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
[http://dx.doi.org/10.1161/CIR.0000000000000558] [PMID: 29386200]
[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]
[http://dx.doi.org/10.1016/j.ijcha.2014.10.002] [PMID: 28785622]
[http://dx.doi.org/10.1080/10590500802494538] [PMID: 19034792]
[http://dx.doi.org/10.1161/CIRCRESAHA.115.306841] [PMID: 27126645]
[http://dx.doi.org/10.1093/eurheartj/ehs215] [PMID: 22922416]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.108.833665] [PMID: 19451347]
[http://dx.doi.org/10.1056/NEJMc080056] [PMID: 18403776]
[http://dx.doi.org/10.1152/physrev.00028.2003] [PMID: 15044683]
[http://dx.doi.org/10.1038/nature06797] [PMID: 18288180]
[http://dx.doi.org/10.1016/j.fct.2018.01.019] [PMID: 29353071]
[http://dx.doi.org/10.1111/j.1476-5381.2011.01578.x] [PMID: 21740405]
[http://dx.doi.org/10.1161/ATVBAHA.115.303397] [PMID: 25792448]
[http://dx.doi.org/10.1016/S0140-6736(13)62343-0] [PMID: 24315724]
[http://dx.doi.org/10.1172/JCI116206] [PMID: 8380817]
[http://dx.doi.org/10.1016/j.neurobiolaging.2003.07.007] [PMID: 15165703]
[http://dx.doi.org/10.1371/journal.pgen.1007948] [PMID: 30870413]
[http://dx.doi.org/10.1016/j.beha.2004.02.002] [PMID: 15171961]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.110.004424] [PMID: 21464059]
[http://dx.doi.org/10.1345/aph.1D066] [PMID: 14742803]
[http://dx.doi.org/10.1111/j.1365-2125.2011.03916.x] [PMID: 21241354]
[http://dx.doi.org/10.1111/j.1365-2044.2005.04192.x] [PMID: 15918828]
[PMID: 12557410]
[http://dx.doi.org/10.1016/0968-0896(95)00104-O] [PMID: 7582987]
[http://dx.doi.org/10.2174/0929867043364540] [PMID: 15379714]
[http://dx.doi.org/10.1002/anie.201004575] [PMID: 21538731]
[http://dx.doi.org/10.1517/13543776.2014.845169] [PMID: 24099091]
[http://dx.doi.org/10.3390/molecules200611046] [PMID: 26083038]
[http://dx.doi.org/10.1016/j.ejmech.2018.01.067] [PMID: 29407959]
[http://dx.doi.org/10.1172/JCI6042] [PMID: 10079109]
[http://dx.doi.org/10.1002/iub.441] [PMID: 21438116]
[http://dx.doi.org/10.1038/35025229] [PMID: 11001069]
[http://dx.doi.org/10.1038/353674a0] [PMID: 1717851]
[http://dx.doi.org/10.1080/09537104.2018.1475632] [PMID: 29799302]
[http://dx.doi.org/10.1016/j.jcin.2011.03.001] [PMID: 21511220]
[http://dx.doi.org/10.1083/jcb.101.3.880] [PMID: 2411738]
[http://dx.doi.org/10.1038/35393] [PMID: 9468137]
[http://dx.doi.org/10.1093/eurheartj/ehp504] [PMID: 19948715]
[http://dx.doi.org/10.1016/j.drudis.2014.04.018] [PMID: 24794465]
[http://dx.doi.org/10.1517/13543776.2016.1154045] [PMID: 26881476]
[http://dx.doi.org/10.1016/j.drudis.2014.05.018] [PMID: 24886766]
[http://dx.doi.org/10.1002/med.20183] [PMID: 19967784]
[http://dx.doi.org/10.1002/med.21503] [PMID: 29727017]
[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]
[http://dx.doi.org/10.1111/j.1538-7836.2007.02491.x] [PMID: 17635713]
[http://dx.doi.org/10.1016/j.thromres.2018.07.008] [PMID: 30005274]
[http://dx.doi.org/10.1021/acs.jmedchem.5b01171] [PMID: 26575094]
[http://dx.doi.org/10.1016/S0960-894X(03)00233-6] [PMID: 12729646]
[http://dx.doi.org/10.1111/jth.12217] [PMID: 23809130]
[http://dx.doi.org/10.1016/S0021-9258(18)91069-0] [PMID: 6715366]
[http://dx.doi.org/10.1074/jbc.M312430200] [PMID: 14722067]
[http://dx.doi.org/10.1002/j.1460-2075.1989.tb08511.x] [PMID: 2583108]
[http://dx.doi.org/10.1021/bi00435a001] [PMID: 2665806]
[http://dx.doi.org/10.1007/s000180050091] [PMID: 9368668]
[http://dx.doi.org/10.1007/978-0-387-09637-7_1]
[http://dx.doi.org/10.1002/med.20016] [PMID: 15389730]
[http://dx.doi.org/10.1016/j.tips.2012.03.004] [PMID: 22503439]
[http://dx.doi.org/10.1021/ci200185q] [PMID: 21761917]
[http://dx.doi.org/10.1182/blood-2012-11-468207] [PMID: 23476049]
[http://dx.doi.org/10.1371/journal.pone.0019969] [PMID: 21603576]
[http://dx.doi.org/10.1073/pnas.0710894105] [PMID: 18250335]
[http://dx.doi.org/10.1182/blood-2002-03-0843] [PMID: 12351390]
[http://dx.doi.org/10.1021/bi980717n] [PMID: 9753436]
[http://dx.doi.org/10.1002/bab.1632] [PMID: 29230873]
[http://dx.doi.org/10.1006/jmbi.1996.0264] [PMID: 8642605]
[http://dx.doi.org/10.1021/bi00250a007] [PMID: 7947766]
[http://dx.doi.org/10.1016/j.thromres.2018.03.013] [PMID: 29573721]
[http://dx.doi.org/10.1016/j.jmb.2013.11.027] [PMID: 24316004]
[http://dx.doi.org/10.1038/s41467-021-21754-8] [PMID: 33727531]
[http://dx.doi.org/10.1515/BC.2008.113] [PMID: 18979627]
[http://dx.doi.org/10.1039/C8CP07293K] [PMID: 30724273]
[http://dx.doi.org/10.1016/S0968-0896(00)00147-4] [PMID: 11026541]
[http://dx.doi.org/10.1016/S0968-0896(99)00069-3] [PMID: 10465405]
[http://dx.doi.org/10.1021/jm990557t] [PMID: 10794688]
[http://dx.doi.org/10.1016/S0968-0896(01)00426-6] [PMID: 11886818]
[http://dx.doi.org/10.1021/jm021065a] [PMID: 12646027]
[http://dx.doi.org/10.1016/S0960-894X(00)00579-5] [PMID: 11133089]
[http://dx.doi.org/10.1016/S0960-894X(02)00093-8] [PMID: 11909707]
[http://dx.doi.org/10.1021/jm030025j] [PMID: 12904065]
[http://dx.doi.org/10.1016/S0960-894X(01)00661-8] [PMID: 11720865]
[http://dx.doi.org/10.1021/jm011133d] [PMID: 12036353]
[http://dx.doi.org/10.1016/S0960-894X(02)00010-0] [PMID: 11858993]
[http://dx.doi.org/10.1016/S0960-894X(01)00664-3] [PMID: 11738569]
[http://dx.doi.org/10.1016/S0960-894X(03)00030-1] [PMID: 12617892]
[http://dx.doi.org/10.1016/j.ejmech.2003.12.006] [PMID: 15051174]
[http://dx.doi.org/10.1016/j.bmcl.2014.01.002] [PMID: 24461292]
[http://dx.doi.org/10.1016/j.bmcl.2004.06.030] [PMID: 15261262]
[http://dx.doi.org/10.1021/jm049423s] [PMID: 15801822]
[http://dx.doi.org/10.1021/jm0303857] [PMID: 15771442]
[http://dx.doi.org/10.1016/j.bmc.2006.06.040] [PMID: 16870455]
[http://dx.doi.org/10.1016/j.bmcl.2006.02.040] [PMID: 16517159]
[http://dx.doi.org/10.1016/j.bmcl.2006.01.046] [PMID: 16460939]
[http://dx.doi.org/10.1016/j.bmcl.2009.04.056] [PMID: 19447619]
[http://dx.doi.org/10.1371/journal.pone.0034354] [PMID: 22457833]
[http://dx.doi.org/10.1021/acsmedchemlett.5b00047] [PMID: 26005532]
[http://dx.doi.org/10.1039/C5MD00479A]
[http://dx.doi.org/10.1016/S0960-894X(00)00283-3] [PMID: 10915052]
[http://dx.doi.org/10.1016/S0968-0896(01)00202-4] [PMID: 11557360]
[PMID: 15497744]
[http://dx.doi.org/10.1016/j.bmcl.2003.12.083] [PMID: 15006404]
[PMID: 15544050]
[http://dx.doi.org/10.1021/jm4005835] [PMID: 24175584]
[http://dx.doi.org/10.1016/S0960-894X(00)00170-0] [PMID: 10843219]
[http://dx.doi.org/10.1016/S0960-894X(02)00946-0] [PMID: 12482415]
[http://dx.doi.org/10.1016/S0960-894X(03)00732-7] [PMID: 14505652]
[http://dx.doi.org/10.1016/S0960-894X(03)00017-9] [PMID: 12617893]
[http://dx.doi.org/10.1021/jm020311f] [PMID: 12570369]
[http://dx.doi.org/10.1016/S0960-894X(03)00099-4] [PMID: 12657281]
[http://dx.doi.org/10.1021/jm030303e] [PMID: 15163182]
[http://dx.doi.org/10.1016/S0960-894X(03)00717-0] [PMID: 12951087]
[http://dx.doi.org/10.1016/j.ejmech.2005.03.007] [PMID: 15890436]
[http://dx.doi.org/10.1016/j.bmcl.2004.03.085] [PMID: 15149685]
[http://dx.doi.org/10.1016/j.bmcl.2008.01.122] [PMID: 18289852]
[http://dx.doi.org/10.1016/j.bmcl.2009.07.107] [PMID: 19674897]
[http://dx.doi.org/10.1016/j.bmcl.2010.12.108] [PMID: 21295466]
[http://dx.doi.org/10.1021/jm901802n] [PMID: 20102150]
[http://dx.doi.org/10.1016/S0960-894X(99)00617-4] [PMID: 10636249]
[http://dx.doi.org/10.1016/S0960-894X(03)00125-2] [PMID: 12668020]
[http://dx.doi.org/10.1016/j.bmcl.2004.05.002] [PMID: 15203151]
[http://dx.doi.org/10.1016/j.bmcl.2007.09.013] [PMID: 17889527]
[http://dx.doi.org/10.1016/j.bmcl.2008.03.087] [PMID: 18420408]
[http://dx.doi.org/10.1016/j.bmcl.2005.10.082] [PMID: 16290930]
[http://dx.doi.org/10.1016/j.bmcl.2011.07.023] [PMID: 21807511]
[http://dx.doi.org/10.1021/jm401169a] [PMID: 24102612]
[http://dx.doi.org/10.1039/b705344d] [PMID: 18019535]
[http://dx.doi.org/10.1016/j.bmcl.2005.07.022] [PMID: 16137886]
[http://dx.doi.org/10.1021/jm0109513] [PMID: 11960487]
[http://dx.doi.org/10.1016/S0960-894X(03)00442-6] [PMID: 12824020]
[http://dx.doi.org/10.1016/S0960-894X(03)00443-8] [PMID: 12824021]
[http://dx.doi.org/10.1021/jm9903388] [PMID: 10691691]
[http://dx.doi.org/10.1021/jm2005767] [PMID: 21714536]
[http://dx.doi.org/10.1021/jm300670q] [PMID: 22788964]
[http://dx.doi.org/10.1021/jm400369q] [PMID: 23718540]
[http://dx.doi.org/10.1016/j.bmcl.2014.10.059] [PMID: 25453807]
[http://dx.doi.org/10.1016/j.bmcl.2018.01.069] [PMID: 29459207]
[http://dx.doi.org/10.1021/jm0307990] [PMID: 12954052]
[http://dx.doi.org/10.1021/jm048984g] [PMID: 15857114]
[http://dx.doi.org/10.1021/jm701622y] [PMID: 18412326]
[http://dx.doi.org/10.1021/jm8003448] [PMID: 18729445]
[http://dx.doi.org/10.1016/j.bmcl.2011.06.089] [PMID: 21757348]
[http://dx.doi.org/10.1016/j.ejmech.2012.01.059] [PMID: 22365562]
[http://dx.doi.org/10.1016/j.bioorg.2019.03.004] [PMID: 30884308]
[http://dx.doi.org/10.1021/ja020814a] [PMID: 12418859]
[http://dx.doi.org/10.1021/np049968p] [PMID: 15332844]
[http://dx.doi.org/10.1021/np070260v] [PMID: 17883259]
[http://dx.doi.org/10.1007/s00343-010-9213-0]
[http://dx.doi.org/10.1016/j.thromres.2010.08.006] [PMID: 20828797]
[http://dx.doi.org/10.1021/np300282a] [PMID: 22950366]
[http://dx.doi.org/10.3390/md12052471] [PMID: 24796305]
[http://dx.doi.org/10.1016/j.jpba.2015.02.020] [PMID: 25819728]
[http://dx.doi.org/10.3390/md13074505] [PMID: 26197325]
[http://dx.doi.org/10.1021/acs.jnatprod.8b00574] [PMID: 30406661]
[http://dx.doi.org/10.1016/j.phytochem.2019.04.018] [PMID: 31207449]
[http://dx.doi.org/10.1016/j.ijbiomac.2019.04.181] [PMID: 31047931]
[http://dx.doi.org/10.1016/j.bioorg.2019.103199] [PMID: 31446241]
[http://dx.doi.org/10.3390/molecules24071420]
[http://dx.doi.org/10.1016/j.pharmthera.2018.05.006] [PMID: 29742480]
[http://dx.doi.org/10.1038/aps.2011.11] [PMID: 21516133]
[http://dx.doi.org/10.1016/j.bmc.2012.10.015] [PMID: 23131413]
[http://dx.doi.org/10.1016/j.bmcl.2012.11.002] [PMID: 23177255]
[http://dx.doi.org/10.1016/j.bmc.2015.09.047] [PMID: 26455656]
[http://dx.doi.org/10.1016/j.ejmech.2015.10.039] [PMID: 26523667]
[http://dx.doi.org/10.1021/jm050448g] [PMID: 16302799]
[http://dx.doi.org/10.1016/j.bmcl.2005.12.070] [PMID: 16413781]
[http://dx.doi.org/10.1021/jm061368v] [PMID: 17580844]
[http://dx.doi.org/10.1038/srep24043] [PMID: 27053426]
[http://dx.doi.org/10.3390/md16110413] [PMID: 30373260]
[http://dx.doi.org/10.1002/cbdv.202000562] [PMID: 33206470]
[http://dx.doi.org/10.1016/j.ejmech.2019.04.066] [PMID: 31082765]
[http://dx.doi.org/10.1002/cjoc.201700401]