Advances in the development of thrombin inhibitors

Expert Opinion on Investigational Drugs

Volumn 10, Issue 5, 2001, Pages 845-864

  Steinmetzer, T ^a   Hauptmann, J ^a   Sturzebecher J ^a  

^a Systeme GmbH   (Germany)

Author keywords

Anticoagulants; Antithrombotics; Clinical trials; Thrombin; Thrombin inhibitor; Thrombosis

Indexed keywords

1 [3 (4 AMIDINOPHENYL) 2 (1,2,3,4 TETRAHYDRO 2 METHYL 7 ISOQUINOLINYLSULFONAMIDO)PROPIONYL] 1,2,3,6 TETRAHYDRO 4 METHYLPICOLINIC ACID; ACETYL DEXTRO PHENYLALANYLPROLYLBOROARGININE; ACETYLSALICYLIC ACID; ACOVA; ALDEHYDE DERIVATIVE; ALTEPLASE; ANTICOAGULANT AGENT; ARGATROBAN; BORONIC ACID DERIVATIVE; DESULFATOHIRUDIN; EFEGATRAN; ENOXAPARIN; HEPARIN; HIRULOG; KETONE DERIVATIVE; LB 30057; LEPIRUDIN; LOW MOLECULAR WEIGHT HEPARIN; MELAGATRAN; NOVARTAN; RECOMBINANT HIRUDIN; S 18326; SERINE PROTEINASE; SERINE PROTEINASE INHIBITOR; STREPTOKINASE; THROMBIN; THROMBIN INHIBITOR; TISSUE PLASMINOGEN ACTIVATOR; TRI 50 B; TRYPSIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; WARFARIN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ASSAY; BLEEDING; BLOOD CLOTTING; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DRUG COST; DRUG FORMULATION; DRUG HALF LIFE; DRUG INDUSTRY; DRUG RESEARCH; DRUG SOLUBILITY; HUMAN; IN VITRO STUDY; MORBIDITY; MORTALITY; NONHUMAN; PHARMACEUTICS; PHARMACOKINETICS; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; PHASE 3 CLINICAL TRIAL; PHYSICAL CHEMISTRY; PROPHYLAXIS; RAT; REVIEW; THROMBOCYTE ACTIVATION; THROMBOEMBOLISM; WESTERN HEMISPHERE;

AZETIDINES; BENZYLAMINES; CLINICAL TRIALS; GLYCINE; HIRUDIN THERAPY; HIRUDINS; PEPTIDE FRAGMENTS; PIPECOLIC ACIDS; RECOMBINANT PROTEINS; THROMBIN;

EID: 0035024232     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543784.10.5.845     Document Type: Review

References (122)

1. Direct thrombin inhibitors: Current status and future prospects
2. Thrombin active site inhibitors
3. Small-molecule direct thrombin inhibitors
4. Synthetic inhibitors of thrombin and factor Xa: From bench to bedside
5. Thrombin activatable fibrinolysis inhibitors and an antifibrinolytic pathway
6. How the protease thrombin talks to cells
7. Direct thrombin inhibitors
8. Inhibition of thrombin and trypsin by tripeptide aldehydes
9. 2Cl-a selective affinity label for thrombin
10. Potent inhibition of thrombin by the newly synthesized arginine derivative No. 805: The importance of the stereostructure of ist hydrophobic carboxamide portion
11. α-arylsulfonylamino-acylated 4-amidinophenylalanine - Tight binding inhibitors of thrombin
12. The refined 1.9 Å crystal structure of α-thrombin interaction with d-Phe-Pro-Arg chloromethylketone and significance of the Tyr-Pro-Pro-Trp insertion segment
13. Crystallographic analysis at 3.0-Å resolution of the binding to human thrombin of four active site-directed inhibitors
14. The structure of a complex of recombinant hirudin and human α-thrombin
15. Argatroban during percutaneous transluminal angioplasty; results of a dose verification study
16. A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: Myocardial infarction with novastan and TPA (MINT) study
17. Anticoagulant properties, clinical efficacy and safety of efegatran, a direct thrombin inhibitor, in patients with unstable angina
18. An exploratory trial of two dosages of a novel synthetic thrombin inhibitor (napsagatran, Ro 46-6240) compared with unfractionated heparin for treatment of proximal deep-vein thrombosis. Results of the European trial
19. Heparin is more effective than inogatran, a low-molecular weight thrombin inhibitor in suppressing ischemia and recurrent angina in unstable coronary disease
20. Synthetic direct thrombin inhibitors in unstable angina - More questions than answers
21. Novastan anticoagulation during renal stent implant in a patient with heparin-induced thrombocytopenia
22. Application of argatroban, a direct thrombin inhibitor, in heparin-intolerant patients requiring extracorporeal circulation
23. The pharmacokinetics and pharmacodynamics of argatroban: Effects of age, gender, and hepatic or renal dysfunction
24. Argatroban and Alteplase in Patients with Acute Myocardial Infarction: The ARGAMI Study
25. The preclinical and clinical pharmacology of Novastan (Argatroban)
26. Anticoagulant activity and pharmacokinetic properties of a sub-cutaneously administered mixed micellar formulation of argatroban in experimental animals
27. Activity of a sub-cutaneously administered novel mixed micellar formulation of argatroban in rat and rabbit models of venous thrombosis
28. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement
29. Design and characterization of hirulogs: A novel class of bivalent peptide inhibitors of thrombin
30. Bivalirudin: A new generation antithrombotic drug
31. Selection of S18326 as a new potent and selective boronic acid direct thrombin inhibitor
32. The selective inhibition of thrombin by peptides of boroarginine
33. S 18326: A thrombin inhibitor that shows potential for oral treatment of thromboembolic disorders
34. Rational design of boropeptide thrombin inhibitors: β,β-dialkyl-phenethylglycine P2 analogs of DuP 714 with greater selectivity over complement factor 1 and improved safety profile
35. The importance of enzyme inhibition kinetics for the effect of thrombin inhibitors in a rat model of arterial thrombosis
36. New peptide boronic acid inhibitors of thrombin
37. Characterization of a class of peptide boronates with neutral P1 side chains as highly selective inhibitors of thrombin
38. Pharmacokinetics and bioavailability of a novel direct thrombin inhibitor in rats following intravenous and intraduodenal administration
39. Highly active and selective anticoagulants: d-Phe-Pro-Arg-H, a free tripeptide aldehyde prone to spontaneous inactivation, and its stable N-methyl derivative, d-MePhe-Pro-Arg-H
40. The mechanism of binding of low-molecular-weight active site inhibitors to human α-thrombin
41. Efegatran, a new direct thrombin inhibitor: Safety and dose response in patients with unstable angina
42. Clinical hemorrhage and coagulation parameters following therapy with efegatran versus heparin in the ESCALAT trial
43. Development of an orally active tripeptide arginal thrombin inhibitor
44. 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
45. Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes
46. Effects of melagatran, a novel direct thrombin inhibitor, in healty volunteers following intravenous, subcutaneous and oral administration
47. Effects of melagatran, a novel direct thrombin inhibitor, during experimental septic shock
48. Effects of melagatran, an inhibitor of thrombin, on fibrin deposits, haemodynamics, and platelet count in endotoxaemic pigs
49. Effect of activated prothrombin complex concentrate of recombinant factor VIIa on the bleeding time and thrombus formation during anticoagulation with a direct thrombin inhibitor
50. Effects of agents, used to treat bleeding disorders, on bleeding time prolonged by a very high dose of a direct thrombin inhibitor in anesthesized rats and rabbits
51. Pharmacokinetic and pharmacodynamics of melagatran, a novel synthetic LMW thrombin inhibitor, in patients with acute DVT
52. The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: Intestinal absorption properties, biochemical and pharmacodynamic effects
53. Single and repeated oral dosing of H 376/95, a prodrug of the direct thrombin inhibitor melagatran, to young healthy male subjects
54. Pharmacodynamic properties of H 376/95, a prodrug of the direct thrombin inhibitor melagatran, intended for oral use
55. Subcutaneous and oral direct thrombin inhibitors for prophylaxis of deep venous thrombosis and pulmonary embolism after total hip and knee replacement
56. The discovery of UK-156,406 - An orally active thrombin inhibitor
57. Rational design of selective thrombin inhibitors
58. Discovery of LB30057, a benzamidrazone-based selective oral thrombin inhibitor
59. Synthese antiproteolytisch wirksamer Nα-arylsulfonylierter Amidinophenylalaninamide
60. Serine Proteases: 3D structures, mechanisms of action and inhibitors
61. The Antithrombotic Effects of CI-1028, an Orally Bioavailable Direct Thrombin Inhibitor, in a Canine Model of Venous and Arterial Thrombosis
62. Biaryl substituted alkylboronate esters as thrombin inhibitors
63. New inhibitors of thrombin and other trypsin-like protease: Hydrogen bonding of an aromatic cyano group with a backbone amide of the P1 binding site replaces binding of a basic side chain
64. Design, synthesis and biological evaluation of selective boron-containing thrombin inhibitors
65. Design, synthesis, and evolution of a novel, selective, and orally bioavailable class of thrombin inhibitors: P1-arginal derivatives incorporating P3-P4 lactam sulfonamide moieties
66. Potent and selective thrombin inhibitors incorporating the constrained arginine mimic L-3-piperidyl(N-guanidino)alanine at P1
67. Potent and selective thrombin inhibitors featuring hydrophobic, basic P3-P4-aminoalkyllactam moieties
68. Design and synthesis of a novel class of thrombin inhibitors incorporating heterocyclic dipeptide surrogates
69. Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 Modifications
70. Potent and selective bicyclic lactam inhibitors of thrombin: Part 3: P1′ Modifications
71. The design of potent and selective inhibitors of thrombin utilizing a piperazinedione template: Part 1
72. Secondary structure peptide mimetics: Design, synthesis, and evaluation of β-strand mimetic thrombin inhibitors
73. Novel natural product 5,5-trans-lactone inhibitors of human α-thrombin: Mechanism of action and structural studies
74. Synthetic [5,5] trans-fused indane lactones as inhibitors of thrombin
75. Thrombin inhibitors based on [5,5] trans-fused indane lactams
76. Structural modification of an orally active thrombin inhibitor, LB30057: Replacement of the d-pocket-binding naphthyl moiety
77. Potent and efficacious thienylamidine-incorporated thrombin inhibitors
78. Benzylamine-based selective and orally bioavailable inhibitors of thrombin
79. Synthesis and structure-activity relationships of potent thrombin inhibitors: Piperazides of 3-amidinophenylalanine
80. Design, synthesis and testing of amino-bicycloaryl based orally bioavailable thrombin inhibitors
81. 1-Aminoisoquinoline as benzamidine isoster in the design and synthesis of orally active thrombin inhibitors
82. The discovery of orally available thrombin inhibitors: Studies towards the optimisation of CGH1668
83. Studies towards the identification of potent, selective and bioavailable thrombin inhibitors
84. Optimisation of the P2 pharmacophore in a series of thrombin inhibitors: Ion-dipole interactions with lysine 60 G
85. The design and synthesis of thrombin inhibitors: Analogues of MD805 containing non-polar surrogates for arginine at the P1 position
86. The design and synthesis of thrombin inhibitors: The introduction of in vivo efficacy and oral bioavailability into benzthiazolylalanine inhibitors
87. Design of highly potent noncovalent thrombin inhibitors that utilize a novel lipophilic binding pocket in the thrombin active site
88. Discovery of a novel, selective, and orally bioavailable class of thrombin inhibitors incorporating amidinopyridyl moieties at the P1 position
89. Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position
90. L-374,087, an efficacious, orally bioavailable, pyridinone acetamide thrombin inhibitor
91. C6 modification of the pyridinone core of thrombin inhibitor L-374,087 as a means of enhancing its oral absorption
92. Efficacous, orally bioavailable thrombin inhibitors based on 3-aminopyridinone or 3-aminopyrazinone acetamide peptidomimetic templates
93. In vitro and in vivo properties of bicyclic-lactam inhibitors. A novel class of low molecular weight peptidomimetic thrombin inhibitors
94. In vitro and in vivo studies of AT-1362, a newly synthesized and orally active inhibitor of thrombin
95. The design of potent, selective, non-covalent, peptide thrombin inhibitors utilizing imidazole as a S1 binding element
96. Noncovalent thrombin inhibitors incorporating an imidazolylethynylP1
97. New thrombin inhibitors based on D-Cha-Pro-derivatives
98. Dibasic benzo[b]thiophene derivatives as a novel class of active site-directed thrombin inhibitors. 1. Determination of the serine protease selectivity, structure-activity relationships, and binding orientation
99. Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 2. Sidechain optimization and demonstration of in vivo efficacy
100. Enzyme flexibility, solvent and 'weak' interactions characterize thrombin-ligand interactions: Implications for drug design
101. Derivatives of 4-amino-pyridine as selective thrombin inhibitors
102. Comparative molecular field analysis and energy interaction studies of thrombin-inhibitor complexes
103. Expanding the envelope of structure-based design using chemical libraries: Application to small-molecule inhibitors of thrombin
104. In vitro evaluation and crystallographic analysis of a new class of selective, non-amide-based thrombin inhibitors
105. Amidinohydrazones as guanidine bioisosteres: Application to a new class of potent selective and orally bioavailable, non-amide-based small-molecule thrombin inhibitors
106. Successful attenuation of venous thrombus growth in rabbits after the administration of a novel oral thrombin inhibitor
107. Drug development pipeline: Terbogrel, BIBR-1048 and ion channel blockers
108. Pharmacokinetics and anticoagulant effect of BMS-189664 following single ascending oral and iv. doses in healthy male subjects
109. Design of potent bivalent thrombin inhibitors based on hirudin sequence: Incorporation of nonsubstrate-type active site inhibitors
110. Design of P1′ and P3′ residues of trivalent thrombin inhibitors and their crystal structures
111. Design and evaluation of novel bivalent thrombin inhibitors based on amidinophenylalanines
112. Bifunctional peptide boronate inhibitors of thrombin: Crystallographic analysis of inhibition enhanced by linkage to an exosite 1 binding peptide
113. Potent Bivalent Thrombin Inhibitors: Replacement of the Scissile Peptide Bond at P1-P1′ with Arginyl Ketomethylene Isosteres
114. Effective use of BCH-2763, a new potent injectable direct thrombin inhibitor, in combination with tissue plasminogen activator (tPA) in a rat arterial thrombolysis model
115. BCH-2763, a novel potent parenteral thrombin inhibitor, is an effective antithrombotic agent in rodent models of arterial and venous thrombosis; Comparisons with heparin, r-hirudin, hirulog, inogatran and argatroban
116. Low molecular weight heparin in unstable coronary artery disease
117. Heparin-induced thrombocytopenia: Towards consensus
118. Platelet glycoprotein IIb-IIIa antagonists as prototypical integrin blockers: Novel parenteral and potential oral antithrombotic agents
119. Anti-aggregatory drugs: I. Platelet receptor antagonists
120. Antiplatelet therapies
121. Factor Xa Inhibitors: Recent advances in anticoagulant agents
122. Direct thrombin inhibitors in acute coronary syndromes and during percutaneous coronary intervention: Design of a meta-analysis based on individual patient data