Abstract
Compound YM-60828 was previously characterized in our laboratory as a potent, selective and orally-bioavailable Factor Xa (FXa) inhibitor. The L-shape conformation of this compound in the active site of FXa was recognized as an important factor in displaying its FXa inhibitory activity. This led to the exploration of conformationally restricted cyclic scaffolds bearing a similar active conformation. The current study investigated a novel series of benzothiadiazine-4-one based compounds as FXa inhibitors. Structure-activity relationship (SAR) investigations revealed some potent FXa inhibitors that were selected for further in vitro and ex vivo anticoagulant studies. Among them, compound 6j (YM-169920) was proved to be most effective anticoagulant in this series. The synthesis and SAR in addition to docking studies of this class of inhibitors are described.
MeSH terms
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Administration, Oral
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Animals
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Anticoagulants / chemical synthesis
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Anticoagulants / chemistry
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Anticoagulants / pharmacology
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Benzothiadiazines / chemical synthesis
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Benzothiadiazines / chemistry*
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Benzothiadiazines / pharmacology*
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Biological Availability
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Factor Xa Inhibitors*
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Female
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Humans
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Inhibitory Concentration 50
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Male
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Mice
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Mice, Inbred ICR
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Models, Molecular
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Molecular Conformation
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Naphthalenes / chemical synthesis
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Naphthalenes / chemistry*
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Naphthalenes / pharmacology*
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Piperidines / chemical synthesis
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Piperidines / chemistry*
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Piperidines / pharmacology*
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Prothrombin Time
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Saimiri
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Structure-Activity Relationship
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Thrombin / antagonists & inhibitors
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Trypsin Inhibitors / chemical synthesis
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Trypsin Inhibitors / chemistry
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Trypsin Inhibitors / pharmacology
Substances
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Anticoagulants
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Benzothiadiazines
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Factor Xa Inhibitors
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Naphthalenes
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Piperidines
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Trypsin Inhibitors
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YM 60828
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Thrombin