{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T04:38:17Z","timestamp":1792211897930,"version":"4.4.0"},"reference-count":108,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T00:00:00Z","timestamp":1676937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018542","name":"Natural Science Foundation of Sichuan Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100018542","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005891","name":"State Administration of Traditional Chinese Medicine of the People\u2019s Republic of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005891","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>As a pathological coagulation process, thrombus can lead to many serious diseases, including ischemic stroke, acute myocardial infarction (AMI), acute coronary syndrome (ACS), and deep venous thrombosis (DVT). And anticoagulant drugs are one of the most effective ways to prevent and treat these diseases. Although macromolecular anticoagulant drugs such as low molecular weight heparins (LMWHs) are widely used in the clinic, their characteristics of requiring injectable use hinder their further promotion in the clinic, and the disadvantages of oral anticoagulant drugs, such as warfarin and dabigatran etexilate, which can easily cause bleeding adverse effects, are also not addressed. Factor Xa (FXa) has gained attention because it lies at the intersection of the coagulation cascade pathways, whereas subsequently introduced Factor Xa inhibitors such as rivaroxaban and apixaban, among others, have gained market popularity because of their high potency for anticoagulation and high specificity for Factor Xa when administered orally. But some of the drawbacks that these Factor Xa inhibitors have simultaneously such as fewer indications and the lack of an effective reversal drug when bleeding occurs are urgently addressed. The development of new Factor Xa inhibitors therefore becomes one means of addressing these questions. This article summarizes the small molecule Factor Xainhibitors developed from 2015 to 2022, classifies them according to their scaffolds, focuses on the analysis of their structure-activity relationships, and provides a brief assessment of them.<\/jats:p>","DOI":"10.3389\/fphar.2023.1105880","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T07:18:25Z","timestamp":1676963905000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Discovery and development of Factor Xa inhibitors (2015\u20132022)"],"prefix":"10.3389","volume":"14","author":[{"given":"Wei","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqin","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binyao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianyou","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1111\/j.1538-7836.2007.02473.x","article-title":"Factor Xa or thrombin: Is factor Xa a better target?","volume":"5","author":"Ansell","year":"2007","journal-title":"J. Thromb. Haemost."},{"key":"B2","doi-asserted-by":"publisher","first-page":"5313","DOI":"10.1016\/j.bmcl.2010.06.126","article-title":"Discovery of a factor Xa inhibitor (3R,4R)-1-(2,2-difluoro-ethyl)-pyrrolidine-3,4-dicarboxylic acid 3-[(5-chloro-pyridin-2-yl)-amide] 4-[[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide] as a clinical candidate","volume":"20","author":"Anselm","year":"2010","journal-title":"Bioorg Med. Chem. Lett."},{"key":"B3","doi-asserted-by":"publisher","first-page":"4045","DOI":"10.1016\/j.bmcl.2004.05.033","article-title":"Parallel synthesis and structure-activity relationships of a series of highly potent, selective, and neutral factor Xa inhibitors","volume":"14","author":"Bauer","year":"2004","journal-title":"Bioorg Med. Chem. Lett."},{"key":"B4","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/s41577-021-00634-8","article-title":"Crosstalk between the renin-angiotensin, complement and kallikrein-kinin systems in inflammation","volume":"22","author":"Bekassy","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.ijbiomac.2014.01.023","article-title":"Polyphenol compounds belonging to flavonoids inhibit activity of coagulation factor X","volume":"65","author":"Bijak","year":"2014","journal-title":"Int. J. Biol. Macromol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.ejphar.2013.09.006","article-title":"Coagulation factor Xa induces an inflammatory signalling by activation of protease-activated receptors in human atrial tissue","volume":"718","author":"Bukowska","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1007\/s11239-021-02456-w","article-title":"Blood coagulation factor X: Molecular biology, inherited disease, and engineered therapeutics","volume":"52","author":"Camire","year":"2021","journal-title":"J. Thromb. Thrombolysis"},{"key":"B8","doi-asserted-by":"publisher","first-page":"6348","DOI":"10.1016\/j.bmc.2009.07.029","article-title":"Microbial transformation of isosteviol oxime and the inhibitory effects on NF-kappaB and AP-1 activation in LPS-stimulated macrophages","volume":"17","author":"Chang","year":"2009","journal-title":"Bioorg Med. Chem."},{"key":"B9","doi-asserted-by":"publisher","first-page":"5312","DOI":"10.1021\/jf991065s","article-title":"Synthesis and fungicidal activity against Rhizoctonia solani of 2-alkyl (Alkylthio)-5-pyrazolyl-1,3,4-oxadiazoles (thiadiazoles)","volume":"48","author":"Chen","year":"2000","journal-title":"J. Agric. Food Chem."},{"key":"B10","doi-asserted-by":"publisher","first-page":"111722","DOI":"10.1016\/j.ejmech.2019.111722","article-title":"Discovery of novel, potent, isosteviol-based antithrombotic agents","volume":"183","author":"Chen","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2845","DOI":"10.1016\/j.bmcl.2008.03.092","article-title":"Structure-activity relationships of anthranilamide-based factor Xa inhibitors containing piperidinone and pyridinone P4 moieties","volume":"18","author":"Corte","year":"2008","journal-title":"Bioorg Med. Chem. Lett."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1007\/s40262-019-00751-7","article-title":"Revisiting the Pharmacology of unfractionated heparin","volume":"58","author":"Derbalah","year":"2019","journal-title":"Clin. Pharmacokinet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.bbrc.2022.03.005","article-title":"Schixator, a new FXa inhibitor from Schistosoma japonicum with antithrombotic effect and low bleeding risk","volume":"603","author":"Ding","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B14","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1053\/j.semperi.2019.03.003","article-title":"Outcomes research on obstetric venous thromboembolism","volume":"43","author":"Duffy","year":"2019","journal-title":"Semin. Perinatol."},{"key":"B15","article-title":"Disubstituted pyrazolyl carboxanilides","author":"Dunkel","year":"2003"},{"key":"B16","article-title":"O-Cyclopropyl-Carboxanilides and their use as fungicides","author":"Ehrenfreund","year":"2003"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1039\/C1MD00145K","article-title":"The synthesis and evaluation of dihydroquinazolin-4-ones and quinazolin-4-ones as thyroid stimulating hormone receptor agonists","volume":"2","author":"Englund","year":"2011","journal-title":"Medchemcomm"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1640","DOI":"10.1182\/blood-2015-08-661439","article-title":"Platelet-derived VWF in the stroke spotlight","volume":"126","author":"Flood","year":"2015","journal-title":"Blood"},{"key":"B19","doi-asserted-by":"publisher","first-page":"7853","DOI":"10.1021\/acs.jmedchem.1c00651","article-title":"Potent cyclic peptide inhibitors of FXIIa discovered by mRNA display with genetic code reprogramming","volume":"64","author":"Ford","year":"2021","journal-title":"J. Med. Chem."},{"key":"B20","doi-asserted-by":"publisher","first-page":"4838","DOI":"10.1016\/j.bmcl.2005.07.030","article-title":"Investigation of factor Xa inhibitors containing non-amidine S1 elements","volume":"15","author":"Franciskovich","year":"2005","journal-title":"Bioorg Med. Chem. Lett."},{"key":"B21","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1021\/jm990373e","article-title":"Substituent effects on the antibacterial activity of nitrogen-carbon-linked (azolylphenyl)oxazolidinones with expanded activity against the fastidious gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis","volume":"43","author":"Genin","year":"2000","journal-title":"J. Med. Chem."},{"key":"B22","doi-asserted-by":"publisher","first-page":"6210","DOI":"10.1038\/s41598-018-24422-y","article-title":"Anticoagulant mechanism, pharmacological activity, and assessment of preclinical safety of a novel fibrin(ogen)olytic serine protease from leaves of Leucas indica","volume":"8","author":"Gogoi","year":"2018","journal-title":"Sci. Rep."},{"key":"B23","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1038\/bjp.2008.321","article-title":"Kallikrein inhibitors limit kinin B(2) antagonist-induced progression of oedematous to haemorrhagic pancreatitis in rats","volume":"155","author":"Griesbacher","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1161\/ATVBAHA.118.312130","article-title":"Intrinsic pathway of coagulation and thrombosis","volume":"39","author":"Grover","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1161\/ATVBAHA.117.309846","article-title":"Tissue factor: An essential mediator of hemostasis and trigger of thrombosis","volume":"38","author":"Grover","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2213","DOI":"10.1016\/j.bmcl.2004.02.019","article-title":"Synthesis and antitumor evaluation of benzoylphenylurea analogs","volume":"14","author":"Gurulingappa","year":"2004","journal-title":"Bioorg Med. Chem. Lett."},{"key":"B27","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/bs.pmbts.2019.02.003","article-title":"Low molecular weight heparins and their clinical applications","volume":"163","author":"Hao","year":"2019","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"4669","DOI":"10.1021\/jm020112w","article-title":"Parallel synthesis of potent, pyrazole-based inhibitors of Helicobacter pylori dihydroorotate dehydrogenase","volume":"45","author":"Haque","year":"2002","journal-title":"J. Med. Chem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"8051","DOI":"10.1021\/jm200868m","article-title":"Discovery of N-[2-hydroxy-6-(4-methoxybenzamido)phenyl]-4- (4-methyl-1,4-diazepan-1-yl)benzamide (darexaban, YM150) as a potent and orally available factor Xa inhibitor","volume":"54","author":"Hirayama","year":"2011","journal-title":"J. Med. Chem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1007\/s12016-016-8540-0","article-title":"Bradykinin: Inflammatory product of the coagulation system","volume":"51","author":"Hofman","year":"2016","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/s10555-017-9677-x","article-title":"Normal platelet function","volume":"36","author":"Holinstat","year":"2017","journal-title":"Cancer Metastasis Rev."},{"key":"B32","doi-asserted-by":"publisher","first-page":"37186","DOI":"10.18632\/oncotarget.16427","article-title":"Synthesis and evaluation of anthranilamide-based derivatives as FXa inhibitors","volume":"8","author":"Huang","year":"2017","journal-title":"Oncotarget"},{"key":"B33","doi-asserted-by":"publisher","first-page":"4124","DOI":"10.1039\/c005066k","article-title":"Acyclic triaryl olefins possessing a sulfohydroxamic acid pharmacophore: Synthesis, nitric oxide\/nitroxyl release, cyclooxygenase inhibition, and anti-inflammatory studies","volume":"8","author":"Huang","year":"2010","journal-title":"Org. Biomol. Chem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"6324","DOI":"10.1016\/j.bmc.2014.09.059","article-title":"Novel strategy to boost oral anticoagulant activity of blood coagulation enzyme inhibitors based on biotransformation into hydrophilic conjugates","volume":"22","author":"Ishihara","year":"2014","journal-title":"Bioorg Med. Chem."},{"key":"B35","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.ejphar.2011.10.009","article-title":"Biochemical and pharmacological profile of darexaban, an oral direct factor Xa inhibitor","volume":"673","author":"Iwatsuki","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1021\/jm9706731","article-title":"Excitatory amino acid receptor ligands: Resolution, absolute stereochemistry, and enantiopharmacology of 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid","volume":"41","author":"Johansen","year":"1998","journal-title":"J. Med. Chem."},{"key":"B37","doi-asserted-by":"publisher","first-page":"3935","DOI":"10.1016\/j.bmc.2011.05.034","article-title":"Synthesis and evaluation of fluorescent heterocyclic aminoadamantanes as multifunctional neuroprotective agents","volume":"19","author":"Joubert","year":"2011","journal-title":"Bioorg Med. Chem."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s13318-013-0141-1","article-title":"Darexaban (YM150), an oral direct factor Xa inhibitor, has no effect on the pharmacokinetics of digoxin","volume":"39","author":"Kadokura","year":"2014","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"B39","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1002\/bdd.1858","article-title":"Clinical pharmacokinetics, pharmacodynamics, safety and tolerability of darexaban, an oral direct factor Xa inhibitor, in healthy Caucasian and Japanese subjects","volume":"34","author":"Kadokura","year":"","journal-title":"Biopharm. Drug Dispos."},{"key":"B40","doi-asserted-by":"publisher","first-page":"200","DOI":"10.5414\/cp201804","article-title":"Effect of food on the pharmacokinetics of darexaban, an oral direct factor Xa inhibitor, in healthy Japanese subjects","volume":"51","author":"Kadokura","year":"","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.2174\/1389557518666180424120726","article-title":"Advances in the development of novel factor Xa inhibitors: A patent review","volume":"18","author":"Khadse","year":"2018","journal-title":"Mini Rev. Med. Chem."},{"key":"B42","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/s13065-018-0378-5","article-title":"Synthesis, characterization, molecular docking evaluation, antiplatelet and anticoagulant actions of 1,2,4 triazole hydrazone and sulphonamide novel derivatives","volume":"12","author":"Khalid","year":"2018","journal-title":"Chem. Cent. J."},{"key":"B43","doi-asserted-by":"publisher","first-page":"9445","DOI":"10.1002\/jcp.29749","article-title":"Novel factor Xa inhibitor, maslinic acid, with antiplatelet aggregation activity","volume":"235","author":"Kim","year":"2020","journal-title":"J. Cell Physiol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1016\/j.bmc.2004.11.005","article-title":"Synthesis and biological activity of novel 1,2-disubstituted benzene derivatives as factor Xa inhibitors","volume":"13","author":"Koshio","year":"2005","journal-title":"Bioorg Med. Chem."},{"key":"B45","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/s0027-5107(00)00117-2","article-title":"In vivo rodent micronucleus assay: Protocol, conduct and data interpretation","volume":"455","author":"Krishna","year":"2000","journal-title":"Mutat. Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1038\/nm1235","article-title":"Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Abeta42 production","volume":"11","author":"Kukar","year":"2005","journal-title":"Nat. Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"636","DOI":"10.2174\/1389200218666170518165443","article-title":"Rivaroxaban - metabolism, pharmacologic properties and drug interactions","volume":"18","author":"Kvasnicka","year":"2017","journal-title":"Curr. Drug Metab."},{"key":"B48","doi-asserted-by":"publisher","first-page":"7646","DOI":"10.1021\/jm060239b","article-title":"A comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of anthranilamide derivatives that are multidrug resistance modulators","volume":"49","author":"Labrie","year":"2006","journal-title":"J. Med. Chem."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1588","DOI":"10.3390\/molecules22101588","article-title":"Novel FXa inhibitor identification through integration of ligand- and structure-based approaches","volume":"22","author":"Lagos","year":"2017","journal-title":"Molecules"},{"key":"B50","doi-asserted-by":"publisher","first-page":"4405","DOI":"10.1021\/jm020578e","article-title":"Structure-based design of novel guanidine\/benzamidine mimics: Potent and orally bioavailable factor Xa inhibitors as novel anticoagulants","volume":"46","author":"Lam","year":"2003","journal-title":"J. Med. Chem."},{"key":"B51","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.ijcard.2016.01.190","article-title":"Anticoagulant therapy after venous thromboembolism and 10-year mortality","volume":"208","author":"Larsen","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1006\/jmbi.1994.1427","article-title":"Structure determination of an Fab fragment that neutralizes human rhinovirus 14 and analysis of the Fab-virus complex","volume":"240","author":"Liu","year":"1994","journal-title":"J. Mol. Biol."},{"key":"B108","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1042\/CS20160669","article-title":"SerpinC1\/Antithrombin III in kidney-related diseases","volume":"131","author":"Lu","year":"2017","journal-title":"Clin. Sci."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1687","DOI":"10.1161\/ATVBAHA.107.141911","article-title":"Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis","volume":"27","author":"Mackman","year":"2007","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"161","DOI":"10.2174\/1568026013395461","article-title":"The use of 3D structural data in the design of specific factor Xa inhibitors","volume":"1","author":"Maignan","year":"2001","journal-title":"Curr. Top. Med. Chem."},{"key":"B55","doi-asserted-by":"publisher","first-page":"733","DOI":"10.2174\/1573406412666160502153417","article-title":"Synthesis, anticlotting and antiplatelet effects of 1,2,3-triazoles derivatives","volume":"12","author":"Moura","year":"2016","journal-title":"Med. Chem."},{"key":"B56","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/j.bmcl.2005.07.067","article-title":"QSAR analysis of meclofenamic acid analogues as selective COX-2 inhibitors","volume":"16","author":"Narsinghani","year":"2006","journal-title":"Bioorg Med. Chem. Lett."},{"key":"B57","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/s0027-5107(02)00076-3","article-title":"Chromosomal aberrations: Formation, identification and distribution","volume":"504","author":"Obe","year":"2002","journal-title":"Mutat. Res."},{"key":"B58","doi-asserted-by":"publisher","first-page":"7478","DOI":"10.1021\/acs.jmedchem.6b00487","article-title":"Discovery of clinical candidate CEP-37440, a selective inhibitor of focal adhesion kinase (FAK) and anaplastic lymphoma kinase (ALK)","volume":"59","author":"Ott","year":"2016","journal-title":"J. Med. Chem."},{"key":"B59","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1007\/s40272-022-00516-z","article-title":"Dabigatran etexilate: A review in pediatric venous thromboembolism","volume":"24","author":"Paik","year":"2022","journal-title":"Paediatr. Drugs"},{"key":"B60","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/j.ejmech.2016.05.039","article-title":"Contemporary developments in the discovery of selective factor Xa inhibitors: A review","volume":"121","author":"Patel","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"B61","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1038\/nrd3185","article-title":"The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor","volume":"10","author":"Perzborn","year":"2011","journal-title":"Nat. Rev. Drug Discov."},{"key":"B62","doi-asserted-by":"publisher","first-page":"5584","DOI":"10.1016\/j.bmcl.2006.08.027","article-title":"Discovery of potent, efficacious, and orally bioavailable inhibitors of blood coagulation factor Xa with neutral P1 moieties","volume":"16","author":"Pinto","year":"","journal-title":"Bioorg Med. Chem. Lett."},{"key":"B63","doi-asserted-by":"publisher","first-page":"5339","DOI":"10.1021\/jm070245n","article-title":"Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa","volume":"50","author":"Pinto","year":"2007","journal-title":"J. Med. Chem."},{"key":"B64","doi-asserted-by":"publisher","first-page":"4141","DOI":"10.1016\/j.bmcl.2006.02.069","article-title":"1-[3-Aminobenzisoxazol-5'-yl]-3-trifluoromethyl-1-[3-Aminobenzisoxazol-5'-yl]-3-trifluoromethyl-6-[2'-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one (BMS-740808) a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa","volume":"16","author":"Pinto","year":"","journal-title":"Bioorg Med. Chem. Lett."},{"key":"B65","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1021\/jm000409z","article-title":"Discovery of 1-[3-(aminomethyl)phenyl]-N-3-fluoro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa","volume":"44","author":"Pinto","year":"2001","journal-title":"J. Med. Chem."},{"key":"B66","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.thromres.2016.12.001","article-title":"Extended non-vitamin K antagonist oral anticoagulation therapy for prevention of recurrent venous thromboembolism","volume":"152","author":"Piovella","year":"2017","journal-title":"Thromb. Res."},{"key":"B67","doi-asserted-by":"publisher","first-page":"13370","DOI":"10.3390\/ijms222413370","article-title":"High molecular weight kininogen: A review of the structural literature","volume":"22","author":"Ponczek","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B68","doi-asserted-by":"publisher","first-page":"5298","DOI":"10.1021\/jm030212h","article-title":"Discovery of 1-(2-aminomethylphenyl)-3-trifluoromethyl-N- [3-fluoro-2'-(aminosulfonyl)[1,1'-biphenyl)]-4-yl]-1H-pyrazole-5-carboxyamide (DPC602), a potent, selective, and orally bioavailable factor Xa inhibitor(1)","volume":"46","author":"Pruitt","year":"2003","journal-title":"J. Med. Chem."},{"key":"B69","doi-asserted-by":"publisher","first-page":"2760","DOI":"10.1021\/jm980406a","article-title":"Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 2","volume":"42","author":"Quan","year":"","journal-title":"J. Med. Chem."},{"key":"B70","doi-asserted-by":"publisher","first-page":"2752","DOI":"10.1021\/jm980405i","article-title":"Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 1","volume":"42","author":"Quan","year":"","journal-title":"J. Med. Chem."},{"key":"B71","first-page":"473","article-title":"Evaluation of protecting groups for 3-hydroxyisoxazoles 2 short access to 3-Alkoxyisoxazole-5-carbaldehydes and 3-Hydroxyisoxazole-5-carbaldehyde, the putative toxic metabolite of muscimol","volume":"1997","author":"Regine Riess","year":"1997","journal-title":"Eur. . J. Org. Chem."},{"key":"B72","doi-asserted-by":"publisher","first-page":"5900","DOI":"10.1021\/jm050101d","article-title":"Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): An oral, direct factor Xa inhibitor","volume":"48","author":"Roehrig","year":"2005","journal-title":"J. Med. Chem."},{"key":"B73","doi-asserted-by":"publisher","first-page":"23","DOI":"10.3109\/10559610213503","article-title":"QSAR of human factor Xa inhibitor N2-aroylanthranilamides using principal component factor analysis","volume":"18","author":"Roy","year":"2002","journal-title":"Drug Des. Discov."},{"key":"B74","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.thromres.2010.09.008","article-title":"The mechanism of action of rivaroxaban--an oral, direct Factor Xa inhibitor--compared with other anticoagulants","volume":"127","author":"Samama","year":"2011","journal-title":"Thromb. Res."},{"key":"B75","doi-asserted-by":"publisher","first-page":"491","DOI":"10.3390\/molecules25030491","article-title":"Innovative three-step microwave-promoted synthesis of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives as a potential factor Xa (FXa) inhibitors: Drug design, synthesis, and biological evaluation","volume":"25","author":"Santana-Romo","year":"2020","journal-title":"Molecules"},{"key":"B76","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1016\/0006-291x(68)90326-4","article-title":"On the active site of proteases. 3. Mapping the active site of papain; specific peptide inhibitors of papain","volume":"32","author":"Schechter","year":"1968","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B77","doi-asserted-by":"publisher","first-page":"1076029618825310","DOI":"10.1177\/1076029618825310","article-title":"Contact system activation and neutrophil extracellular trap markers: Risk factors for portal vein thrombosis in patients with hepatocellular carcinoma","volume":"25","author":"Seo","year":"2019","journal-title":"Clin. Appl. Thromb. Hemost."},{"key":"B78","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1182\/blood-2006-01-0094","article-title":"Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin","volume":"108","author":"Shariat-Madar","year":"2006","journal-title":"Blood"},{"key":"B79","doi-asserted-by":"publisher","first-page":"126585","DOI":"10.1016\/j.bmcl.2019.07.044","article-title":"Synthesis and biological evaluation of Isosteviol derivatives as FXa inhibitors","volume":"30","author":"Shi","year":"2020","journal-title":"Bioorg Med. Chem. Lett."},{"key":"B80","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1021\/np50058a026","article-title":"Isolation of a new alkaloid from evodia rutaecarpa","volume":"51","author":"Shoji","year":"1988","journal-title":"J. Nat. Prod."},{"key":"B81","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/j.jconrel.2009.05.035","article-title":"Contact activation of kallikrein-kinin system by superparamagnetic iron oxide nanoparticles in vitro and in vivo","volume":"140","author":"Simberg","year":"2009","journal-title":"J. Control Release"},{"key":"B82","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1042\/BJ20131099","article-title":"Phosphatidylserine and FVa regulate FXa structure","volume":"459","author":"Srivasatava","year":"2014","journal-title":"Biochem. J."},{"key":"B83","doi-asserted-by":"publisher","first-page":"1653","DOI":"10.1111\/jth.14806","article-title":"Anti-factor IIa (FIIa) heparin assay for patients on direct factor Xa (FXa) inhibitors","volume":"18","author":"Stuart","year":"2020","journal-title":"J. Thromb. Haemost."},{"key":"B84","doi-asserted-by":"publisher","first-page":"2800","DOI":"10.1016\/j.bmc.2017.03.055","article-title":"Design, synthesis, and biological activity of novel tetrahydropyrazolopyridone derivatives as FXa inhibitors with potent anticoagulant activity","volume":"25","author":"Sun","year":"2017","journal-title":"Bioorg Med. Chem."},{"key":"B85","doi-asserted-by":"publisher","first-page":"2407","DOI":"10.1111\/jth.15439","article-title":"First evaluation of the safety, pharmacokinetics, and pharmacodynamics of BAY 2433334, a small molecule targeting coagulation factor XIa","volume":"19","author":"Thomas","year":"2021","journal-title":"J. Thromb. Haemost."},{"key":"B86","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1002\/1439-7633(20021004)3:10<1023::AID-CBIC1023>3.0.CO;2-9","article-title":"The first orally active low molecular weight agonists for the LH receptor: thienopyr(im)idines with therapeutic potential for ovulation induction","volume":"3","author":"van Straten","year":"2002","journal-title":"Chembiochem"},{"key":"B87","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1021\/ml500493r","article-title":"Retraction of \"novel 2-aminobenzamides as potential orally active antithrombotic agents","volume":"6","author":"Verma","year":"2015","journal-title":"ACS Med. Chem. Lett."},{"key":"B88","doi-asserted-by":"publisher","first-page":"2937","DOI":"10.1016\/j.cclet.2021.12.091","article-title":"Nanoplateletsomes for rapid hemostasis performance","volume":"33","author":"Wang","year":"2022","journal-title":"Chin. Chem. Lett."},{"key":"B89","doi-asserted-by":"publisher","first-page":"3813","DOI":"10.1016\/j.bmcl.2018.05.036","article-title":"Semisynthesis of ent-norstrobane diterpenoids as potential inhibitor for factor Xa","volume":"28","author":"Wang","year":"2018","journal-title":"Bioorg Med. Chem. Lett."},{"key":"B90","doi-asserted-by":"publisher","first-page":"1320","DOI":"10.1016\/j.bmc.2019.02.032","article-title":"Semisynthesis of epoxy-pimarane diterpenoids from kirenol and their FXa inhibition activities","volume":"27","author":"Wang","year":"2019","journal-title":"Bioorg Med. Chem."},{"key":"B91","doi-asserted-by":"publisher","first-page":"491","DOI":"10.3390\/molecules21040491","article-title":"Novel anthranilamide-based FXa inhibitors: Drug design, synthesis and biological evaluation","volume":"21","author":"Wang","year":"","journal-title":"Molecules"},{"key":"B92","doi-asserted-by":"publisher","first-page":"5646","DOI":"10.1016\/j.bmc.2016.09.024","article-title":"Design, synthesis, and structure-activity relationship of novel and effective apixaban derivatives as FXa inhibitors containing 1,2,4-triazole\/pyrrole derivatives as P2 binding element","volume":"24","author":"Wang","year":"","journal-title":"Bioorg Med. Chem."},{"key":"B93","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1007\/s11239-015-1319-y","article-title":"Guidance for the practical management of warfarin therapy in the treatment of venous thromboembolism","volume":"41","author":"Witt","year":"2016","journal-title":"J. Thromb. Thrombolysis"},{"key":"B94","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1021\/jo9509723","article-title":"An efficient synthesis of the cholinergic channel activator ABT-418","volume":"61","author":"Wittenberger","year":"1995","journal-title":"J. Org. Chem."},{"key":"B95","first-page":"212","article-title":"Nonpeptide factor Xa inhibitors II. Antithrombotic evaluation in a rabbit model of electrically induced carotid artery thrombosis","volume":"295","author":"Wong","year":"","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B96","first-page":"351","article-title":"Nonpeptide factor Xa inhibitors: I. Studies with SF303 and SK549, a new class of potent antithrombotics","volume":"292","author":"Wong","year":"","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B97","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1016\/j.cclet.2021.06.029","article-title":"Graphene-based hemostatic sponge","volume":"33","author":"Wu","year":"2022","journal-title":"Chin. Chem. Lett."},{"key":"B98","doi-asserted-by":"publisher","first-page":"1464","DOI":"10.1016\/j.bmc.2009.01.017","article-title":"Stereoselective synthesis of bioactive isosteviol derivatives as alpha-glucosidase inhibitors","volume":"17","author":"Wu","year":"2009","journal-title":"Bioorg Med. Chem."},{"key":"B99","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/j.ejmech.2015.03.052","article-title":"Identification of anthranilamide derivatives as potential factor Xa inhibitors: Drug design, synthesis and biological evaluation","volume":"95","author":"Xing","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"B100","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/j.ejmech.2016.09.055","article-title":"Design, synthesis and biological evaluation of novel 2,3-dihydroquinazolin- 4(1H)-one derivatives as potential fXa inhibitors","volume":"125","author":"Xing","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"B101","doi-asserted-by":"publisher","first-page":"5987","DOI":"10.1016\/j.bmc.2018.09.012","article-title":"Design, synthesis and biological evaluation of anthranilamide derivatives as potential factor Xa (fXa) inhibitors","volume":"26","author":"Xing","year":"2018","journal-title":"Bioorg Med. Chem."},{"key":"B102","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1016\/j.bmcl.2014.12.039","article-title":"Design, synthesis and evaluation of isoxazolo[5,4-d]pyrimidin-4(5H)-one derivatives as antithrombotic agents","volume":"25","author":"Yang","year":"","journal-title":"Bioorg Med. Chem. Lett."},{"key":"B103","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.ejmech.2015.06.012","article-title":"Synthesis of 3,4-diaminobenzoyl derivatives as factor Xa inhibitors","volume":"101","author":"Yang","year":"","journal-title":"Eur. J. Med. Chem."},{"key":"B104","doi-asserted-by":"publisher","first-page":"2967","DOI":"10.1021\/jm070125f","article-title":"Thiophene-anthranilamides as highly potent and orally available factor Xa inhibitors","volume":"50","author":"Ye","year":"2007","journal-title":"J. Med. Chem."},{"key":"B105","doi-asserted-by":"publisher","first-page":"8221","DOI":"10.1016\/j.bmc.2009.10.024","article-title":"Design, synthesis, and SAR of cis-1,2-diaminocyclohexane derivatives as potent factor Xa inhibitors. Part II: Exploration of 6-6 fused rings as alternative S1 moieties","volume":"17","author":"Yoshikawa","year":"2009","journal-title":"Bioorg Med. Chem."},{"key":"B106","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1021\/ci200003c","article-title":"Novel strategy for three-dimensional fragment-based lead discovery","volume":"51","author":"Yuan","year":"2011","journal-title":"J. Chem. Inf. Model"},{"key":"B107","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.ejmech.2013.04.044","article-title":"Design and stereoselective synthesis of novel isosteviol-fused pyrazolines and pyrazoles as potential anticancer agents","volume":"65","author":"Zhu","year":"2013","journal-title":"Eur. J. Med. Chem."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1105880\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T12:29:39Z","timestamp":1677068979000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1105880\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,21]]},"references-count":108,"alternative-id":["10.3389\/fphar.2023.1105880"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1105880","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,21]]},"article-number":"1105880"}}