ABSTRACT
Parallel synthesis and iterative optimization led to the discovery of a series of potent and specific factor Xa inhibitors demonstrating excellent in vitro activity with promising pharmacokinetics.
Subject(s)
Antithrombin III/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Factor Xa Inhibitors , Antithrombin III/pharmacology , Enzyme Inhibitors/chemistry , Humans , Molecular Conformation , Molecular Structure , Structure-Activity RelationshipABSTRACT
A class of N,N-dialkylated 4-(4-arylsulfonylpiperazine-1-carbonyl)-benzamidines and 4-((4-arylsulfonyl)-2-oxo-piperazin-1-ylmethyl)-benzamidines has been discovered as potent factor Xa inhibitors with desirable in vitro and in vivo anticoagulant activity, but with low oral bioavailability. The 5-chloroindole and 6-chlorobenzo[b]thiophene groups are optimal as the factor Xa S1 binding elements. The strategy of incorporating a side chain on the piperazine nucleus to enhance binding affinity has been examined.
Subject(s)
Benzamidines/pharmacology , Factor Xa Inhibitors , Serine Proteinase Inhibitors/pharmacology , Benzamidines/chemistry , Benzamidines/pharmacokinetics , Biological Availability , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacokineticsABSTRACT
Anthranilamides 4 and 5 were designed and synthesized as selective and orally bioavailable factor Xa inhibitors. Structural modifications aimed at lowering their lipophilicity were performed at the central phenyl ring and at the S4 binding biphenyl region by incorporating water solublizing substituents. The resulting compounds (e.g., 7, 8, 14, 30a, and 32b) are highly potent in vitro, and show improved activity in human plasma-based thrombin generation assay.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Factor Xa Inhibitors , ortho-Aminobenzoates/chemical synthesis , ortho-Aminobenzoates/pharmacology , Administration, Oral , Animals , Biological Availability , Drug Design , Drug Evaluation, Preclinical , Humans , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thrombosis/drug therapy , Thrombosis/prevention & controlABSTRACT
Compound 2 containing an aminomethylbenzoyl moiety as the S4 binding motif was synthesized in order to modulate hydrophlicity of anthranilamide-based factor Xa inhibitors with substituted biphenyl P4 groups. Structure-activity relationship studies around 2 have led to a series of potent factor Xa inhibitors which are highly active in the human plasma-based thrombin generation assay with 2XTG values less than 1 microM. Compound 55 shows strong antithrombotic activity in our rabbit deep vein thrombosis model, and also exhibits good oral bioavailability and a long half life in rats.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Factor Xa Inhibitors , ortho-Aminobenzoates/chemical synthesis , ortho-Aminobenzoates/pharmacology , Administration, Oral , Animals , Biological Availability , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Design , Humans , Molecular Structure , Rabbits , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thrombosis/drug therapyABSTRACT
A series of benzoxazinone derivatives was designed and synthesized as factor Xa inhibitors. We demonstrated that the naphthyl moiety in the aniline-based compounds 1 and 2 can be replaced with benzene-fused heterobicycles and biaryls to give factor Xa inhibitors with improved trypsin selectivity. The P4 modifications lead to monoamidines which are moderately active. The benzoxazinones 41-45 are potent against factor Xa, retain the improved trypsin selectivity of the corresponding aniline-based compounds, and show strong antithrombotic effect dose responsively.
Subject(s)
Factor Xa Inhibitors , Oxazines/chemical synthesis , Oxazines/pharmacology , Aniline Compounds/chemical synthesis , Aniline Compounds/pharmacology , Animals , Binding, Competitive/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , In Vitro Techniques , Indicators and Reagents , Models, Molecular , Molecular Conformation , Rabbits , Structure-Activity Relationship , Thrombin/metabolism , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/pharmacologyABSTRACT
Monoamidine FXa inhibitors 3 were designed and synthesized. SAR studies and molecular modeling led to the design of conformationally constrained diaryl ethers 4 and 5, as well as benzopyrrolidinone 7 as potent FXa inhibitors. The monoamidines show high efficacy in a DVT model, but lack desirable oral bioavailability. The benzopyrrolidinone-based aminoisoquinolines 8 do not show significant improvement in oral bioavailability.
