RESUMEN
PAR4 is a promising antithrombotic target with potential for separation of efficacy from bleeding risk relative to current antiplatelet therapies. In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based HTS hit 3 with low µM potency was identified. Optimization of the HTS hit through the use of positional SAR scanning and the design of conformationally constrained cores led to the discovery of a quinoxaline-benzothiazole series as potent and selective PAR4 antagonists. The lead compound 48, possessing a 2 nM IC50 against PAR4 activation by γ-thrombin in platelet-rich plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated robust antithrombotic efficacy and minimal bleeding in the cynomolgus monkey models.
Asunto(s)
Fibrinolíticos , Trombosis , Animales , Fibrinolíticos/farmacología , Fibrinolíticos/uso terapéutico , Macaca fascicularis , Quinoxalinas/farmacología , Quinoxalinas/uso terapéutico , Receptores de Trombina , Trombina , Hemorragia , Trombosis/tratamiento farmacológico , Trombosis/prevención & control , Receptor PAR-1 , Plaquetas , Agregación PlaquetariaRESUMEN
Two novel series of meta-linked phenylglycine-based macrocyclic FVIIa inhibitors have been designed to improve the rodent metabolic stability and PK observed with the precursor para-linked phenylglycine macrocycles. Through iterative structure-based design and optimization, the TF/FVIIa Ki was improved to subnanomolar levels with good clotting activity, metabolic stability, and permeability.