Abstract
In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzofurans / chemistry
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Benzofurans / pharmacokinetics
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Benzofurans / pharmacology*
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Biological Availability
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Disease Models, Animal
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Fibrinolytic Agents / chemistry
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Fibrinolytic Agents / pharmacokinetics
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Fibrinolytic Agents / pharmacology*
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HEK293 Cells
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Hemorrhage / metabolism
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Hemorrhage / prevention & control*
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Humans
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Macaca fascicularis
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Models, Chemical
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Molecular Structure
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Platelet Aggregation / drug effects
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Receptors, Thrombin / antagonists & inhibitors*
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Receptors, Thrombin / genetics
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Receptors, Thrombin / metabolism
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Structure-Activity Relationship
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Thrombosis / metabolism
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Thrombosis / prevention & control*
Substances
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Benzofurans
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Fibrinolytic Agents
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Receptors, Thrombin
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protease-activated receptor 4