ABSTRACT
A new series of pyrazole-based factor Xa inhibitors have been identified as part of our ongoing efforts to optimize previously reported clinical candidate razaxaban. Concern over the possible formation of primary aniline metabolites via amide hydrolysis led to the replacement of the primary amide linker between the pyrazole and phenyl moieties with secondary amides. This was accomplished by replacing the aniline with a variety of heterobicycles, of which indolines were the most potent. The indoline series demonstrated subnanomolar factor Xa binding K(i)s, modest to high selectivity versus other serine proteases, and good in vitro clotting activity. A small number of indoline fXa inhibitors were profiled in a dog pharmacokinetic model, one of which demonstrated pharmacokinetic parameters similar to that of clinical candidate razaxaban.
Subject(s)
Antithrombin III/chemical synthesis , Antithrombin III/pharmacokinetics , Factor Xa Inhibitors , Indoles/chemistry , Indoles/pharmacokinetics , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Antithrombin III/metabolism , Antithrombin III/pharmacology , Caco-2 Cells , Drug Design , Humans , Indoles/pharmacology , Protein Binding , Pyrazoles/pharmacology , Structure-Activity RelationshipABSTRACT
Attempts to further optimize the pyrazole factor Xa inhibitors centered on masking the aryl aniline P4 moiety. Scaffold optimization resulted in the identification of a novel bicyclic pyrazolo-pyridinone scaffold which retained fXa potency. The novel bicyclic scaffold preserved all binding interactions observed with the monocyclic counterpart and importantly the carboxamido moiety was integrated within the scaffold making it less susceptible to hydrolysis. These efforts led to the identification of 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 6f (BMS-740808), a highly potent (fXa Ki=30 pM) with a rapid onset of inhibition (2.7x10(7) M-1 s-1) in vitro, selective (>1000-fold over other proteases), efficacious in the AVShunt thrombosis model, and orally bioavailable inhibitor of blood coagulation factor Xa.
Subject(s)
Factor Xa Inhibitors , Pyrazoles/pharmacology , Pyridones/pharmacology , Serine Proteinase Inhibitors/pharmacology , Models, Molecular , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Pyridones/administration & dosage , Pyridones/chemistry , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/chemistryABSTRACT
Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P(1) ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P(4) moiety led to compounds with enhanced permeability and reduced protein binding. The SAR and pharmacokinetic profile of this series of compounds is described herein. These efforts culminated in 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide (11d), a potent, selective, and orally bioavailable inhibitor of factor Xa. On the basis of its excellent in vitro potency and selectivity profile, high free fraction in human plasma, good oral bioavailability, and in vivo efficacy in antithrombotic models, the HCl salt of this compound was selected for clinical development as razaxaban (DPC 906, BMS-561389).
Subject(s)
Factor Xa Inhibitors , Fibrinolytic Agents/chemical synthesis , Imidazoles/chemical synthesis , Isoxazoles/chemical synthesis , Pyrazoles/chemical synthesis , Administration, Oral , Animals , Biological Availability , Blood Proteins/metabolism , Caco-2 Cells , Crystallography, X-Ray , Dogs , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Isoxazoles/chemistry , Isoxazoles/pharmacology , Models, Molecular , Permeability , Protein Binding , Pyrazoles/chemistry , Pyrazoles/pharmacology , Rabbits , Structure-Activity Relationship , Thrombosis/prevention & controlABSTRACT
Factor Xa (fXa) is an important serine protease in the blood coagulation cascade. Inhibition of fXa has emerged as an attractive target for potential therapeutic applications in the treatments of both arterial and venous thrombosis. Herein, we describe a series of non-benzamidine isoxazoline derivatives as fXa inhibitors. The chloroaniline group was found to be the most potent benzamidine mimic in this series. Chloroaniline 1 (ST368) has a K(i) value of 1.5 nM against fXa and is highly selective for fXa relative to thrombin and trypsin.
Subject(s)
Factor Xa Inhibitors , Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Animals , Biological Availability , Chromatography, High Pressure Liquid , Dogs , Fibrinolytic Agents/chemical synthesis , Fibrinolytic Agents/pharmacokinetics , Fibrinolytic Agents/pharmacology , Half-Life , Humans , In Vitro Techniques , Indicators and Reagents , Isoxazoles/pharmacokinetics , Kinetics , Models, Molecular , RabbitsABSTRACT
Factor Xa (fXa) is an important serine protease that holds the central position linking the intrinsic and extrinsic activation mechanisms in the blood coagulation cascade. Therefore, inhibition of fXa has potential therapeutic applications in the treatments of both arterial and venous thrombosis. Herein we describe a series of tetrazole fXa inhibitors containing benzamidine mimics as the P(1) substrate, of which the aminobenzisoxazole moiety was found to be the most potent benzamidine mimic. SR374 (12) inhibits fXa with a K(i) value of 0.35 nM and is very selective for fXa over thrombin and trypsin.
