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Expert Opinion on Therapeutic Patents Volume 19, 2009 - Issue 11
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Reviews

Novel factor Xa inhibitors: a patent review

Modesto de Candia Assistant Professor, University of Bari, Dipartimento Farmaco-Chimico, Via E. Orabona 4, I-70125 Bari, Italy
, PhD,
Gianfranco Lopopolo PhD Student, University of Bari, Dipartimento Farmaco-Chimico, Via E. Orabona 4, I-70125 Bari, Italy
&
Cosimo Altomare Full Professor of Medicinal Chemistry, Head of the Department, University of Bari, Dipartimento Farmaco-Chimico, Via E. Orabona 4, I-70125 Bari, Italy +39 080 5442781; +39 080 5442230; [email protected]
Pages 1535-1580 | Published online: 10 Sep 2009

Bibliography

  • Mackman N. Triggers, targets and treatment for thrombosis. Nature 2008;451:914-8
  • World Health Organization. Atlas of Heart Disease and Stroke. World Health Organization, Geneva, Switzerland; 2004
  • American Heart Association. Heart Disease and Stroke Statistics – 2008 Update. American Heart Association, Dallas, TX; 2008
  • Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 2007;100:1261-75
  • Weitz JI, Linkins LA. Beyond heparin and warfarin: the new generation of anticoagulants. Expert Opin Investig Drugs 2007;16:271-82
  • Vacca JP. New advances in the discovery of thrombin and factor Xa inhibitors. Curr Opin Chem Biol 2000;4:394-400
  • Harenberg J. Development of new anticoagulants: Present and future. Semin Thromb Hemost 2008;34:779-93
  • Krynetskly E. Building individualized medicine: prevention of adverse reactions to warfarin therapy. J Pharmacol Exp Ther 2007;322:427-34
  • Chan YC, Valenti D, Mansfield AO, Stansby G. Warfarin induced skin necrosis. Br J Surg 2000;87:266-72
  • Arepally GM, Ortel TL. Heparin-induced trombocitopenia. N Engl J Med 2006;355:809-17
  • Khoo CW, Tay K-E, Shantsila E, Lip GYH. Novel oral anticoagulants. Int J Clin Pract 2009;63:630-41
  • Eikelboom JW, Hirsh J. Combined antiplatelet and anticoagulant therapy: clinical benefits and risks. J Thromb Haemost 2007;5(Suppl 1):255-63
  • Pérez-Gómez F, Alegría E, Berjón J, Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and non valvular atrial fibrillation. A randomized multicenter study. J Am Coll Cardiol 2004;44:1557-66
  • Schneider DJ, Sobel BE. Conundrums in the combined use of anticoagulants and antiplatelet drugs. Circulation 2007;116:305-15
  • Anderluh PŠ, Anderluh M, Ilaš J, 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;48:3110-3
  • de Candia M, Liantonio F, Carotti A, Fluorinated benzyloxyphenyl piperidine-4-carboxamides with dual function against thrombosis: inhibitors of factor Xa and platelet aggregation. J Med Chem 2009;52:1018-28
  • Steinmettzer T, Stürzebecher J. Progress in the development of synthetic thrombin inhibitors as new orally active anticoagulants. Curr Med Chem 2004;11:2297-321
  • Gould WR. Recent advances in the discovery and development of direct coagulation factor Xa inhibitors. Curr Pharm Des 2003;9:2337-47
  • Lee WM, Larrey D, Olsson R, Hepatic findings in long-term clinical trials of ximelagatran. Drug Saf 2005;28:351-70
  • Hauel NH, Nar H, Priepke H, Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002;45:1757-66
  • Eriksson BI, Dahl OE, Rosencher N, Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomized, double-blind, non-inferiority trial. Lancet 2007;370:949-56
  • Eriksson BI, Smith H, Yasothan U, Kirkpatrick P. Dabigatran etexilate. Nat Rev Drug Discov 2008;7:557-58
  • Leadley RJ. Coagulation factor Xa inhibition: biological background and rationale. Curr Top Med Chem 2001;1:151-9
  • Linkins L-A, Weitz JI. New anticoagulant therapy. Annu Rev Med 2005;56:63-77
  • Quan ML, Smallher JM. The race to an orally active factor Xa inhibitor. Curr Opin Drug Discov Dev 2004;7:460-9
  • Maignan S, Mikol V. The use of 3D structural data in the design of specific factor Xa inhibitors. Curr Top Med Chem 2001;1:161-74
  • Al-Obeidi F, Ostrem JA. Factor Xa inhibitors. Expert Opin Ther Patents 1999;9:931-53
  • Lam PY, Clark CG, Li R, Structure-based design of novel guanidine/benzamidine mimics: potent and orally bioavailable Factor Xa inhibitors as novel anticoagulants. J Med Chem 2003;46:4405-18
  • Casimiro-Garcia A, Dudley DA, Heemstra RJ, Progress in the discovery of factor Xa inhibitors. Expert Opin Ther Patents 2006;16:119-45
  • Nagahara T, Yokoyama Y, Inamura K, Dibasic (amidinoaryl)propanoic acid derivatives as novel blood coagulation Factor Xa inhibitors. J Med Chem 1994;37:1200-7
  • Guertin KR, Gardner CI, Klein SI, Optimization of the beta-aminoester class of Factor Xa inhibitors. Part 2: identification of FXV673 as a potent and selective inhibitor with excellent in vivo anticoagulant activity. Bioorg Med Chem Lett 2002;12:1671-4
  • Pinto DJ, Orwat MJ, Wang S, Discovery of 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC-423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation Factor Xa. J Med Chem 2001;44:566-78
  • Wong PC, Pinto DJ, Knabb RM. Nonpeptide Factor Xa inhibitors: DPC423, a highly potent and orally bioavailable pyrazole antithrombotic agent. Cardiovasc Drug Rev 2002;20:137-52
  • Quan MI, Lam PY, Han Q, Discovery of 1-(3′-aminobenzisoxazol- 5′-yl)-3-trifluoromethyl-N-[2-fluoro- 4-[(2′-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxamide hydrochloride (razaxaban), a highly potent, selective, and orally biovailable Factor Xa inhibitor. J Med Chem 2005;48:1729-44
  • Roherig S, Straub A, Pohlmann J, 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. J Med Chem 2005;48:5900-8
  • Pinto DJ, Orwat MJ, Koch S, 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. J Med Chem 2007;50:5339-56
  • Maignan S, Guilloteau J-P, Choi-Sledeski YM, Molecular structures of human factor Xa complexed with ketopiperazine inhibitors: Preferences for a neutral group in the S1 pocket. J Med Chem 2003;46:685-90
  • Nazaré M, Will DW, Matter H, Probing the subpockets of factor Xa reveals two binding modes for inhibitors based on a 2-carboxyindole scaffold: a study combining structure-activity relationship and X-ray crystallography. J Med Chem 2005;48:4511-25
  • Matter H, Will DW, Nazaré M, Structural requirements for factor Xa inhibition with neutral P1 substituents: combining X-ray crystallography, 3D-QSAR, and tailored scoring function. J Med Chem 2005;48:3290-312
  • Ye B, Arnaiz DO, Chou Y-L, Thiophene-anthranilamides as highly potent and orally available factor Xa inhibitors. J Med Chem 2007;50:2967-80
  • Haginoya N, Kobayashi S, Komorija S, Orally active Factor Xa inhibitors: 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine derivatives. Bioorg Med Chem Lett 2004;14:2935-39
  • Melnikoca I. The anticoagulant market. Nat Rev Drug Discov 2009;8:353-4
  • Fisher WD, Eriksson BI, Bauer KA, Rivaroxaban for thromboprophylaxis after orthopaedic therapy: pooled analysis of two studies. Thromb Haemost 2007;97:931-7
  • Turpie AC, Fisher WD, Bauer K, An oral, direct factor Xa inhibitor – BAY 59-7939 – for prophylaxis against venous thromboembolism after total knee replacement: a dose-ranging study. International Society for Thrombosis and Haemostasis. Sydney, Australia, 2005, abstract 02573
  • Kubitza D, Becka M, Roth A, Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin 2008;24:2757-65
  • Mueck W, Eriksson BI, Bauer K, Population pharmacokinetics and pharmacodynamics of rivaroxaban – an oral, direct factor Xa inhibitor – in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 2008;47:203-16
  • Lassen MR, Davidson BL, Gallus A, The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost 2007;5:2368-75
  • Lassen MR, Gallus AS, Pineo GF, Raskob GE. Late breaking clinical trial. The ADVANCE-2 study: a randomized double-blind trial comparing apixaban with enoxaparin for thromboprophylaxis after total knee replacement. XXII Congress of The International Society for Thrombosis and Haemostasis. Boston, Massachusetts, USA (2009). Abstract LB-MO-005. Available from: http://isth2009.com
  • Furugohri T, Isobe K, Honda Y, DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J Thromb Haemost 2008;6:1542-49
  • Hylek E. DU-176b, an oral, direct factor Xa antagonist. Curr Opin Investig Drugs 2007;8:778-83
  • Zafar MU, Vorchheimer DA, Gaztanaga J, Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-I study of an oral, direct, factor Xa inhibitor using an ex-vivo flow chamber. Thromb Hemost 2007;98:883-8
  • Daiichi Sankyo Europe GmbH. Edoxaban – Factor Xa inhibitor enters phase III with optimal dose (press release), 27 March 2009. Available from: http://www.bioportpholio.com
  • Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet 2009;48:1-22
  • Saiah E, Soares C. Small molecule coagulation cascade inhibitors in the clinic. Curr Top Med Chem 2005;5:1677-95
  • Hirayama F, Koshio H, Ishihara T, Design, synthesis and biological activity of YM-60828 derivatives: potent and orally-bioavailable Factor Xa inhibitors based on naphthoanilide and naphtalensulfonanilide templates. Bioorg Med Chem 2002;10:2597-610
  • Konishi N, Katsuhiko H, Imaeda Y, Effects of TAK-442, a direct Factor Xa inhibitor, and fondaparinux on platelet-associated prothrombinase in the balloon injured artery of rats. XXII Congress of The International Society for Thrombosis and Haemostasis. Boston, Massachusetts, USA, 2009, abstract PP-WE-398. Available from: http://isth2009.com
  • Ajinomoto. Novel benzamidine compound. WO2006083003; 2006
  • Stürzebecher A, Dönnecke D, Schweinitz A, Highly potent and selective substrate analogue factor Xa inhibitors containing D-homophenylalanine analogues as P3 residue: part 2. ChemMedChem 2007;2:1043-53
  • Dönnecke D, Schweinitz A, Stürzebecher A, From selective substrate analogue factor Xa inhibitors to dual inhibitors of thrombin and factor Xa. Part 3. Bioorg Med Chem Lett 2007;17:3322-29
  • Curacyte Chemistry GmbH. 2-(Aminomethyl)-5-chlorobenzylamide derivatives and their use as inhibitors of the clotting factor Xa. WO2007031343; 2007
  • Morphochem Chemie. Novel compounds that inhibit factor Xa activity. WO2006008141; 2006
  • Morphochem Chemie. Two part wound dressing. US2008051688; 2008
  • Rossi C, Hess S, Eckl RW, Effect of MCM09, an active site-directed inhibitor of factor Xa, on B16-BL6 melanoma lung colonies in mice. J Thromb Haemost 2006;4:608-13
  • Janssen. Factor Xa compounds. WO2006047415; 2006
  • Lee Y-K, Parks DJ, Lu T, 7-Fluoroindazoles as Potent and Selective Inhibitors of Factor Xa. J Med Chem 2008;51:282-97
  • Schebo Biotech AG. New oxazolidinone derivatives are factor Xa inhibitors useful to treat e.g. acute coronary syndrome, myocardial infarction, angina pectoris, reocclusion, restenosis, stroke, artrial fibrillation, arrhythmia and blood clotting disorder. DE102007037373; 2009
  • Schebo Biotech AG. Novel pharmaceuticals, method for the production thereof, and use thereof in therapy. WO2009018807; 2009
  • Bristol-Myers Squibb Co. Novel guanidine mimics as factor Xa inhibitors. US2006040973; 2006
  • Bristol-Myers Squibb Co. Lactam-containing compounds and derivatives thereof as factor Xa inhibitors. US2007135426; 2007
  • Bayer HealthCare AG. Imino-oxazolidines und ihre Verwendung. DE102005018690; 2006
  • Bayer HealthCare AG. Phenylenebisoxazolidine derivatives and their use as anticoagulants. WO2007051532; 2007
  • Bayer HealthCare AG. Combination therapy comprising substituted oxazolidinones for the prevention and treatment of cerebral circulatory disorders. WO2007039134; 2007
  • Bayer HealthCare AG. Behandlung und Prophylaxe von Mikroangiopathien. DE102005048824; 2007
  • Bayer HealthCare AG. New 5-thienylaminocarbonylmethyl-oxazolidin-2-one derivatives, useful for treating and preventing thromboembolic diseases, are selective inhibitors of coagulation factor Xa. DE102005045518; 2007
  • Bayer HealthCare AG. Combination therapy of substituted oxazolidinones. WO2008052671; 2008
  • Bayer HealthCare AG. Substituted oxazolidinones and use thereof. WO2008155034; 2008
  • Bayer HealthCare AG. Substituted (oxazolidinon-5-yl-methyl)- 2-thiophenecarboxamides and use thereof in the field of blood coagulation. WO2008155032; 2008
  • Bayer HealthCare AG. Substituted (oxazolidinon-5-yl-methyl)- 2-thiophenecarboxamides and use thereof in the field of blood coagulation. WO2008155033; 2008
  • Bayer HealthCare AG. Substituted oxazolidinones and use thereof. WO2008155069; 2008
  • Bayer HealthCare AG. Prevention and treatment of thromboembolic disorders. WO2006079474; 2006
  • Bayer HealthCare AG. Feste, oral applizierbare pharmazeutische Darreichungsformen mit modifizierter Freisetzung. DE102004062475; 2006
  • Bayer HealthCare AG. Oxazolidinone for the treatment and prophylaxis of pulmonary hypertension. WO2008128653; 2008
  • Bayer HealthCare AG. Oxazolidinones for the treatment and prophylaxis of sepsis. WO2008155035; 2008
  • Bayer HealthCare AG. Substituted heterocycles and use thereof. WO2007137792; 2007
  • Bayer HealthCare AG. Isoindolin-1-one-, isoindolin-3-one- and isoindolin-1, 3-dione-derivatives and use thereof. DE102006025316; 2007
  • Bayer HealthCare AG. Isoindolin-1-one-, isoindolin-3-one- and isoindolin-1, 3-dione-derivatives and use thereof. WO2007137800; 2007
  • Bayer HealthCare AG. Dihydro-pyrrolopyridine-, dihydro-pyrrolopyridazine- and dihydro-pyrrolopyrimidine-derivatives and use thereof. WO2007137793; 2007
  • Bayer HealthCare AG. Tetrahydropyrrolopyridine, tetrahydropyrazolopyridine, tetrahydro-imidazopyridine and tetrahydrotriazolopyridine derivatives and use thereof. WO2007137801; 2007
  • Bayer HealthCare AG. Pyrazine dicarboxamides and the use thereof. WO2006061116; 2006
  • Bayer HealthCare AG. Cyclic iminocarbamates and use thereof. WO2006058630; 2006
  • Bayer HealthCare AG. Iminooxazolidine derivatives and use thereof. WO2007028520; 2007
  • Boehringer Ingelheim International GmbH. Substituted glycinamides having an antithrombotic and factor Xa-inhibiting effect. WO2007003536; 2007
  • Boehringer Ingelheim International GmbH. Substituted amides, their preparation and their use as pharmaceuticals. WO2007009963; 2007
  • Boehringer Ingelheim International GmbH. New substituted pyrrolidinones, their manufacture and their use as medicaments. US2006142263; 2006
  • Boehringer Ingelheim International GmbH. Substituted pyrrolidine amides, the production thereof, and the use thereof as medications. WO2008116881; 2008
  • Boehringer Ingelheim International GmbH. Substituted biaryls and their use as factor Xa inhibitors. WO2007025940; 2007
  • Boehringer Ingelheim International GmbH. Substituted prolinamides, production thereof and their use as drugs. WO2007131982; 2007
  • Boehringer Ingelheim International GmbH. Substituted anthranilamides and analogues, manufacturing and use thereof as medicaments. WO2008135524; 2008
  • Boehringer Ingelheim Pharma GmbH & Co. KG. Substituierte Prolinamide, deren Herstellung und deren Verwendung als Arzneimittel. EP1818330; 2007
  • Boehringer Ingelheim Pharma GmbH & Co. KG. New 4-heterocyclyl-benzamide derivatives, useful as antithrombotic agents for treating or preventing e.g. deep vein thrombosis or reocclusion after angioplasty, are inhibitors of factor Xa and other serine proteases. DE102004060984; 2006
  • Boehringer Ingelheim International GmbH. Carboxylic acid amides as factor Xa inhibitors. WO2008135526; 2008
  • Boehringer Ingelheim Pharma GmbH & Co. KG. Neue substituierte Thiophencarbonsäureamide, deren Herstellung und deren Verwendung als Arzneimittel. DE102004047840; 2006
  • Boehringer Ingelheim International GmbH. Substituted azetidines, manufacturing and use thereof as medicaments. WO2008135525; 2008
  • Qiao JX, Chang CH, Cheney DL, SAR and X-ray structures of enantiopure 1,2-cis-(1R,2S)-cyclopentyldiamine and cyclohexyldiamine derivatives as inhibitors of coagulation Factor Xa. Bioorg Med Chem Lett 2007;17:4419-27
  • Qiao JX, Wang TC, Wang GZ, Enantiopure five-membered cyclic diamine derivatives as potent and selective inhibitors of factor Xa. Improving in vitro metabolic stability via core modifications. Bioorg Med Chem Lett 2007;17:5041-8
  • Hoffman-La Roche Pharm. Novel dicarboxamide derivatives. WO2006048152; 2006
  • Hoffman-La Roche Pharm. Dicarboxamide derivatives. WO2007122104; 2007
  • Hoffman-La Roche Pharm. Heteroarylacetamides as factor Xa inhibitors. EP1846381; 2007
  • Groebke Zbinden K, Anselm L, Banner DW, Design of novel aminopyrrolidine factor Xa inhibitors from a screening hit. Eur J Med Chem 2009;44:2787-95
  • Hoffman-La Roche Pharm. Novel heteroarylacetamides. WO2006066778; 2006
  • Hoffman-La Roche Pharm. Novel cyclic amines. WO2006114401; 2006
  • Hoffman-La Roche Pharm. Factor Xa inhibitors. US2007015812; 2007
  • Hoffman-La Roche Pharm. Novel carbocyclic fused cyclic amines. WO2007054453; 2007
  • Bristol-Myers Squibb Co. Lactam-containing compounds and derivatives thereof as factor Xa inhibitors. US2007135426; 2007
  • Bristol-Myers Squibb Co. Lactam-containing compounds and derivatives thereof as factor Xa inhibitors. US2008090807; 2008
  • Corte JR, Fang T, Pinto DJ, Structure-activity relationships of anthranilamide-based factor Xa inhibitors containing piperidinone and pyridinone P4 moieties. Bioorg Med Chem Lett 2008;18:2845-9
  • Bristol-Myers Squibb Co. Cyclic amino acid derivatives as factor Xa inhibitors. WO2006041831; 2006
  • Fevig JM, Cacciola J, Buriak JJr, Preparation of 1-(4-methoxyphenyl)- 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones as potent, selective and bioavailable inhibitors of coagulation factor Xa. Bioorg Med Chem Lett 2006;16:3755-60
  • Pinto DJP, Orwat MJ, Quan ML, 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. Bioorg Med Chem Lett 2006;16:4141-7
  • Bristol-Myers Squibb Co. Pyrazolobenzamides and derivatives as factor Xa inhibitors. US2006089496; 2006
  • Bristol-Myers Squibb Co. Crystalline forms of a factor Xa inhibitor. WO2006065853; 2006
  • Bristol-Myers Squibb Co. Crystalline forms of a factor Xa inhibitor. US2006069118; 2006
  • Bristol-Myers Squibb Co. Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones. US2006069258; 2006
  • Pinto DJP, Galemmo RAJr, Quan ML, Discovery of potent, efficacious, and orally bioavailable inhibitors of blood coagulation factor Xa with neutral P1 moieties. Bioorg Med Chem Lett 2006;16:5584-9
  • Qiao JX, Cheng X, Smallheer JM, Pyrazole-based factor Xa inhibitors containing N-arylpiperidinyl P4 residues. Bioorg Med Chem Lett 2007;17:1432-7
  • Shantsila E, Lip GY. Apixaban, an oral, direct inhibitor of activated Factor Xa. Curr Opin Invest Drugs 2008;9:1020-33
  • Jiang X, Crain EJ, Luettgen JM, Apixaban, an oral direct factor Xa inhibitor, inhibits human clot-bound factor Xa activity in vitro. Thromb Haemost 2009;101:780-2
  • Wong PC, Crain EJ, Xin B, Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost 2008;6:820-9
  • Millenium Pharm., Inc. Factor Xa inhibitors. WO2006002099; 2006
  • Millenium Pharm., Inc. Factor Xa inhibitors. US2007259924; 2007
  • Millenium Pharm., Inc. Factor Xa inhibitors. WO2008086226; 2008
  • Millenium Pharm., Inc. Factor Xa inhibitors. WO2008086188; 2008
  • Millenium Pharm., Inc. Methods of synthesizing pharmaceutical salts of a factor Xa inhibitor. WO2008057972; 2008
  • Millenium Pharm., Inc. Novel pharmaceutical salts and polymorphs of a factor Xa inhibitor. WO2007056517; 2007
  • Zhang P, Huang W, Wang L, Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N, N-dimethylcarbamidoyl)benzamido)- 5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Bioorg Med Chem Lett 2009;19:2179-85
  • Zhang P, Bao L, Fan J, Anthranilamide-based N, N-dialkylbenzamidines as potent and orally bioavailable factor Xa inhibitors: P4 SAR. Bioorg Med Chem Lett 2009;19:2186-9
  • Millenium Pharm., Inc. Combination anticoagulant therapy with a compound that acts as a factor Xa inhibitor. US2008254036; 2008
  • Glaxo Group Ltd. Chemical compounds. WO2007059952; 2007
  • Glaxo Group Ltd. Pharmaceutical composition comprising a plurality of mini-tablets comprising a factor Xa inhibitor. WO2008031782; 2008
  • Glaxo Group Ltd. Dosage formulations and methods of treatment and prevention. WO2006110726; 2006
  • Glaxo Group Ltd. Pyrrolidine derivatives as factor Xa inhibitors. US2007155745; 2007
  • Glaxo Group Ltd. Chemical compounds. EP1839659; 2007
  • Chan C, Borthwick AD, Brown D, Factor Xa Inhibitors: S1 Binding Interactions of a series of N-{(3S)- 1-[(1S)-1-Methyl-2-morpholin-4-yl- 2-oxoethyl]-2-oxopyrrolidin-3-yl}-sulfonamides. J Med Chem 2007;50:1546-57
  • Young RJ, Brown D, Burns-Kurtis CL, Selective and dual action orally active inhibitors of thrombin and factor Xa. Bioorg Med Chem Lett 2007;17:2927-30
  • Glaxo Group Ltd. 3-Sulfonylamino-pyrrolidine-2-one derivatives as factor Xa inhibitors. WO2006108709; 2006
  • Glaxo Group Ltd. N-(1-(2,3-dihydro- 1H-inden-5-yl)-2-oxo-3-pyrrolidinyl)-sulfonamide derivatives for use as factor Xa inhibitors. WO2006027186; 2006
  • Daiichi Pharm. Co. Ltd. Triamine derivative. WO2006106963; 2006
  • Daiichi Pharm. Co. Ltd. Novel diamide derivative. WO2008111299; 2008
  • Daiichi Pharm. Co. Ltd. Novel diamide derivative. WO2008111300; 2008
  • Daiichi Pharm. Co. Ltd. Novel diamide derivative. WO2008123017; 2008
  • Daiichi Pharm. Co. Ltd. Optically active diamine derivative and process for producting the same. EP1925611; 2008
  • Komoriya S, Kobayashi S, Osanai K, Design, synthesis, and biological activity of novel factor Xa inhibitors: improving metabolic stability by S1 and S4 ligand modification. Bioorg Med Chem 2006;14:1309-30
  • Nagata T, Yoshino T, Haginoya N, Cycloalkanediamine derivatives as novel blood coagulation factor Xa inhibitors. Bioorg Med Chem Lett 2007;17:4683-8
  • Astrazeneca AB. Heterocyclic sulfonamide derivatives as inhibitors of factor Xa. WO2007008144; 2007
  • Astrazeneca AB. Heterocyclic sulfonamide derivatives as inhibitors of factor Xa. WO2007008145; 2007
  • Astrazeneca AB. Heterocyclic sulfonamide derivatives as inhibitors of factor Xa. WO2007008142; 2007
  • Astrazeneca AB. Heterocyclic sulfonamide derivatives as inhibitors of factor Xa. WO2007008146; 2007
  • Merck Patent GmbH. 2-(Phenyl)- 2H-pyrazole-3-carboxilic acid- N-4-(imino-heterocyclyl)-phenyl-amide and related compounds for use as inhibitors of the coagulation factors Xa and/or VIIa for treating thromboses. EP1679073; 2006
  • Merck Patent GmbH. Arzneimittel enthaltend Carbonylverbindungen sowie deren Verwendung. DE102004045796; 2006
  • Merck Patent GmbH. Carbonyl compounds usable as coagulation factor Xa inhibitors. WO2006034769; 2006
  • Merck Patent GmbH. Proline derivatives. WO2006034789; 2006
  • Merck Patent GmbH. Carboxamides. US2006052376; 2006
  • Eli Lilly & Co. 1-(Indole-6-carbonyl- D-phenylglycinyl)-4-(1-methylpiperidin-4-yl)piperazine D-tartrate. WO2006011955; 2006
  • Eli Lilly & Co. Aromatic ether derivatives useful as thrombin ihibitors. WO2006057845; 2006
  • Eli Lilly & Co. Antithrombotic diamides. WO2006057868; 2006
  • Takeda Pharm. Co. Ltd. Sustained release preparation. WO2008066102; 2008
  • Takeda Pharm. Co. Ltd. Imidazole derivative, method for producting the same, and use of the same. JP2006008664; 2006
  • Takeda Pharm. Co. Ltd. Five membered aromatic heterocycle derivative, its manufacturing method and use. JP2007045752; 2007
  • Portola Pharm., Inc. Ureas as factor Xa inhibitors. WO2006063113; 2006
  • Portola Pharm., Inc. Thioureas as factor Xa inhibitors. WO2006063293; 2006
  • Portola Pharm., Inc. [4-(6-Halo- 7-substituted-2,4-dioxo-1,4-dihydro- 2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureas and forms and methods related thereto. WO2007056219; 2007
  • Pfizer Products, Inc. (R)-5-methyl-4, 5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4-chlorophenyl)amide-5-{[2-fluoro- 4-(2-oxo-2H-pyridin-1-yl)-phenyl]amide) as a factor Xa inhibitor. WO2008065503; 2008
  • Van Huis CA, Bigge CF, Casimiro-Garcia A, Structure-based drug design of pyrrolidine-1,2-dicarboxamides as a novel series of orally bioavailable factor Xa inhibitors. Chem Biol Drug Des 2007;69:444-50
  • Warner-Lambert Company LLC. Crystalline forms of a known pyrrolidine factor Xa inhibitor. WO2006100565; 2006
  • Aventis. Heteroaryl-carboxylic acid (sulfamoylalkyl)amide-derivatives as factor Xa inhibitors. WO2006122661; 2006
  • Legochem Biosciences Ltd. FXa inhibitors with cyclic amidines as P4 subunit, processes for their preparations, and pharmaceutical compositions and derivatives thereof. WO2008140220; 2008
  • Legochem Biosciences Ltd. Novel oxazolidinone derivatives, process for preparing thereof and pharmaceutical composition containing the same. KR20080053209; 2008
  • Tanabe Seiyaku Co. Ltd. Medicine composition. JP2006298910; 2006
  • Tanabe Seiyaku Co. Ltd. Medicine composition. JP2006298909; 2006
  • Astellas Pharma., Inc. Benzene derivative or salt thereof. WO2007055183; 2007
  • Saitoh F, Mukaihira T, Nishida H, Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitors. V. A series of new derivatives containing a spiro[imidazo[1,2-a]pyrazine-2(3H), 4′-piperidin]-5(1H)-one scaffold. Chem Pharm Bull 2006;54:1535-44
  • Saitoh F, Nishida H, Mukaihira T, Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitors VI. A series of new derivatives containing N,S- and N,SO2-spiro acetal scaffolds. Chem Pharm Bull 2007;55:317-23
  • Mochida Pharm. Co. Tricyclic spiro compound comprising acyl group bound to nitrogen atom in the ring. EP1864984; 2006
  • Mochida Pharm. Co. Spirotetracyclic compound. EP2020411; 2009
  • Concert Pharm., Inc. Substituted oxazolidinone derivatives. WO2009023233; 2009
  • Protia LLC. Deuterium-enriched apixaban. US20090076069; 2009

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