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1.
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
2.
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
3.
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
4.
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
5.
J Med Chem ; 38(12): 2061-9, 1995 Jun 09.
Article in English | MEDLINE | ID: mdl-7783137

ABSTRACT

An analysis of the free energy perturbation (FEP) method is presented that attempts to evaluate the efficacy of the FEP method in the drug discovery process. To accomplish this we have evaluated whether the FEP technique can accurately predict energetic and structural quantities relating to the inhibition of human carbonic anhydrase II (HCAII) by sulfonamides. Three well-characterized (both structurally and energetically) sulfonamide inhibitors of HCAII were examined in this study, 1a, 1b, and 1c. Results from FEP simulations on these compounds indicate that the FEP method can predict energetic trends reasonably well; however, the FEP method was less successful in reproducing detailed structural data. In particular, an expected movement of His-64 when inhibitor 1c was bound did not occur. We conclude that the FEP method can be used to determine relative free energies of binding but cannot be relied upon to reproduce subtle geometric changes.


Subject(s)
Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrases/metabolism , Carbonic Anhydrase Inhibitors/pharmacology , Humans , Molecular Structure , Thermodynamics
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