freund, S.M.V.; Huntington, J.A. GpIbα interacts exclusively with exosite II of thrombin. J. Mol. Biol., 2014, 426(4), 881-893.
[http://dx.doi.org/10.1016/j.jmb.2013.11.027] [PMID: 24316004]
[76]
Uliana, F.; Vizovišek, M.; Acquasaliente, L.; Ciuffa, R.; Fossati, A.; Frommelt, F.; Goetze, S.; Wollscheid, B.; Gstaiger, M.; De Filippis, V.; Auf dem Keller, U.; Aebersold, R. Mapping specificity, cleavage entropy, allosteric changes and substrates of blood proteases in a high-throughput screen. Nat. Commun., 2021, 12(1), 1693.
[http://dx.doi.org/10.1038/s41467-021-21754-8] [PMID: 33727531]
[77]
Huntington, J.A. How Na+ activates thrombin--a review of the functional and structural data. Biol. Chem., 2008, 389(8), 1025-1035.
[http://dx.doi.org/10.1515/BC.2008.113] [PMID: 18979627]
[78]
Xiao, J.; Salsbury, F.R. Na+-binding modes involved in thrombin’s allosteric response as revealed by molecular dynamics simulations, correlation networks and Markov modeling. Phys. Chem. Chem. Phys., 2019, 21(8), 4320-4330.
[http://dx.doi.org/10.1039/C8CP07293K] [PMID: 30724273]
[79]
von Matt, A.; Ehrhardt, C.; Burkhard, P.; Metternich, R.; Walkinshaw, M.; Tapparelli, C. Selective boron-containing thrombin inhibitors--X-ray analysis reveals surprising binding mode. Bioorg. Med. Chem., 2000, 8(9), 2291-2303.
[http://dx.doi.org/10.1016/S0968-0896(00)00147-4] [PMID: 11026541]
[80]
Wienand, A.; Ehrhardt, C.; Metternich, R.; Tapparelli, C. Design, synthesis and biological evaluation of selective boron-containing thrombin inhibitors. Bioorg. Med. Chem., 1999, 7(7), 1295-1307.
[http://dx.doi.org/10.1016/S0968-0896(99)00069-3] [PMID: 10465405]
[81]
Nöteberg, D.; Brånalt, J.; Kvarnström, I.; Linschoten, M.; Musil, D.; Nyström, J.E.; Zuccarello, G.; Samuelsson, B. New proline mimetics: Synthesis of thrombin inhibitors incorporating cyclopentane- and cyclopentenedicarboxylic acid templates in the P2 position. Binding conformation investigated by X-ray crystallography. J. Med. Chem., 2000, 43(9), 1705-1713.
[http://dx.doi.org/10.1021/jm990557t] [PMID: 10794688]
[82]
Dahlgren, A.; Brånalt, J.; Kvarnström, I.; Nilsson, I.; Musil, D.; Samuelsson, B. Synthesis of potential thrombin inhibitors. Incorporation of tartaric acid templates as P2 proline mimetics. Bioorg. Med. Chem., 2002, 10(5), 1567-1580.
[http://dx.doi.org/10.1016/S0968-0896(01)00426-6] [PMID: 11886818]
[83]
Thorstensson, F.; Kvarnström, I.; Musil, D.; Nilsson, I.; Samuelsson, B. Synthesis of novel thrombin inhibitors. Use of ring-closing metathesis reactions for synthesis of P2 cyclopentene- and cyclohexenedicarboxylic acid derivatives. J. Med. Chem., 2003, 46(7), 1165-1179.
[http://dx.doi.org/10.1021/jm021065a] [PMID: 12646027]
[84]
Lee, K.; Jung, W.H.; Kang, M.; Lee, S.H. Noncovalent thrombin inhibitors incorporating an imidazolylethynyl P1. Bioorg. Med. Chem. Lett., 2000, 10(24), 2775-2778.
[http://dx.doi.org/10.1016/S0960-894X(00)00579-5] [PMID: 11133089]
[85]
Lee, K.; Jung, W.H.; Park, C.W.; Park, H.D.; Lee, S.H.; Kwon, O.H. Noncovalent tripeptidic thrombin inhibitors incorporating amidrazone, amine and amidine functions at P1. Bioorg. Med. Chem. Lett., 2002, 12(7), 1017-1022.
[http://dx.doi.org/10.1016/S0960-894X(02)00093-8] [PMID: 11909707]
[86]
Lee, K.; Park, C.W.; Jung, W.H.; Park, H.D.; Lee, S.H.; Chung, K.H.; Park, S.K.; Kwon, O.H.; Kang, M.; Park, D.H.; Lee, S.K.; Kim, E.E.; Yoon, S.K.; Kim, A. Efficacious and orally bioavailable thrombin inhibitors based on a 2,5-thienylamidine at the P1 position: Discovery of N-carboxymethyl-d-diphenylalanyl-l-prolyl[(5-amidino-2-thienyl)methyl]amide. J. Med. Chem., 2003, 46(17), 3612-3622.
[http://dx.doi.org/10.1021/jm030025j] [PMID: 12904065]
[87]
Lévesque, S.; St-Denis, Y.; Bachand, B.; Préville, P.; Leblond, L.; Winocour, P.D.; Edmunds, J.J.; Rubin, J.R.; Siddiqui, M.A. Novel bicyclic lactam inhibitors of thrombin: Potency and selectivity optimization through P1 residues. Bioorg. Med. Chem. Lett., 2001, 11(24), 3161-3164.
[http://dx.doi.org/10.1016/S0960-894X(01)00661-8] [PMID: 11720865]
[88]
Danilewicz, J.C.; Abel, S.M.; Brown, A.D.; Fish, P.V.; Hawkeswood, E.; Holland, S.J.; James, K.; McElroy, A.B.; Overington, J.; Powling, M.J.; Rance, D.J. Design of selective thrombin inhibitors based on the (R)-Phe-Pro-Arg sequence. J. Med. Chem., 2002, 45(12), 2432-2453.
[http://dx.doi.org/10.1021/jm011133d] [PMID: 12036353]
[89]
Ho, J.Z.; Gibson, T.S.; Semple, J.E. Novel, potent noncovalent thrombin inhibitors incorporating p(3)-lactam scaffolds. Bioorg. Med. Chem. Lett., 2002, 12(5), 743-748.
[http://dx.doi.org/10.1016/S0960-894X(02)00010-0] [PMID: 11858993]
[90]
Das, J.; Kimball, S.D.; Reid, J.A.; Wang, T.C.; Lau, W.F.; Roberts, D.G.M.; Seiler, S.M.; Schumacher, W.A.; Ogletree, M.L. Thrombin active site inhibitors: Chemical synthesis, in vitro and in vivo pharmacological profile of a novel and selective agent BMS-189090 and analogues. Bioorg. Med. Chem. Lett., 2002, 12(1), 41-44.
[http://dx.doi.org/10.1016/S0960-894X(01)00664-3] [PMID: 11738569]
[91]
Peterlin-Masic, L.; Mlinsek, G.; Solmajer, T.; Trampus-Bakija, A.; Stegnar, M.; Kikelj, D. Novel thrombin inhibitors incorporating non-basic partially saturated heterobicyclic P1-arginine mimetics. Bioorg. Med. Chem. Lett., 2003, 13(5), 789-794.
[http://dx.doi.org/10.1016/S0960-894X(03)00030-1] [PMID: 12617892]
[92]
Marinko, P.; Krbavcic, A.; Mlinsek, G.; Solmajer, T.; Bakija, A.T.; Stegnar, M.; Stojan, J.; Kikelj, D. Novel non-covalent thrombin inhibitors incorporating P(1) 4,5,6,7-tetrahydrobenzothiazole arginine side chain mimetics. Eur. J. Med. Chem., 2004, 39(3), 257-265.
[http://dx.doi.org/10.1016/j.ejmech.2003.12.006] [PMID: 15051174]
[93]
Blizzard, T.A.; Singh, S.; Patil, B.; Chidurala, N.; Komanduri, V.; Debnath, S.; Belyakov, S.; Crespo, A.; Struck, A.; Kurtz, M.; Wiltsie, J.; Shen, X.; Sonatore, L.; Arocho, M.; Lewis, D.; Ogletree, M.; Biftu, T. Heterocyclic core analogs of a direct thrombin inhibitor. Bioorg. Med. Chem. Lett., 2014, 24(4), 1111-1115.
[http://dx.doi.org/10.1016/j.bmcl.2014.01.002] [PMID: 24461292]
[94]
Morrissette, M.M.; Stauffer, K.J.; Williams, P.D.; Lyle, T.A.; Vacca, J.P.; Krueger, J.A.; Lewis, S.D.; Lucas, B.J.; Wong, B.K.; White, R.B.; Miller-Stein, C.; Lyle, E.A.; Wallace, A.A.; Leonard, Y.M.; Welsh, D.C.; Lynch, J.J.; McMasters, D.R. Low molecular weight thrombin inhibitors with excellent potency, metabolic stability, and oral bioavailability. Bioorg. Med. Chem. Lett., 2004, 14(16), 4161-4164.
[http://dx.doi.org/10.1016/j.bmcl.2004.06.030] [PMID: 15261262]
[95]
Stauffer, K.J.; Williams, P.D.; Selnick, H.G.; Nantermet, P.G.; Newton, C.L.; Homnick, C.F.; Zrada, M.M.; Lewis, S.D.; Lucas, B.J.; Krueger, J.A.; Pietrak, B.L.; Lyle, E.A.; Singh, R.; Miller-Stein, C.; White, R.B.; Wong, B.; Wallace, A.A.; Sitko, G.R.; Cook, J.J.; Holahan, M.A.; Stranieri-Michener, M.; Leonard, Y.M.; Lynch, J.J., Jr.; McMasters, D.R.; Yan, Y. 9-hydroxyazafluorenes and their use in thrombin inhibitors. J. Med. Chem., 2005, 48(7), 2282-2293.
[http://dx.doi.org/10.1021/jm049423s] [PMID: 15801822]
[96]
Costanzo, M.J.; Almond, H.R., Jr; Hecker, L.R.; Schott, M.R.; Yabut, S.C.; Zhang, H.C.; Andrade-Gordon, P.; Corcoran, T.W.; Giardino, E.C.; Kauffman, J.A.; Lewis, J.M.; de Garavilla, L.; Haertlein, B.J.; Maryanoff, B.E. In-depth study of tripeptide-based α-ketoheterocycles as inhibitors of thrombin. Effective utilization of the S1′ subsite and its implications to structure-based drug design. J. Med. Chem., 2005, 48(6), 1984-2008.
[http://dx.doi.org/10.1021/jm0303857] [PMID: 15771442]
[97]
Staas, D.D.; Savage, K.L.; Sherman, V.L.; Shimp, H.L.; Lyle, T.A.; Tran, L.O.; Wiscount, C.M.; McMasters, D.R.; Sanderson, P.E.; Williams, P.D.; Lucas, B.J., Jr.; Krueger, J.A.; Lewis, S.D.; White, R.B.; Yu, S.; Wong, B.K.; Kochansky, C.J.; Anari, M.R.; Yan, Y.; Vacca, J.P. Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability. Bioorg. Med. Chem., 2006, 14(20), 6900-6916.
[http://dx.doi.org/10.1016/j.bmc.2006.06.040] [PMID: 16870455]
[98]
Mack, H.; Baucke, D.; Hornberger, W.; Lange, U.E.W.; Seitz, W.; Höffken, H.W. Orally active thrombin inhibitors. Part 1: Optimization of the P1-moiety. Bioorg. Med. Chem. Lett., 2006, 16(10), 2641-2647.
[http://dx.doi.org/10.1016/j.bmcl.2006.02.040] [PMID: 16517159]
[99]
Lange, U.E.; Baucke, D.; Hornberger, W.; Mack, H.; Seitz, W.; Höffken, H.W. Orally active thrombin inhibitors. Part 2: Optimization of the P2-moiety. Bioorg. Med. Chem. Lett., 2006, 16(10), 2648-2653.
[http://dx.doi.org/10.1016/j.bmcl.2006.01.046] [PMID: 16460939]
[100]
Wang, G.; Goyal, N.; Hopkinson, B. Preparation of L-proline based aeruginosin 298-A analogs: Optimization of the P1-moiety. Bioorg. Med. Chem. Lett., 2009, 19(14), 3798-3803.
[http://dx.doi.org/10.1016/j.bmcl.2009.04.056] [PMID: 19447619]
[101]
Figueiredo, A.C.; Clement, C.C.; Zakia, S.; Gingold, J.; Philipp, M.; Pereira, P.J.B. Rational design and characterization of D-Phe-Pro-D-Arg-derived direct thrombin inhibitors. PLoS One, 2012, 7(3), e34354.
[http://dx.doi.org/10.1371/journal.pone.0034354] [PMID: 22457833]
[102]
Chobanian, H.R.; Pio, B.; Guo, Y.; Shen, H.; Huffman, M.A.; Madeira, M.; Salituro, G.; Terebetski, J.L.; Ormes, J.; Jochnowitz, N.; Hoos, L.; Zhou, Y.; Lewis, D.; Hawes, B.; Mitnaul, L.; O’Neill, K.; Ellsworth, K.; Wang, L.; Biftu, T.; Duffy, J.L. Improved stability of proline-derived direct thrombin inhibitors through hydroxyl to heterocycle replacement. ACS Med. Chem. Lett., 2015, 6(5), 553-557.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00047] [PMID: 26005532]
[103]
Abrahamsson, K.; Andersson, P.; Bergman, J.; Bredberg, U.; Branalt, J.; Egnell, A.C.; Eriksson, U.; Gustafsson, D.; Hoffman, K.J.; Nielsen, S.; Nilsson, I.; Pehrsson, S.; Polla, M.O.; Skjaeret, T.; Strimfors, M.; Wern, C.; Olwegard-Halvarsson, M.; Ortengren, Y. Discovery of AZD8165–a clinical candidate from a novel series of neutral thrombin inhibitors. MedChemComm, 2016, 7, 272-281.
[http://dx.doi.org/10.1039/C5MD00479A]
[104]
Hayler, J.; Kane, P.D.; LeGrand, D.; Lugrin, F.; Menear, K.; Price, R.; Allen, M.; Cockcroft, X.; Ambler, J.; Butler, K.; Dunnet, K.; Mitchelson, A.; Talbot, M.; Tweed, M.; Wills, N. The design and synthesis of thrombin inhibitors: The introduction of in vivo efficacy and oral bioavailability into benzthiazolylalanine inhibitors. Bioorg. Med. Chem. Lett., 2000, 10(14), 1567-1570.
[http://dx.doi.org/10.1016/S0960-894X(00)00283-3] [PMID: 10915052]
[105]
Zega, A.; Mlinsek, G.; Sepic, P.; Golic Grdadolnik, S.; Solmajer, T.; Tschopp, T.B.; Steiner, B.; Kikelj, D.; Urleb, U. Design and structure-activity relationship of thrombin inhibitors with an azaphenylalanine scaffold: Potency and selectivity enhancements via P2 optimization. Bioorg. Med. Chem., 2001, 9(10), 2745-2756.
[http://dx.doi.org/10.1016/S0968-0896(01)00202-4] [PMID: 11557360]
[106]
Obreza, A.; Stegnar, M.; Urleb, U. Novel non-covalent azaphenylalanine thrombin inhibitors with an aminomethyl or amino group at the P1 position. Pharmazie, 2004, 59(9), 659-667.
[PMID: 15497744]
[107]
Zega, A.; Mlinsek, G.; Solmajer, T.; Trampus-Bakija, A.; Stegnar, M.; Urleb, U. Thrombin inhibitors built on an azaphenylalanine scaffold. Bioorg. Med. Chem. Lett., 2004, 14(6), 1563-1567.
[http://dx.doi.org/10.1016/j.bmcl.2003.12.083] [PMID: 15006404]
[108]
Obreza, A.; Stegnar, M.; Trampus-Bakija, A.; Prezelj, A.; Urleb, U. Synthesis and in vitro evaluation of new azaphenylalanine derivatives as serine protease inhibitors. Pharmazie, 2004, 59(10), 739-743.
[PMID: 15544050]
[109]
Meneyrol, J.; Follmann, M.; Lassalle, G.; Wehner, V.; Barre, G.; Rousseaux, T.; Altenburger, J.M.; Petit, F.; Bocskei, Z.; Schreuder, H.; Alet, N.; Herault, J.P.; Millet, L.; Dol, F.; Florian, P.; Schaeffer, P.; Sadoun, F.; Klieber, S.; Briot, C.; Bono, F.; Herbert, J.M. 5-Chlorothiophene-2-carboxylic acid [(S)-2-[2-methyl-3-(2-oxopyrrolidin-1-yl)benzenesulfonylamino]-3-(4-methylpiperazin-1-yl)-3-oxopropyl]amide (SAR107375), a selective and potent orally active dual thrombin and factor Xa inhibitor. J. Med. Chem., 2013, 56(23), 9441-9456.
[http://dx.doi.org/10.1021/jm4005835] [PMID: 24175584]
[110]
Coburn, C.A.; Rush, D.M.; Williams, P.D.; Homnick, C.; Lyle, E.A.; Lewis, S.D.; Lucas, B.J., Jr.; Di Muzio-Mower, J.M.; Juliano, M.; Krueger, J.A.; Vastag, K.; Chen, I.W.; Vacca, J.P. Bicyclic pyridones as potent, efficacious and orally bioavailable thrombin inhibitors. Bioorg. Med. Chem. Lett., 2000, 10(10), 1069-1072.
[http://dx.doi.org/10.1016/S0960-894X(00)00170-0] [PMID: 10843219]
[111]
Sanderson, P.E.J.; Cutrona, K.J.; Dyer, D.L.; Krueger, J.A.; Kuo, L.C.; Lewis, S.D.; Lucas, B.J.; Yan, Y. Small, low nanomolar, non-covalent thrombin inhibitors lacking a group to fill the ‘distal binding pocket’. Bioorg. Med. Chem. Lett., 2003, 13(2), 161-164.
[http://dx.doi.org/10.1016/S0960-894X(02)00946-0] [PMID: 12482415]
[112]
Rittle, K.E.; Barrow, J.C.; Cutrona, K.J.; Glass, K.L.; Krueger, J.A.; Kuo, L.C.; Lewis, S.D.; Lucas, B.J.; McMasters, D.R.; Morrissette, M.M.; Nantermet, P.G.; Newton, C.L.; Sanders, W.M.; Yan, Y.; Vacca, J.P.; Selnick, H.G. Unexpected enhancement of thrombin inhibitor potency with o-aminoalkylbenzylamides in the P1 position. Bioorg. Med. Chem. Lett., 2003, 13(20), 3477-3482.
[http://dx.doi.org/10.1016/S0960-894X(03)00732-7] [PMID: 14505652]
[113]
Sanderson, P.E.J.; Stanton, M.G.; Dorsey, B.D.; Lyle, T.A.; McDonough, C.; Sanders, W.M.; Savage, K.L.; Naylor-Olsen, A.M.; Krueger, J.A.; Lewis, S.D.; Lucas, B.J.; Lynch, J.J.; Yan, Y. Azaindoles: Moderately basic P1 groups for enhancing the selectivity of thrombin inhibitors. Bioorg. Med. Chem. Lett., 2003, 13(5), 795-798.
[http://dx.doi.org/10.1016/S0960-894X(03)00017-9] [PMID: 12617893]
[114]
Burgey, C.S.; Robinson, K.A.; Lyle, T.A.; Sanderson, P.E.J.; Lewis, S.D.; Lucas, B.J.; Krueger, J.A.; Singh, R.; Miller-Stein, C.; White, R.B.; Wong, B.; Lyle, E.A.; Williams, P.D.; Coburn, C.A.; Dorsey, B.D.; Barrow, J.C.; Stranieri, M.T.; Holahan, M.A.; Sitko, G.R.; Cook, J.J.; McMasters, D.R.; McDonough, C.M.; Sanders, W.M.; Wallace, A.A.; Clayton, F.C.; Bohn, D.; Leonard, Y.M.; Detwiler, T.J., Jr; Lynch, J.J., Jr; Yan, Y.; Chen, Z.; Kuo, L.; Gardell, S.J.; Shafer, J.A.; Vacca, J.P. 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(4), 461-473.
[http://dx.doi.org/10.1021/jm020311f] [PMID: 12570369]
[115]
Burgey, C.S.; Robinson, K.A.; Lyle, T.A.; Nantermet, P.G.; Selnick, H.G.; Isaacs, R.C.A.; Lewis, S.D.; Lucas, B.J.; Krueger, J.A.; Singh, R.; Miller-Stein, C.; White, R.B.; Wong, B.; Lyle, E.A.; Stranieri, M.T.; Cook, J.J.; McMasters, D.R.; Pellicore, J.M.; Pal, S.; Wallace, A.A.; Clayton, F.C.; Bohn, D.; Welsh, D.C.; Lynch, J.J., Jr; Yan, Y.; Chen, Z.; Kuo, L.; Gardell, S.J.; Shafer, J.A.; Vacca, J.P. Pharmacokinetic optimization of 3-amino-6-chloropyrazinone acetamide thrombin inhibitors. Implementation of P3 pyridine N-oxides to deliver an orally bioavailable series containing P1 N-benzylamides. Bioorg. Med. Chem. Lett., 2003, 13(7), 1353-1357.
[http://dx.doi.org/10.1016/S0960-894X(03)00099-4] [PMID: 12657281]
[116]
Young, M.B.; Barrow, J.C.; Glass, K.L.; Lundell, G.F.; Newton, C.L.; Pellicore, J.M.; Rittle, K.E.; Selnick, H.G.; Stauffer, K.J.; Vacca, J.P.; Williams, P.D.; Bohn, D.; Clayton, F.C.; Cook, J.J.; Krueger, J.A.; Kuo, L.C.; Lewis, S.D.; Lucas, B.J.; McMasters, D.R.; Miller-Stein, C.; Pietrak, B.L.; Wallace, A.A.; White, R.B.; Wong, B.; Yan, Y.; Nantermet, P.G. Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors. J. Med. Chem., 2004, 47(12), 2995-3008.
[http://dx.doi.org/10.1021/jm030303e] [PMID: 15163182]
[117]
Peterlin-Masic, L.; Kranjc, A.; Marinko, P.; Mlinsek, G.; Solmajer, T.; Stegnar, M.; Kikelj, D. Selective 3-amino-2-pyridinone acetamide thrombin inhibitors incorporating weakly basic partially saturated heterobicyclic P1-arginine mimetics. Bioorg. Med. Chem. Lett., 2003, 13(19), 3171-3176.
[http://dx.doi.org/10.1016/S0960-894X(03)00717-0] [PMID: 12951087]
[118]
Kranjc, A.; Masic, L.P.; Reven, S.; Mikic, K.; Prezelj, A.; Stegnar, M.; Kikelj, D. Novel pyrazinone and pyridinone thrombin inhibitors incorporating weakly basic heterobicyclic P(1)-arginine mimetics. Eur. J. Med. Chem., 2005, 40(8), 782-791.
[http://dx.doi.org/10.1016/j.ejmech.2005.03.007] [PMID: 15890436]
[119]
Kranjc, A.; Peterlin-Masic, L.; Ilas, J.; Prezelj, A.; Stegnar, M.; Kikelj, D. Novel thrombin inhibitors incorporating weakly basic heterobicyclic P1-arginine mimetics: Optimization via modification of P1 and P3 moieties. Bioorg. Med. Chem. Lett., 2004, 14(12), 3251-3256.
[http://dx.doi.org/10.1016/j.bmcl.2004.03.085] [PMID: 15149685]
[120]
Hanessian, S.; Simard, D.; Bayrakdarian, M.; Therrien, E.; Nilsson, I.; Fjellström, O. Design, synthesis, and thrombin-inhibitory activity of pyridin-2-ones as P2/P3 core motifs. Bioorg. Med. Chem. Lett., 2008, 18(6), 1972-1976.
[http://dx.doi.org/10.1016/j.bmcl.2008.01.122] [PMID: 18289852]
[121]
Hanessian, S.; Therrien, E.; Zhang, J.; Otterlo, Wv.; Xue, Y.; Gustafsson, D.; Nilsson, I.; Fjellström, O. From natural products to achiral drug prototypes: Potent thrombin inhibitors based on P2/P3 dihydropyrid-2-one core motifs. Bioorg. Med. Chem. Lett., 2009, 19(18), 5429-5432.
[http://dx.doi.org/10.1016/j.bmcl.2009.07.107] [PMID: 19674897]
[122]
Isaacs, R.C.A.; Newton, C.L.; Cutrona, K.J.; Mercer, S.P.; Dorsey, B.D.; McDonough, C.M.; Cook, J.J.; Krueger, J.A.; Lewis, S.D.; Lucas, B.J.; Lyle, E.A.; Lynch, J.J.; Miller-Stein, C.; Michener, M.T.; Wallace, A.A.; White, R.B.; Wong, B.K. P3 optimization of functional potency, in vivo efficacy and oral bioavailability in 3-aminopyrazinone thrombin inhibitors bearing non-charged groups at the P1 position. Bioorg. Med. Chem. Lett., 2011, 21(5), 1532-1535.
[http://dx.doi.org/10.1016/j.bmcl.2010.12.108] [PMID: 21295466]
[123]
Lu, T.; Markotan, T.; Ballentine, S.K.; Giardino, E.C.; Spurlino, J.; Crysler, C.S.; Brown, K.; Maryanoff, B.E.; Tomczuk, B.E.; Damiano, B.P.; Shukla, U.; End, D.; Andrade-Gordon, P.; Bone, R.F.; Player, M.R. Discovery and clinical evaluation of 1-N-[2-(amidinoaminooxy)ethyl]aminocarbonylmethyl-6-methyl-3-[2,2-difluoro-2-phenylethylamino]pyrazinone (RWJ-671818), a thrombin inhibitor with an oxyguanidine P1 motif. J. Med. Chem., 2010, 53(4), 1843-1856.
[http://dx.doi.org/10.1021/jm901802n] [PMID: 20102150]
[124]
Lu, T.; Soll, R.M.; Illig, C.R.; Bone, R.; Murphy, L.; Spurlino, J.; Salemme, F.R.; Tomczuk, B.E. Structure-activity and crystallographic analysis of a new class of non-amide-based thrombin inhibitor. Bioorg. Med. Chem. Lett., 2000, 10(1), 79-82.
[http://dx.doi.org/10.1016/S0960-894X(99)00617-4] [PMID: 10636249]
[125]
Tomczuk, B.; Lu, T.; Soll, R.M.; Fedde, C.; Wang, A.; Murphy, L.; Crysler, C.; Dasgupta, M.; Eisennagel, S.; Spurlino, J.; Bone, R. Oxyguanidines: Application to non-peptidic phenyl-based thrombin inhibitors. Bioorg. Med. Chem. Lett., 2003, 13(8), 1495-1498.
[http://dx.doi.org/10.1016/S0960-894X(03)00125-2] [PMID: 12668020]
[126]
Lu, T.; Markotan, T.; Coppo, F.; Tomczuk, B.; Crysler, C.; Eisennagel, S.; Spurlino, J.; Gremminger, L.; Soll, R.M.; Giardino, E.C.; Bone, R. 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(14), 3727-3731.
[http://dx.doi.org/10.1016/j.bmcl.2004.05.002] [PMID: 15203151]
[127]
Lee, L.; Kreutter, K.D.; Pan, W.; Crysler, C.; Spurlino, J.; Player, M.R.; Tomczuk, B.; Lu, T. 2-(2-Chloro-6-fluorophenyl)acetamides as potent thrombin inhibitors. Bioorg. Med. Chem. Lett., 2007, 17(22), 6266-6269.
[http://dx.doi.org/10.1016/j.bmcl.2007.09.013] [PMID: 17889527]
[128]
Kreutter, K.D.; Lu, T.; Lee, L.; Giardino, E.C.; Patel, S.; Huang, H.; Xu, G.; Fitzgerald, M.; Haertlein, B.J.; Mohan, V.; Crysler, C.; Eisennagel, S.; Dasgupta, M.; McMillan, M.; Spurlino, J.C.; Huebert, N.D.; Maryanoff, B.E.; Tomczuk, B.E.; Damiano, B.P.; Player, M.R. Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif. Bioorg. Med. Chem. Lett., 2008, 18(9), 2865-2870.
[http://dx.doi.org/10.1016/j.bmcl.2008.03.087] [PMID: 18420408]
[129]
Hanessian, S.; Therrien, E.; van Otterlo, W.A.L.; Bayrakdarian, M.; Nilsson, I.; Fjellström, O.; Xue, Y. Phenolic P2/P3 core motif as thrombin inhibitors--design, synthesis, and X-ray co-crystal structure. Bioorg. Med. Chem. Lett., 2006, 16(4), 1032-1036.
[http://dx.doi.org/10.1016/j.bmcl.2005.10.082] [PMID: 16290930]
[130]
Siles, R.; Kawasaki, Y.; Ross, P.; Freire, E. Synthesis and biochemical evaluation of triazole/tetrazole-containing sulfonamides against thrombin and related serine proteases. Bioorg. Med. Chem. Lett., 2011, 21(18), 5305-5309.
[http://dx.doi.org/10.1016/j.bmcl.2011.07.023] [PMID: 21807511]
[131]
de Candia, M.; Fiorella, F.; Lopopolo, G.; Carotti, A.; Romano, M.R.; Lograno, M.D.; Martel, S.; Carrupt, P.A.; Belviso, B.D.; Caliandro, R.; Altomare, C. Synthesis and biological evaluation of direct thrombin inhibitors bearing 4-(piperidin-1-yl)pyridine at the P1 position with potent anticoagulant activity. J. Med. Chem., 2013, 56(21), 8696-8711.
[http://dx.doi.org/10.1021/jm401169a] [PMID: 24102612]
[132]
Blomberg, D.; Fex, T.; Xue, Y.; Brickmann, K.; Kihlberg, J. Design, synthesis and biological evaluation of thrombin inhibitors based on a pyridine scaffold. Org. Biomol. Chem., 2007, 5(16), 2599-2605.
[http://dx.doi.org/10.1039/b705344d] [PMID: 18019535]
[133]
Deng, J.Z.; McMasters, D.R.; Rabbat, P.M.A.; Williams, P.D.; Coburn, C.A.; Yan, Y.; Kuo, L.C.; Lewis, S.D.; Lucas, B.J.; Krueger, J.A.; Strulovici, B.; Vacca, J.P.; Lyle, T.A.; Burgey, C.S. Development of an oxazolopyridine series of dual thrombin/factor Xa inhibitors via structure-guided lead optimization. Bioorg. Med. Chem. Lett., 2005, 15(20), 4411-4416.
[http://dx.doi.org/10.1016/j.bmcl.2005.07.022] [PMID: 16137886]
[134]
Hauel, N.H.; Nar, H.; Priepke, H.; Ries, U.; Stassen, J.M.; Wienen, W. Structure-based design of novel potent nonpeptide thrombin inhibitors. J. Med. Chem., 2002, 45(9), 1757-1766.
[http://dx.doi.org/10.1021/jm0109513] [PMID: 11960487]
[135]
Ries, U.J.; Priepke, H.W.M.; Hauel, N.H.; Haaksma, E.E.J.; Stassen, J.M.; Wienen, W.; Nar, H. Heterocyclic thrombin inhibitors. Part 1: Design and synthesis of amidino-phenoxy quinoline derivatives. Bioorg. Med. Chem. Lett., 2003, 13(14), 2291-2295.
[http://dx.doi.org/10.1016/S0960-894X(03)00442-6] [PMID: 12824020]
[136]
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(14), 2297-2302.
[http://dx.doi.org/10.1016/S0960-894X(03)00443-8] [PMID: 12824021]
[137]
Sall, D.J.; Bailey, D.L.; Bastian, J.A.; Buben, J.A.; Chirgadze, N.Y.; Clemens-Smith, A.C.; Denney, M.L.; Fisher, M.J.; Giera, D.D.; Gifford-Moore, D.S.; Harper, R.W.; Johnson, L.M.; Klimkowski, V.J.; Kohn, T.J.; Lin, H.S.; McCowan, J.R.; Palkowitz, A.D.; Richett, M.E.; Smith, G.F.; Snyder, D.W.; Takeuchi, K.; Toth, J.E.; Zhang, M. Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors. 5. Potency, efficacy, and pharmacokinetic properties of modified C-3 side chain derivatives. J. Med. Chem., 2000, 43(4), 649-663.
[http://dx.doi.org/10.1021/jm9903388] [PMID: 10691691]
[138]
Sidhu, P.S.; Liang, A.; Mehta, A.Y.; Abdel Aziz, M.H.; Zhou, Q.; Desai, U.R. Rational design of potent, small, synthetic allosteric inhibitors of thrombin. J. Med. Chem., 2011, 54(15), 5522-5531.
[http://dx.doi.org/10.1021/jm2005767] [PMID: 21714536]
[139]
Abdel Aziz, M.H.; Sidhu, P.S.; Liang, A.; Kim, J.Y.; Mosier, P.D.; Zhou, Q.; Farrell, D.H.; Desai, U.R. Designing allosteric regulators of thrombin. Monosulfated benzofuran dimers selectively interact with Arg173 of exosite 2 to induce inhibition. J. Med. Chem., 2012, 55(15), 6888-6897.
[http://dx.doi.org/10.1021/jm300670q] [PMID: 22788964]
[140]
Sidhu, P.S.; Abdel Aziz, M.H.; Sarkar, A.; Mehta, A.Y.; Zhou, Q.; Desai, U.R. Designing allosteric regulators of thrombin. Exosite 2 features multiple subsites that can be targeted by sulfated small molecules for inducing inhibition. J. Med. Chem., 2013, 56(12), 5059-5070.
[http://dx.doi.org/10.1021/jm400369q] [PMID: 23718540]
[141]
Sidhu, P.S.; Zhou, Q.; Desai, U.R. A simple, general approach of allosteric coagulation enzyme inhibition through monosulfated hydrophobic scaffolds. Bioorg. Med. Chem. Lett., 2014, 24(24), 5716-5720.
[http://dx.doi.org/10.1016/j.bmcl.2014.10.059] [PMID: 25453807]
[142]
Afosah, D.K.; Verespy, S., III; Al-Horani, R.A.; Boothello, R.S.; Karuturi, R.; Desai, U.R. A small group of sulfated benzofurans induces steady-state submaximal inhibition of thrombin. Bioorg. Med. Chem. Lett., 2018, 28(6), 1101-1105.
[http://dx.doi.org/10.1016/j.bmcl.2018.01.069] [PMID: 29459207]
[143]
Nilsson, J.W.; Kvarnström, I.; Musil, D.; Nilsson, I.; Samulesson, B. Synthesis and SAR of thrombin inhibitors incorporating a novel 4-amino-morpholinone sscaffold: Analysis of X-ray crystal structure of enzyme inhibitor complex. J. Med. Chem., 2003, 46(19), 3985-4001.
[http://dx.doi.org/10.1021/jm0307990] [PMID: 12954052]
[144]
Stefanic Anderluh, P.; Anderluh, M.; Ilas, J.; Mravljak, J.; Sollner Dolenc, M.; 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(9), 3110-3113.
[http://dx.doi.org/10.1021/jm048984g] [PMID: 15857114]
[145]
Ilas, J.; Tomasić, T.; Kikelj, D. Novel potent and selective thrombin inhibitors based on a central 1,4-benzoxazin-3(4H)-one scaffold. J. Med. Chem., 2008, 51(9), 2863-2867.
[http://dx.doi.org/10.1021/jm701622y] [PMID: 18412326]
[146]
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(18), 5617-5629.
[http://dx.doi.org/10.1021/jm8003448] [PMID: 18729445]
[147]
Ilić, M.; Kontogiorgis, C.; Hadjipavlou-Litina, D.; Ilaš, J.; Kikelj, D. Thrombin inhibitors with lipid peroxidation and lipoxygenase inhibitory activities. Bioorg. Med. Chem. Lett., 2011, 21(16), 4705-4709.
[http://dx.doi.org/10.1016/j.bmcl.2011.06.089] [PMID: 21757348]
[148]
Ilić, M.; Kikelj, D.; Ilaš, J. Fluorinated dual antithrombotic compounds based on 1,4-benzoxazine scaffold. Eur. J. Med. Chem., 2012, 50, 255-263.
[http://dx.doi.org/10.1016/j.ejmech.2012.01.059] [PMID: 22365562]
[149]
Baburajeev, C.P.; Mohan, C.D.; Pandey, V.; Rangappa, S.; Shivalingegowda, N.; Kalash, L.; Devaraja, S.; Bender, A.; Lobie, P.E.; Rangappa, K.S.; Basappa Synthesis of CC, CN coupled novel substituted dibutyl benzothiazepinone derivatives and evaluation of their thrombin inhibitory activity. Bioorg. Chem., 2019, 87, 142-154.
[http://dx.doi.org/10.1016/j.bioorg.2019.03.004] [PMID: 30884308]
[150]
Carroll, A.R.; Pierens, G.K.; Fechner, G.; De Almeida Leone, P.; Ngo, A.; Simpson, M.; Hyde, E.; Hooper, J.N.; Boström, S.L.; Musil, D.; Quinn, R.J. Dysinosin A: A novel inhibitor of Factor VIIa and thrombin from a new genus and species of Australian sponge of the family Dysideidae. J. Am. Chem. Soc., 2002, 124(45), 13340-13341.
[http://dx.doi.org/10.1021/ja020814a] [PMID: 12418859]
[151]
Carroll, A.R.; Buchanan, M.S.; Edser, A.; Hyde, E.; Simpson, M.; Quinn, R.J. Dysinosins B-D, inhibitors of factor VIIa and thrombin from the Australian sponge Lamellodysidea chlorea. J. Nat. Prod., 2004, 67(8), 1291-1294.
[http://dx.doi.org/10.1021/np049968p] [PMID: 15332844]
[152]
Zhu, Y.; Zhang, P.; Yu, H.; Li, J.; Wang, M.W.; Zhao, W. Anti-Helicobacter pylori and thrombin inhibitory components from Chinese dragon’s blood, Dracaena cochinchinensis. J. Nat. Prod., 2007, 70(10), 1570-1577.
[http://dx.doi.org/10.1021/np070260v] [PMID: 17883259]
[153]
Shi, D.; Li, X.; Li, J.; Guo, S.; Su, H.; Fan, X. Antithrombotic effects of bromophenol, an alga-derived thrombin inhibitor. Chin. J. Oceanol. Limnol., 2010, 28, 96-98.
[http://dx.doi.org/10.1007/s00343-010-9213-0]
[154]
Liu, L.; Ma, H.; Yang, N.; Tang, Y.; Guo, J.; Tao, W.; Duan, J. A series of natural flavonoids as thrombin inhibitors: Structure-activity relationships. Thromb. Res., 2010, 126(5), e365-e378.
[http://dx.doi.org/10.1016/j.thromres.2010.08.006] [PMID: 20828797]
[155]
Anas, A.R.J.; Kisugi, T.; Umezawa, T.; Matsuda, F.; Campitelli, M.R.; Quinn, R.J.; Okino, T. Thrombin inhibitors from the freshwater cyanobacterium Anabaena compacta. J. Nat. Prod., 2012, 75(9), 1546-1552.
[http://dx.doi.org/10.1021/np300282a] [PMID: 22950366]
[156]
de Andrade Moura, L.; Marqui de Almeida, A.C.; Domingos, T.F.S.; Ortiz-Ramirez, F.; Cavalcanti, D.N.V.; Teixeira, V.L.; Fuly, A.L. Antiplatelet and anticoagulant effects of diterpenes isolated from the marine alga, Dictyota menstrualis. Mar. Drugs, 2014, 12(5), 2471-2484.
[http://dx.doi.org/10.3390/md12052471] [PMID: 24796305]
[157]
Lu, J.; Song, H.P.; Li, P.; Zhou, P.; Dong, X.; Chen, J. Screening of direct thrombin inhibitors from Radix Salviae Miltiorrhizae by a peak fractionation approach. J. Pharmaceut. Biomed., 2015, 109, 85-90.
[http://dx.doi.org/10.1016/j.jpba.2015.02.020] [PMID: 25819728]
[158]
Rodrigues, C.F.B.; Gaeta, H.H.; Belchor, M.N.; Ferreira, M.J.P.; Pinho, M.V.T.; Toyama, Dde.O.; Toyama, M.H. Evaluation of potential thrombin inhibitors from the white mangrove (Laguncularia racemosa (L.) C.F. Gaertn.). Mar. Drugs, 2015, 13(7), 4505-4519.
[http://dx.doi.org/10.3390/md13074505] [PMID: 26197325]
[159]
Gogoi, D.; Pal, A.; Chattopadhyay, P.; Paul, S.; Deka, R.C.; Mukherjee, A.K. First report of plant-derived β-sitosterol with antithrombotic, in vivoanticoagulant, and thrombus-preventing ativities in a mouse model. J. Nat. Prod., 2018, 81(11), 2521-2530.
[http://dx.doi.org/10.1021/acs.jnatprod.8b00574] [PMID: 30406661]
[160]
Yu, X.; Wei, L.H.; Zhang, J.K.; Chen, T.R.; Jin, Q.; Wang, Y.N.; Zhang, S.J.; Dou, T.Y.; Cao, Y.F.; Guo, W.Z.; Ge, G.B.; Yang, L. Anthraquinones from Cassiae semen as thrombin inhibitors: in vitro and in silico studies. Phytochemistry, 2019, 165, 112025.
[http://dx.doi.org/10.1016/j.phytochem.2019.04.018] [PMID: 31207449]
[161]
Wei, L.H.; Chen, T.R.; Fang, H.B.; Jin, Q.; Zhang, S.J.; Hou, J.; Yu, Y.; Dou, T.Y.; Cao, Y.F.; Guo, W.Z.; Ge, G.B. Natural constituents of St. John’s Wort inhibit the proteolytic activity of human thrombin. Int. J. Biol. Macromol., 2019, 134, 622-630.
[http://dx.doi.org/10.1016/j.ijbiomac.2019.04.181] [PMID: 31047931]
[162]
Chen, T.R.; Wei, L.H.; Guan, X.Q.; Huang, C.; Liu, Z.Y.; Wang, F.J.; Hou, J.; Jin, Q.; Liu, Y.F.; Wen, P.H.; Zhang, S.J.; Ge, G.B.; Guo, W.Z. Biflavones from Ginkgo biloba as inhibitors of human thrombin. Bioorg. Chem., 2019, 92, 103199.
[http://dx.doi.org/10.1016/j.bioorg.2019.103199] [PMID: 31446241]
[163]
Wen, F.; Chen, T.; Yin, H.; Lin, J.; Zhang, H. In vitro effects on thrombin of paris saponins and in vivo hemostatic activity evaluation of Paris fargesii var. Brevipetala. Molecules, 2019, 24, 1420.
[http://dx.doi.org/10.3390/molecules24071420]
[164]
Wang, L.; Ma, Q. Clinical benefits and pharmacology of scutellarin: A comprehensive review. Pharmacol. Ther., 2018, 190, 105-127.
[http://dx.doi.org/10.1016/j.pharmthera.2018.05.006] [PMID: 29742480]
[165]
Qing, G.E.; Zhou, Z.; Zhi, X.; Ma, L.; Chen, X. Pharmacokinetics and absolute bioavailability of breviscapine in beagle dogs. Carol. J. Pharm., 2003, 34, 618-620.
[166]
Xing, J.F.; You, H.S.; Dong, Y.L.; Lu, J.; Chen, S.Y.; Zhu, H.F.; Dong, Q.; Wang, M.Y.; Dong, W.H. Metabolic and pharmacokinetic studies of scutellarin in rat plasma, urine, and feces. Acta Pharmacol. Sin., 2011, 32(5), 655-663.
[http://dx.doi.org/10.1038/aps.2011.11] [PMID: 21516133]
[167]
Li, N.G.; Song, S.L.; Shen, M.Z.; Tang, Y.P.; Shi, Z.H.; Tang, H.; Shi, Q.P.; Fu, Y.F.; Duan, J.A. Mannich bases of scutellarein as thrombin-inhibitors: Design, synthesis, biological activity and solubility. Bioorg. Med. Chem., 2012, 20(24), 6919-6923.
[http://dx.doi.org/10.1016/j.bmc.2012.10.015] [PMID: 23131413]
[168]
Li, N.G.; Shen, M.Z.; Wang, Z.J.; Tang, Y.P.; Shi, Z.H.; Fu, Y.F.; Shi, Q.P.; Tang, H.; Duan, J.A. Design, synthesis and biological evaluation of glucose-containing scutellarein derivatives as neuroprotective agents based on metabolic mechanism of scutellarin in vivo. Bioorg. Med. Chem. Lett., 2013, 23(1), 102-106.
[http://dx.doi.org/10.1016/j.bmcl.2012.11.002] [PMID: 23177255]
[169]
Shi, Z.H.; Li, N.G.; Shi, Q.P.; Zhang, W.; Dong, Z.X.; Tang, Y.P.; Zhang, P.X.; Gu, T.; Wu, W.Y.; Fang, F.; Xin-Xue; Li, H.M.; Yang, J.P.; Duan, J.A. Synthesis of scutellarein derivatives to increase biological activity and water solubility. Bioorg. Med. Chem., 2015, 23(21), 6875-6884.
[http://dx.doi.org/10.1016/j.bmc.2015.09.047] [PMID: 26455656]
[170]
Shi, Z.H.; Li, N.G.; Wang, Z.J.; Tang, Y.P.; Dong, Z.X.; Zhang, W.; Zhang, P.X.; Gu, T.; Wu, W.Y.; Yang, J.P.; Duan, J.A. Synthesis and biological evaluation of methylated scutellarein analogs based on metabolic mechanism of scutellarin in vivo. Eur. J. Med. Chem., 2015, 106, 95-105.
[http://dx.doi.org/10.1016/j.ejmech.2015.10.039] [PMID: 26523667]
[171]
Frédérick, R.; Robert, S.; Charlier, C.; de Ruyck, J.; Wouters, J.; Pirotte, B.; Masereel, B.; Pochet, L. 3,6-disubstituted coumarins as mechanism-based inhibitors of thrombin and factor Xa. J. Med. Chem., 2005, 48(24), 7592-7603.
[http://dx.doi.org/10.1021/jm050448g] [PMID: 16302799]
[172]
Frédérick, R.; Charlier, C.; Robert, S.; Wouters, J.; Masereel, B.; Pochet, L. Investigation of mechanism-based thrombin inhibitors: Implications of a highly conserved water molecule for the binding of coumarins within the S pocket. Bioorg. Med. Chem. Lett., 2006, 16(7), 2017-2021.
[http://dx.doi.org/10.1016/j.bmcl.2005.12.070] [PMID: 16413781]
[173]
Frédérick, R.; Robert, S.; Charlier, C.; Wouters, J.; Masereel, B.; Pochet, L. Mechanism-based thrombin inhibitors: Design, synthesis, and molecular docking of a new selective 2-oxo-2H-1-benzopyran derivative. J. Med. Chem., 2007, 50(15), 3645-3650.
[http://dx.doi.org/10.1021/jm061368v] [PMID: 17580844]
[174]
Verespy, S., III; Mehta, A.Y.; Afosah, D.; Al-Horani, R.A.; Desai, U.R. Allosteric partial inhibition of monomeric proteases. Sulfated coumarins induce regulation, not just inhibition, of thrombin. Sci. Rep., 2016, 6, 24043.
[http://dx.doi.org/10.1038/srep24043] [PMID: 27053426]
[175]
Žula, A.; Będziak, I.; Kikelj, D.; Ilaš, J. Synthesis and evaluation of spumigin analogues library with thrombin inhibitory activity. Mar. Drugs, 2018, 16(11), 413.
[http://dx.doi.org/10.3390/md16110413] [PMID: 30373260]
[176]
Lu, S.; Wang, J.; Sheng, R.; Fang, Y.; Guo, R. Novel bioactive polyketides isolated from marine actinomycetes: An update review from 2013 to 2019. Chem. Biodivers., 2020, 17(12), e2000562.
[http://dx.doi.org/10.1002/cbdv.202000562] [PMID: 33206470]
[177]
Wang, J.; Su, S.; Zhang, S.; Zhai, S.; Sheng, R.; Wu, W.; Guo, R. Structure-activity relationship and synthetic methodologies of α-santonin derivatives with diverse bioactivities: A mini-review. Eur. J. Med. Chem., 2019, 175, 215-233.
[http://dx.doi.org/10.1016/j.ejmech.2019.04.066] [PMID: 31082765]
[178]
Guo, R.; Guo, C.; He, D.; Zhao, D.; Shen, Y. Two new C19-diterpenoid alkaloids with anti-inflammatory activity from Aconitum iochanicum. Chin. J. Chem., 2017, 35, 1644-1647.
[http://dx.doi.org/10.1002/cjoc.201700401]

Rights & Permissions Print Cite
Article Metrics
74
3
Wayfinder Image
Open Access Journals Promotions
World Antimicrobial Awareness Week
© 2024 Bentham Science Publishers | Privacy Policy