Discovery of 1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2′-(methylsulfonyl)-[1,1′-b iphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa

Journal of Medicinal Chemistry

Volumn 44, Issue 4, 2001, Pages 566-578

  Pinto, D J P ^a   Orwat, M J ^a   Wang, S ^a   Fevig, J M ^a   Quan, M L ^a   Amparo, E ^a   Cacciola, J ^a   Rossi, K A ^a   Alexander, R S ^a   Smallwood, A M ^a   Luettgen, J M ^a   Liang, L ^a   Aungst, B J ^a   Wright, M R ^a   Knabb, R M ^a   Wong, P C ^a   Wexler, R R ^a   Lam, P Y S ^a  

^a DUPONT COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 [3 (AMINOMETHYL)PHENYL] N [3 FLUORO 2' (METHYLSULFONYL)(1,1' BIPHENYL) 4 YL] 3 (TRIFLUOROMETHYL) 1H PYRAZOLE 5 CARBOXAMIDE; 1 [3 (AMINOMETHYL)PHENYL] N [3 FLUORO 2' (METHYLSULFONYL)[1,1' BIPHENYL] 4 YL] 3 (TRIFLUOROMETHYL) 1H PYRAZOLE 5 CARBOXAMIDE; BENZAMIDINE; BENZYLAMINE; BLOOD CLOTTING FACTOR 10A INHIBITOR; FIBRIN; FIBRINOGEN; PHOSPHOLIPID; PYRAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

ANTICOAGULATION; ARTICLE; BLOOD CLOTTING; CALCIUM TRANSPORT; DRUG MECHANISM; DRUG POTENCY; ENDOTHELIUM CELL; HUMAN; HUMAN CELL; SYNTHESIS; THROMBOEMBOLISM;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; CRYSTALLOGRAPHY, X-RAY; DOGS; FACTOR XA; FIBRINOLYTIC AGENTS; MODELS, MOLECULAR; PYRAZOLES; RATS; SERINE PROTEINASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONES;

EID: 0035865785     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm000409z     Document Type: Article

References (68)

1. The design and synthesis of orally bioavailable noncovalent factor Xa inhibitors
2. The discovery of a novel pyrazole SN429, a highly potent inhibitor of coagulation factor Xa
3. Guide to anticoagulant therapy. Part 2: Oral anticoagulants
4. Oral anticoagulant drugs
5. Direct thrombin inhibitors in cardiovascular medicine
6. Advances in antithrombotic drug therapy for coronary artery disease
7. Recent development in antithrombotic agents
8. Use of Warfarin (Coumadin)
9. Antithrombotic therapy. Introduction
10. Therapeutic level of anticoagulation with warfarin in patients with mechanical prosthetic heart valves; review of literature and recommendations based on internal normalized ratio
11. The international normalized ratio. A guide to understanding and correcting its problems
12. Effects of synthetic thrombin inhibitor argatroban on fibrin or clot-incorporated thrombin: Comparison with heparin and recombinant hirudin
13. Hirudin interruption of heparin-resistant arterial thrombus formation in baboons
14. Synthetic low-Molecular weight thrombin inhibitors: Molecular design and pharmacological profile
15. Direct thrombin inhibitors
16. Activation of human prothrombin by highly purified human factor V and FXa in presence of human antithrombin
17. The coagulation cascade: Initiation, maintenance and regulation
18. Purification and mechanism of action of human antithrombin-heparin cofactor
19. Surface-dependent enzyme complexes
20. Anticoagulants: Thrombin and factor Xa inhibitors
21. Small, non-covalent serine protease inhibitors
22. Synthetic inhibitors of thrombin and factor Xa: From bench to bedside
23. Antithrombin agents as anticoagulants and antithrombotics: Implications in drug development
24. Oral thrombin inhibitors: Challenges and progress
25. Recent advances in inhibitors of factor Xa in the prothrombinase complex
26. Factor Xa inhibitors by classical and combinatorial chemistry
27. Coagulation factor Xa: The pro-thrombinase complex as an emerging therapeutic target for small molecule inhibitors
28. DX-9065a an orally active specific inhibitor of factor Xa inhibits thrombosis without affecting bleeding time in rats
29. Antithrombotic efficacy of recombinant tick anticoagulant peptide: A potent inhibitor of coagulation factor Xa in a primate model of arterial thrombosis
30. Primary prevention of coronary arterial thrombosis with the factor Xa inhibitor rTAP in a canine electrolytic injury model
31. Conjunctive enhancement of enzymatic thrombolysis and prevention of thrombotic reocclusion with the selective factor Xa inhibitor, Tick anticoagulant peptide: Comparison to hirudin and heparin in a canine model of acute coronary artery thrombosis
32. Design, synthesis and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors
33. The de novo design and synthesis of cyclic urea inhibitors of factor Xa: Initial SAR studies
34. Rational design and synthesis of novel potent Bis-phenylamidine carboxylate factor Xa inhibitors
35. Design and synthesis of isoxazoline derivatives as factor Xa inhibitors
36. YM-60828, a novel factor Xa inhibitor: Separation of its antithrombotic effects from its prolongation of bleeding time
37. Design, synthesis and biological activities of orally active coagulation factor Xa inhibitors
38. Dibasic (amidinoaryl)propanoic acid derivatives as novel blood coagulation factor Xa inhibitors
39. Synthetic inhibition of serine proteinases XXIII. Inhibition of factor Xa by diamidines
40. Synthetic inhibitors of serine proteinases XIV. Inhibition of factor Xa by derivatives of benzamidines
41. Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 1
42. Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 2
43. Isoxazolines and isoxazoles as factor Xa inhibitors
44. Vic-Dicarboxylic acid derivatives of pyrazole, isoxazole and pyrimidine
45. Regioselective route to 3-alkyl-1aryl-1H-pyrazole-5-carboxylates: Synthetic studies and structural assignments
46. Kisiel, Structure of human Des (1-45) factor Xa at 2.2 Ang. resolution W
47. Assembly of the prothrombinase complex enhances the inhibition of bovine factor Xa by tick anticoagulant peptide
48. Tick anticoagulant peptide: Kinetic analysis of the recombinant inhibitor with blood coagulation factor Xa
49. Tick anticoagulant peptide (TAP) is a novel inhibitor of blood coagulation factor Xa
50. Structural Aspects of Factor Xa Inhibition
51. Crystal structures of factor Xa inhibitors in complex with trypsin: Structural grounds for inhibition of factor Xa and selectivity against thrombin
52. Refined 2.3 Å X-ray crystal structure of bovine thrombin complexes formed with the benzamidine and arginine-based thrombin inhibitors NAPAP, 4-TAPAP and MQPA. A starting point for improving antithrombotics
53. Geometry of binding of the N-alpha-tosylated piperidides of m-amidino, p-amidino and p-guanidino phenylalanine to thrombin and trypsin. X-ray crystal structures of their trypsin complexes and modeling of their thrombin complexes
54. Crystallographic analysis at 3.0-A resolution of the binding to human thrombin of four active site-directed inhibitors
55. Geometry of binding of the benzamidine and arginine-based inhibitors N-alpha-(2-naphthylsulphonyl-glycyl)-DL-p-amidinophenylalanyl-piperidine (NA-PAP) and (2R,4R)-4-methyl-1-[N-alpha-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulphonyl )-L-arginyl]-2-piperidine carboxylic acid (MQPA) to human alpha-thrombin
56. X-ray analysis of a thrombin inhibitor-trypsin complex
57. The synthesis of Methyl 1-Aryl-2-pyrrole-carboxylates
58. The selective inhibition of thrombin by peptides of boroarginine
59. Nonpeptide Factor Xa Inhibitors I. Studies with SF303 and SK549, a new class of potent antithrombotics
60. Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa
61. Introduction: Blood coagulation
62. Nonpeptide factor Xa inhibitors II. Antithrombotic evaluation in a rabbit model of electrically induced carotid artery thrombosis
63. Antithrombotic effects of DPC 423, a potent and orally active nonpeptide factor Xa inhibitor, in rabbit models of thrombosis