Discovery of Potent Protease-Activated Receptor 4 Antagonists with in Vivo Antithrombotic Efficacy.
J Med Chem
; 62(16): 7400-7416, 2019 08 22.
Article
em En
| MEDLINE
| ID: mdl-31246024
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.
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Base de dados:
MEDLINE
Assunto principal:
Trombose
/
Benzofuranos
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Receptores de Trombina
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Fibrinolíticos
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Hemorragia
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article