Abstract
2-(2-Chloro-6-fluorophenyl)acetamides having 2,2-difluoro-2-aryl/heteroaryl-ethylamine P3 and oxyguanidine P1 substituents are potent thrombin inhibitors (K(i)=0.9-33.9 nM). 2-(5-Chloro-pyridin-2-yl)-2,2-difluoroethylamine was the best P3 substituent, yielding the most potent inhibitor (K(i)=0.7 nM). Replacing the P3 heteroaryl group with a phenyl ring or replacing the difluoro substitution with dimethyl or cyclopropyl groups in the linker reduced the affinity for thrombin significantly. The aminopyridine P1s also provided an increase in potency.
MeSH terms
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Acetamides / chemical synthesis*
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Acetamides / chemistry
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Acetamides / pharmacology*
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Anticoagulants / chemical synthesis*
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Anticoagulants / chemistry
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Anticoagulants / pharmacology*
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Crystallography, X-Ray
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Drug Evaluation, Preclinical
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Humans
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Hydrocarbons, Halogenated / chemical synthesis*
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Hydrocarbons, Halogenated / chemistry
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Hydrocarbons, Halogenated / pharmacology*
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Molecular Structure
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Structure-Activity Relationship
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Thrombin / antagonists & inhibitors*
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Thrombin / chemistry
Substances
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Acetamides
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Anticoagulants
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Hydrocarbons, Halogenated
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Thrombin