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1.
J Thromb Haemost ; 6(5): 820-9, 2008 May.
Article in English | MEDLINE | ID: mdl-18315548

ABSTRACT

BACKGROUND: Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. OBJECTIVE: We evaluated the in vitro properties of apixaban and its in vivo activities in rabbit models of thrombosis and hemostasis. METHODS: Studies were conducted in arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), electrically mediated carotid arterial thrombosis (ECAT) and cuticle bleeding time (BT) models. RESULTS: In vitro, apixaban is potent and selective, with a K(i) of 0.08 nm for human FXa. It exhibited species difference in FXa inhibition [FXa K(i) (nm): 0.16, rabbit; 1.3, rat; 1.7, dog] and anticoagulation [EC(2x) (microm, concentration required to double the prothrombin time): 3.6, human; 2.3, rabbit; 7.9, rat; 6.7, dog]. Apixaban at 10 microm did not alter human and rabbit platelet aggregation to ADP, gamma-thrombin, and collagen. In vivo, the values for antithrombotic ED(50) (dose that reduced thrombus weight or increased blood flow by 50% of the control) in AVST, VT and ECAT and the values for BT ED(3x) (dose that increased BT by 3-fold) were 0.27 +/- 0.03, 0.11 +/- 0.03, 0.07 +/- 0.02 and > 3 mg kg(-1) h(-1) i.v. for apixaban, 0.05 +/- 0.01, 0.05 +/- 0.01, 0.27 +/- 0.08 and > 3 mg kg(-1) h(-1) i.v. for the indirect FXa inhibitor fondaparinux, and 0.53 +/- 0.04, 0.27 +/- 0.01, 0.08 +/- 0.01 and 0.70 +/- 0.07 mg kg(-1) day(-1) p.o. for the oral anticoagulant warfarin, respectively. CONCLUSIONS: In summary, apixaban was effective in the prevention of experimental thrombosis at doses that preserve hemostasis in rabbits.


Subject(s)
Pyrazoles/pharmacology , Pyridones/pharmacology , Thrombosis/drug therapy , Animals , Carotid Artery Thrombosis , Disease Models, Animal , Dogs , Factor Xa Inhibitors , Hemostasis/drug effects , Humans , Platelet Aggregation/drug effects , Pyrazoles/administration & dosage , Pyridones/administration & dosage , Rabbits , Rats , Thrombosis/prevention & control , Venous Thrombosis
3.
J Med Chem ; 44(4): 566-78, 2001 Feb 15.
Article in English | MEDLINE | ID: mdl-11170646

ABSTRACT

Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K(i) = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.


Subject(s)
Factor Xa Inhibitors , Fibrinolytic Agents/chemical synthesis , Pyrazoles/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Sulfones/chemical synthesis , Administration, Oral , Animals , Biological Availability , Crystallography, X-Ray , Dogs , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacokinetics , Fibrinolytic Agents/pharmacology , Models, Molecular , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacokinetics , Sulfones/pharmacology
4.
J Med Chem ; 43(23): 4398-415, 2000 Nov 16.
Article in English | MEDLINE | ID: mdl-11087565

ABSTRACT

Thrombotic diseases are a major cause of death and morbidity. Factor Xa (fXa) plays a vital role in the regulation of normal homeostasis and abnormal intravascular thrombus development in the blood coagulation cascade. A novel series of fXa inhibitors incorporating an amidino 6,5-fused bicyclic moiety at the P1 position has been designed and synthesized based on molecular modeling studies. Structure-activity relationship (SAR) studies have led to selective subnanomolar fXa inhibitors. The most potent fXa inhibitor in this series (72, SE170) has a potent inhibition constant (K(i) = 0.3 nM), is 350-fold selective for fXa over trypsin, and also shows good in vivo efficacy in a rabbit arterio-venous thrombosis model (ID(50) = 0.14 micromol/kg/h). An X-ray crystal structure of 72 complexed to bovine trypsin was completed, and a binding mode of 72 with fXa has been proposed based on modeling with human des-Gla-fXa.


Subject(s)
Amidines/chemical synthesis , Benzimidazoles/chemical synthesis , Factor Xa Inhibitors , Fibrinolytic Agents/chemical synthesis , Indazoles/chemical synthesis , Indoles/chemical synthesis , Sulfonamides/chemical synthesis , Amidines/chemistry , Amidines/pharmacokinetics , Amidines/pharmacology , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Cattle , Crystallography, X-Ray , Dogs , Drug Design , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacokinetics , Fibrinolytic Agents/pharmacology , Humans , Indazoles/chemistry , Indazoles/pharmacokinetics , Indazoles/pharmacology , Indoles/chemistry , Indoles/pharmacokinetics , Indoles/pharmacology , Models, Molecular , Rabbits , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Trypsin/chemistry , Venous Thrombosis/drug therapy
5.
J Pharmacol Exp Ther ; 295(1): 212-8, 2000 Oct.
Article in English | MEDLINE | ID: mdl-10991981

ABSTRACT

SK549 (mol. wt. 546 Da) is a synthetic, selective inhibitor of human coagulation factor Xa (fXa) (K(i) = 0.52 nM). This study compared the antithrombotic effects of SK549 and a series of benzamidine isoxazoline fXa inhibitors with aspirin, DuP 714 (a direct thrombin inhibitor), recombinant tick anticoagulant peptide, or heparin in a rabbit model of electrically induced carotid arterial thrombosis. Compounds were infused i.v. continuously from 60 min before electrical stimulation to the end of the experiment. Values of ED(50) (dose that increases the carotid blood flow to 50% of the control) were 0.12 micromol/kg/h for SK549, 0.56 micromol/kg/h for aspirin, 0.14 micromol/kg/h for DuP 714, 0.06 micromol/kg/h for recombinant tick anticoagulant peptide, and >100 U/kg/h for heparin. The EC(50) (plasma concentration that increased blood flow to 50% of the control) for SK549 was 97 nM. Unlike aspirin and heparin, SK549 was efficacious and, at 1.5 micromol/kg/h i.v. (n = 9), maintained carotid blood flow at 87 +/- 6% of control level for greater than 90 min. Unlike heparin, SK549 inhibited ex vivo fXa activity but not ex vivo thrombin activity. There was a highly significant correlation between K(i) (fXa) and ED(50) of a series of fXa inhibitors (r = 0. 85, P <.001). Therefore, these results suggest that SK549 is a novel, potent, and effective antithrombotic agent in a rabbit model of arterial thrombosis. It is likely that SK549 exerts its antithrombotic effect through selective inhibition of fXa. Furthermore, SK549 may be clinically useful for the prevention of arterial thrombosis.


Subject(s)
Carotid Artery Thrombosis/drug therapy , Factor Xa Inhibitors , Fibrinolytic Agents/therapeutic use , Isoxazoles/therapeutic use , Tetrazoles/therapeutic use , Animals , Aspirin/pharmacology , Blood Pressure/drug effects , Boron Compounds/pharmacology , Heart Rate/drug effects , Heparin/pharmacology , Humans , Isoxazoles/pharmacology , Male , Microscopy, Electron, Scanning , Oligopeptides/pharmacology , Platelet Aggregation/drug effects , Rabbits , Recombinant Proteins/pharmacology , Tetrazoles/pharmacology
6.
Bioorg Med Chem Lett ; 10(11): 1253-6, 2000 Jun 05.
Article in English | MEDLINE | ID: mdl-10866393

ABSTRACT

Conformationally restricted borolysine compounds containing a 2-(2-cyanophenylthio) benzoyl in the P3 position unexpectedly led to enhanced factor Xa inhibition. In an effort to improve both the potency and selectivity of this series by extending into the S' domain, we have replaced the boronic acid with alpha-ketoamides, utilizing a novel process that was developed in our labs.


Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Factor Xa Inhibitors , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Amides/chemistry , Models, Molecular , Serine Proteinase Inhibitors/chemistry , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 10(8): 685-9, 2000 Apr 17.
Article in English | MEDLINE | ID: mdl-10782664

ABSTRACT

3,4,5-Trisubstituted isoxazolines (2) and isoxazoles (3) were prepared and evaluated for their in vitro and in vivo antithrombotic efficacy. They were compared to 3,5,5-trisubstituted isoxazolines (1) for Factor Xa selectivity and potency. They were also compared in an arterio-venous (A-V) shunt model of thrombosis.


Subject(s)
Factor Xa Inhibitors , Isoxazoles/pharmacology , Serine Proteinase Inhibitors/pharmacology , Animals , Crystallography, X-Ray , Isoxazoles/chemistry , Isoxazoles/pharmacokinetics , Models, Molecular , Rabbits , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacokinetics , Structure-Activity Relationship , Thrombosis/prevention & control
8.
Bioorg Med Chem Lett ; 10(3): 301-4, 2000 Feb 07.
Article in English | MEDLINE | ID: mdl-10698459

ABSTRACT

In this report refinements to the S4 ligand group leads to compound 19, an inhibitor of fXa with good potency in vitro and an improved pharmacokinetic profile in rabbit. The X-ray crystallographic study of a representative analogue confirms our binding model for this series.


Subject(s)
Factor Xa Inhibitors , Serine Proteinase Inhibitors/chemical synthesis , Urea/chemical synthesis , Animals , Crystallography, X-Ray , Ligands , Models, Molecular , Rabbits , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Urea/pharmacokinetics , Urea/pharmacology
9.
J Pharmacol Exp Ther ; 292(1): 351-7, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10604970

ABSTRACT

A series of benzamidine isoxazoline derivatives was evaluated for their inhibitory potency against purified human factor Xa (fXa) and in a rabbit model of arteriovenous shunt thrombosis for their antithrombotic activities, expressed as K(I) and IC(50), respectively. A highly significant correlation was found between K(I) and IC(50) (r = 0.93, P <.0001). The antithrombotic effects of SF303 [mol. wt. 536; K(I): fXa, 6.3 nM; thrombin, 3,100 nM; trypsin, 110 nM; tissue plasminogen activator >20,000 nM; plasmin, 2,500 nM] and SK549 [mol. wt. 546; K(I): fXa, 0.52 nM; thrombin, 400 nM; trypsin, 45 nM; tissue plasminogen activator >33,000 nM; plasmin, 890 nM] were compared with recombinant tick anticoagulant peptide [K(I)(fXa) = 0.5 nM], DX-9065a [K(I)(fXa) = 30 nM], and heparin or low molecular weight heparin (dalteparin) in a rabbit model of arteriovenous shunt thrombosis. ID(50) values for preventing arteriovenous shunt-induced thrombosis were 0.6 micromol/kg/h for SF303, 0.035 micromol/kg/h for SK549, 0.01 micromol/kg/h for recombinant tick anticoagulant peptide, 0.4 micromol/kg/h for DX-9065a, 21 U/kg/h for heparin, and 23 U/kg/h for low molecular weight heparin. SK549 produced a concentration-dependent antithrombotic effect with an IC(50) of 0.062 microM. To evaluate its potential oral efficacy, SK549 was given intraduodenally at a dose of 5 mg/kg; it produced a peak antithrombotic effect of 59 +/- 4% with a duration of action greater than 6.7 h. Therefore, our study suggests that SF303, SK549, and their analogs represent a new class of synthetic fXa inhibitors that may be clinically useful as antithrombotic agents.


Subject(s)
Blood Coagulation/drug effects , Factor Xa Inhibitors , Isoxazoles/pharmacology , Platelet Aggregation/drug effects , Sulfonamides/pharmacology , Tetrazoles/pharmacology , Thrombosis/drug therapy , Animals , Anticoagulants/pharmacology , Arteriovenous Shunt, Surgical , Dalteparin/pharmacology , Dose-Response Relationship, Drug , Fibrinolytic Agents/pharmacology , Fibrinolytic Agents/therapeutic use , Heparin/pharmacology , Humans , In Vitro Techniques , Isoxazoles/therapeutic use , Male , Naphthalenes/pharmacology , Propionates/pharmacology , Rabbits , Recombinant Proteins/pharmacology , Tetrazoles/therapeutic use
10.
J Med Chem ; 42(15): 2760-73, 1999 Jul 29.
Article in English | MEDLINE | ID: mdl-10425087

ABSTRACT

Intravascular clot formation is an important factor in a number of cardiovascular diseases. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for thrombin activation. Herein we report a series of isoxazoline derivatives which are potent FXa inhibitors. Optimization of the side chain at the quaternary position of the isoxazoline ring led to SK549 which showed subnanomolar FXa potency (K(i) 0.52 nM). SK549 shows good selectivity for FXa compared to thrombin and trypsin, potent antithrombotic effect in the rabbit arterio-venous thrombosis model, and improved pharmacokinetics relative to other compounds evaluated from this series.


Subject(s)
Factor Xa Inhibitors , Fibrinolytic Agents/chemical synthesis , Isoxazoles/chemical synthesis , Tetrazoles/chemical synthesis , Animals , Arteriovenous Shunt, Surgical , Binding Sites , Crystallography, X-Ray , Dogs , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Humans , Isoxazoles/chemistry , Isoxazoles/pharmacology , Models, Molecular , Rabbits , Structure-Activity Relationship , Tetrazoles/chemistry , Tetrazoles/pharmacology , Thrombin/antagonists & inhibitors , Thrombosis/drug therapy , Trypsin/metabolism , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/chemistry , Trypsin Inhibitors/pharmacokinetics , Trypsin Inhibitors/pharmacology
11.
J Med Chem ; 42(15): 2752-9, 1999 Jul 29.
Article in English | MEDLINE | ID: mdl-10425086

ABSTRACT

Thrombosis is a major cause of mortality in the industrialized world. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for prothrombin activation. We report a series of novel biaryl-substituted isoxazoline derivatives in which the biaryl moiety was designed to interact with the S(4) aryl-binding domain of the FXa active site. Several of the compounds herein have low nanomolar affinity for FXa, have good in vitro selectivity for FXa, and show potent antithrombotic efficacy in vivo. The three most potent compounds (33, 35, and 37) have inhibition constants for human FXa of 3.9, 2.3, and 0.83 nM, respectively, and ID(50)'s ranging from 0.15 to 0.26 micromol/kg/h in the rabbit arterio-venous thrombosis model.


Subject(s)
Acetates/chemical synthesis , Factor Xa Inhibitors , Fibrinolytic Agents/chemical synthesis , Isoxazoles/chemical synthesis , Acetates/chemistry , Acetates/pharmacology , Animals , Arteriovenous Shunt, Surgical , Binding Sites , Biphenyl Compounds , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Humans , Isoxazoles/chemistry , Isoxazoles/pharmacology , Models, Molecular , Rabbits , Structure-Activity Relationship , Thrombosis/drug therapy
12.
Bioorg Med Chem Lett ; 9(8): 1195-200, 1999 Apr 19.
Article in English | MEDLINE | ID: mdl-10328312

ABSTRACT

The serine protease factor Xa is a critical enzyme in the blood coagulation cascade. Recently, the inhibition of factor Xa has begun to emerge as an attractive strategy for the discovery of novel antithrombotic agents. Here we describe pyrrolidine and isoxazolidine benzamidines as novel and potent inhibitors of factor Xa.


Subject(s)
Benzamidines/chemical synthesis , Benzamidines/pharmacokinetics , Factor Xa Inhibitors , Isoxazoles/chemical synthesis , Isoxazoles/pharmacokinetics , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Animals , Models, Molecular , Rabbits
13.
Bioorg Med Chem Lett ; 9(7): 925-30, 1999 Apr 05.
Article in English | MEDLINE | ID: mdl-10230612

ABSTRACT

Thrombin, a serine protease, plays a central role in the initiation of thrombotic events. We report the design, synthesis, and antithrombotic efficacy of XU817 (7), a nonpeptide 5-(amidino) indole thrombin inhibitor. Utilizing the co-crystal structure of XU817 bound in the active site of thrombin we were able to synthesize analogs with enhanced thrombin affinity.


Subject(s)
Amidines/chemistry , Antithrombins/chemistry , Heterocyclic Compounds/chemistry , Indoles/chemistry , Amidines/chemical synthesis , Amidines/pharmacology , Animals , Antithrombins/chemical synthesis , Antithrombins/pharmacology , Drug Design , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacology , Hydrogen Bonding , Indoles/chemical synthesis , Indoles/pharmacology , Molecular Structure , Rats
14.
Thromb Res ; 93(3): 101-12, 1999 Feb 01.
Article in English | MEDLINE | ID: mdl-10030826

ABSTRACT

The suitability of rabbit prothrombin activation fragment F 1.2 as a marker for the activation of the coagulation system was tested. Monoclonal antibodies to rabbit F 1.2 were raised, and a competitive F 1.2 ELISA was developed. Within the detection limit of the ELISA, no increase in rabbit F 1.2 was detected upon recalcification of plasma, whereas human F 1.2 increased 1500-fold. The apparent lack of F 1.2 formation in rabbit serum was confirmed by immunoblotting analysis of endogenous and biotin-labeled prothrombin. Meizothrombin and the B-chain of thrombin were the only prothrombin fragments detectable. In contrast, labeled human prothrombin formed, in addition, prethrombin 2 and F 1.2 in both human and rabbit serum. In contrast, rabbit F 1.2 formation could be demonstrated using purified rabbit prothrombin and factor Xa. These observations raise the possibility that rabbit prothrombin is less susceptible than the human counterpart to factor Xa cleavage at the 271/272 peptide bond. Thus, the primary structure of rabbit prothrombin was deduced by cDNA sequencing. While the 320/321 Xa cleavage site giving rise to meizothrombin was identical in rabbit and human prothrombin, the flanking region of the 271/272 Xa sensitive site contained a six amino acid deletion in the rabbit sequence. Taken together, these observations suggest that the observed differences between human and rabbit prothrombin activation may be due to different susceptibilities of the two Xa cleavage sites rather than plasma or serum cofactor(s).


Subject(s)
Blood Coagulation , Peptide Fragments/physiology , Prothrombin/physiology , Amino Acid Sequence , Animals , DNA, Complementary/genetics , Enzyme-Linked Immunosorbent Assay , Humans , Molecular Sequence Data , Rabbits , Sequence Alignment , Sequence Analysis, DNA , Species Specificity
15.
Thromb Haemost ; 80(4): 686-91, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9798991

ABSTRACT

Cardiopulmonary bypass causes hemorrhagic complications, and initiates a chemical and cellular inflammatory response. Contact of blood with synthetic surfaces leads to qualitative and quantitative alterations in platelets, neutrophils, complement, and contact systems. Despite the fact that cardiopulmonary bypass is carried out in the presence of high doses of heparin, there is significant activation of both platelets and neutrophils. Thrombin is protected on cell and fibrin surfaces from antithrombin, even in the presence of high doses of heparin (approximately 5 U/ml). We therefore studied the effect of a small (Mr = 497), highly effective (Ki = 41 pM), reversible tripeptide inhibitor of thrombin, DUP 714 (1 microM), in a well characterized model of simulated extracorporeal circulation. In the absence of DUP 714, platelet counts decreased by 75% 5 min after the start of extracorporeal bypass and increased to 48% at 120 min of recirculation. DUP 714 significantly preserved platelet counts, decreased plasma levels of platelet beta-thromboglobulin levels, but did not prevent a decrease in sensitivity of platelets to adenosine diphosphate. Kallikrein-C1-inhibitor and C1-C1-inhibitor complexes increased progressively from 0.32 U/ml to 0.67 U/ml and from 4.45 U/ml to 7.25 U/ml, respectively, during 120 min of recirculation without DUP 714. Addition of DUP 714 significantly inhibited kallikrein-C1-inhibitor complex formation but did not affect C1-C1-inhibitor complexes. In the absence of DUP 714, human neutrophil elastase levels rose from a baseline of 0.01 +/- 0.00 microg/ml to 1.18 +/- 0.21 microg/ml during 120 min of recirculation. Human neutrophil elastase release at 120 min was significantly inhibited in the presence of DUP 714 to 37% of the value with heparin alone. These results indicated that addition of this novel thrombin (and kallikrein) inhibitor to heparin preserved platelet counts, decreased platelet secretion, and provided the additional benefit of partially blocking neutrophil activation during simulated extracorporeal circulation.


Subject(s)
Cardiopulmonary Bypass , Extracorporeal Circulation , Kallikreins/metabolism , Thrombin/metabolism , Humans , Neutrophil Activation , Platelet Activation
16.
J Med Chem ; 41(1): 53-62, 1998 Jan 01.
Article in English | MEDLINE | ID: mdl-9438022

ABSTRACT

The molecular modeling studies, rational design, and synthesis of a novel series of bisphenylamidine carboxylate compounds which are inhibitors of factor Xa in the blood coagulation cascade are described. Inhibition of blood coagulation has been proposed to have several potential therapeutic utilities (Kaiser and Hauptmann, Cardiovasc. Drug Rev. 1994, 12, 225-236). Factor Xa (fXa) holds a central position in the coagulation cascade (Coleman et al. in Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 1994, pp 3-18). Its major role is the generation of thrombin by the proteolytic cleavage of prothrombin. Inhibition of fXa would serve to reduce the formation of platelet clots. The fXa dimer crystal structure (Tulinsky et al., J. Mol. Biol. 1993, 232, 947-966) was used in our molecular modeling studies to design a novel series of fXa inhibitors. We initially docked and minimized isolated small molecule fragments in the S1 and S4 aryl-binding subsites. Subsequently, these fragments were connected with a tether, so as not to disturb the orientation of the fragments in their respective pockets. These modeling studies led to the initial compound (1) which was found to have significant inhibitory potency for fXa (Ki = 34 nM). The synthesis of the core structure, structure-activity relationships (SAR), and proposed binding orientation based on molecular modeling for this novel bis-phenylamidine series of fXa inhibitors are described.


Subject(s)
Amidines/chemical synthesis , Anticoagulants/chemical synthesis , Carboxylic Acids/chemical synthesis , Factor Xa Inhibitors , Serine Proteinase Inhibitors/chemical synthesis , Amidines/chemistry , Amidines/pharmacology , Anticoagulants/chemistry , Anticoagulants/pharmacology , Binding Sites , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Crystallography, X-Ray , Dimerization , Drug Design , Factor Xa/chemistry , Kinetics , Mass Spectrometry , Models, Molecular , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Protein Conformation , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology
17.
Bioorg Med Chem Lett ; 8(22): 3143-8, 1998 Nov 17.
Article in English | MEDLINE | ID: mdl-9873692

ABSTRACT

The serine protease factor Xa is a critical enzyme in the blood coagulation cascade. Recently, the inhibition of factor Xa has begun to emerge as an attractive strategy for the discovery of novel antithrombotic agents. Here we describe a series of meta-amidino-N,N-disubstituted anilines as structurally simple and very potent inhibitors of factor Xa.


Subject(s)
Aniline Compounds/chemical synthesis , Factor Xa Inhibitors , Fibrinolytic Agents/chemical synthesis , Aniline Compounds/pharmacology , Animals , Fibrinolytic Agents/pharmacology , Humans , Rabbits , Structure-Activity Relationship
19.
Bioorg Med Chem Lett ; 8(3): 301-6, 1998 Feb 03.
Article in English | MEDLINE | ID: mdl-9871674

ABSTRACT

The potent boropeptide thrombin inhibitor DuP 714 caused side effects in laboratory animals that appear to be related to its ability to inhibit complement factor I, thereby activating the complement cascade. Using X-ray crystal structure information, we have designed compounds that have greater selectivity for thrombin over factor I and that have reduced tendency to produce these side effects.


Subject(s)
Antithrombins/chemical synthesis , Boron Compounds/chemistry , Complement Factor I/drug effects , Drug Design , Oligopeptides/chemistry , Animals , Antithrombins/adverse effects , Antithrombins/pharmacology , Crystallography, X-Ray , Models, Molecular , Rats
20.
Bioorg Med Chem Lett ; 8(19): 2705-10, 1998 Oct 06.
Article in English | MEDLINE | ID: mdl-9873607

ABSTRACT

In this report we discuss the design, synthesis, and validation of a novel series of cyclic urea inhibitors of the blood coagulation protein Factor Xa. This work culminates in compound 11, a monoamidine inhibitor of fXa employing a new S4 ligand that reduces the cationic character of these analogs. Compound 11 represents a lead for a series of more potent and selective inhibitors.


Subject(s)
Factor Xa Inhibitors , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Urea/analogs & derivatives , Binding Sites , Drug Design , Hydrogen Bonding , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Kinetics , Protein Conformation , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Structure-Activity Relationship , Urea/chemistry , Urea/pharmacology
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