RESUMEN
Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 (43), and a backup clinical candidate, BMS-986141 (49). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.
Asunto(s)
Agregación Plaquetaria , Trombosis , Benzofuranos , Plaquetas , Humanos , Imidazoles , Morfolinas , Receptor PAR-1 , Receptores de Trombina , Tiazoles , Trombina , Trombosis/tratamiento farmacológicoRESUMEN
A number of new amine scaffolds with good inhibitory activity in the ADP-induced platelet aggregation assay have been found to be potent antagonists of the P2Y1 receptor. SAR optimization led to the identification of isoindoline 3c and piperidine 4a which showed good in vitro binding and functional activities, as well as improved aqueous solubility. Among them, the piperidine 4a showed the best overall profile with favorable PK parameters.
Asunto(s)
Aminas/química , Agonistas del Receptor Purinérgico P2Y/química , Receptores Purinérgicos P2Y1/química , Urea/análogos & derivados , Adenosina Difosfato/farmacología , Aminas/síntesis química , Aminas/farmacocinética , Animales , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Semivida , Humanos , Microsomas Hepáticos/metabolismo , Piperidinas/química , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacocinética , Unión Proteica , Agonistas del Receptor Purinérgico P2Y/síntesis química , Agonistas del Receptor Purinérgico P2Y/farmacocinética , Ratas , Receptores Purinérgicos P2Y1/metabolismo , Relación Estructura-Actividad , Urea/síntesis química , Urea/farmacocinéticaRESUMEN
The crystal structure of the ligand-binding domain of RARbeta, a suspect tumour suppressor, reveals important features that distinguish it from the two other RAR isotypes. The most striking difference is an extra cavity allowing RARbeta to bind more bulky agonists. Accordingly, we identified a ligand that shows RARbeta selectivity with a 100-fold higher affinity to RARbeta than to alpha or gamma isotypes. The structural differences between the three RAR ligand-binding pockets revealed a rationale explaining how a single retinoid can be at the same time an RARalpha, gamma antagonist and an RARbeta agonist. In addition, we demonstrate how to generate an RARbeta antagonist by gradually modifying the bulkiness of a single substitution. Together, our results provide structural guidelines for the synthesis of RARbeta-selective agonists and antagonists, allowing for the first time to address pharmacologically the tumour suppressor role of RARbeta in vitro and in animal models.