RESUMEN
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.
Asunto(s)
Benzofuranos/farmacología , Fibrinolíticos/farmacología , Hemorragia/prevención & control , Receptores de Trombina/antagonistas & inhibidores , Trombosis/prevención & control , Animales , Benzofuranos/química , Benzofuranos/farmacocinética , Disponibilidad Biológica , Modelos Animales de Enfermedad , Fibrinolíticos/química , Fibrinolíticos/farmacocinética , Células HEK293 , Hemorragia/metabolismo , Humanos , Macaca fascicularis , Modelos Químicos , Estructura Molecular , Agregación Plaquetaria/efectos de los fármacos , Receptores de Trombina/genética , Receptores de Trombina/metabolismo , Relación Estructura-Actividad , Trombosis/metabolismoRESUMEN
The introduction of an aryl ring onto the 4-position of the C-6 benzyl amino group of the Cdk inhibitor roscovitine (2), maintained the potent Cdk inhibition demonstrated by roscovitine (2) as well as greatly improving the antiproliferative activity. A series of C-6 biarylmethylamino derivatives was prepared addressing modifications on the C-6 biaryl rings, N-9 and C-2 positions to provide compounds that displayed potent cytotoxic activity against tumor cell lines. In particular, derivative 21h demonstrated a >750-fold improvement in the growth inhibition of HeLa cells compared to roscovitine (2).
Asunto(s)
Antineoplásicos/farmacología , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Purinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Purinas/síntesis química , Purinas/química , Roscovitina , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel series of 7-[1H-indol-2-yl]-2,3-dihydro-isoindol-1-ones designed to be inhibitors of VEGF-R2 kinase was synthesized and found to potently inhibit VEGF-R2 and Aurora-A kinases. The structure-based design, synthesis, and initial SAR of the series are discussed.
Asunto(s)
Indoles , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Animales , Aurora Quinasa A , Aurora Quinasas , Técnicas Químicas Combinatorias , Diseño de Fármacos , Indoles/síntesis química , Indoles/farmacología , Ratones , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The N-amination of heterocyclic compounds 1a-k with O-benzoylhydroxylamine derivatives 5 was developed and demonstrated to be a superior alternative to existing N-amination methods. A structure-reactivity relationship study was performed on variously substituted O-benzoylhydroxylamine derivatives, leading to the discovery of the novel and more efficient aminating reagents 5h and 5i.
