Abstract
A series of noncovalent tripeptidic thrombin inhibitors incorporating amidrazone, amine and amidine functions at P1 was investigated. While the amidrazone and the amine series displayed limited oral absorption, the amidine series demonstrated generally good oral absorption and strong antithrombotic activity; the single-digit picomolar K(i) achieved from this series is among the best yet reported. The present work highlights the benzamidine compound 11f (LB30812) that exhibits excellent overall profiles of potency, oral absorption and antithrombotic efficacy.
MeSH terms
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Administration, Oral
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Amidines / chemistry*
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Amidines / metabolism
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Amines / chemistry*
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Amines / metabolism
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Animals
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Biological Availability
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Dogs
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Fibrinolytic Agents / chemical synthesis*
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Fibrinolytic Agents / pharmacokinetics
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Fibrinolytic Agents / therapeutic use
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Haplorhini
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Hemostatics / antagonists & inhibitors*
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Models, Molecular
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Molecular Structure
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Peptide Fragments / chemical synthesis*
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Peptide Fragments / pharmacokinetics
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Peptide Fragments / therapeutic use
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Rats
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Serine Proteinase Inhibitors / chemical synthesis*
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Serine Proteinase Inhibitors / pharmacology
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Structure-Activity Relationship
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Thrombin / antagonists & inhibitors*
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Thrombin / metabolism
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Trypsin / metabolism
Substances
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Amidines
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Amines
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Fibrinolytic Agents
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Hemostatics
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Peptide Fragments
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Serine Proteinase Inhibitors
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Trypsin
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Thrombin