RESUMEN
Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development.
Asunto(s)
Anticoagulantes/síntesis química , Anticoagulantes/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Descubrimiento de Drogas/métodos , Inhibidores del Factor Xa , Piridinas/síntesis química , Piridinas/farmacología , Administración Oral , Animales , Anticoagulantes/administración & dosificación , Benzamidas/administración & dosificación , Dominio Catalítico/efectos de los fármacos , Línea Celular , Perros , Relación Dosis-Respuesta a Droga , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/genética , Factor Xa/metabolismo , Humanos , Macaca fascicularis , Piridinas/administración & dosificación , Conejos , RatasRESUMEN
Parallel synthesis and iterative optimization led to the discovery of a series of potent and specific factor Xa inhibitors demonstrating excellent in vitro activity with promising pharmacokinetics.
Asunto(s)
Antitrombina III/síntesis química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores del Factor Xa , Antitrombina III/farmacología , Inhibidores Enzimáticos/química , Humanos , Conformación Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A class of N,N-dialkylated 4-(4-arylsulfonylpiperazine-1-carbonyl)-benzamidines and 4-((4-arylsulfonyl)-2-oxo-piperazin-1-ylmethyl)-benzamidines has been discovered as potent factor Xa inhibitors with desirable in vitro and in vivo anticoagulant activity, but with low oral bioavailability. The 5-chloroindole and 6-chlorobenzo[b]thiophene groups are optimal as the factor Xa S1 binding elements. The strategy of incorporating a side chain on the piperazine nucleus to enhance binding affinity has been examined.
Asunto(s)
Benzamidinas/farmacología , Inhibidores del Factor Xa , Inhibidores de Serina Proteinasa/farmacología , Benzamidinas/química , Benzamidinas/farmacocinética , Disponibilidad Biológica , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacocinéticaRESUMEN
With the cloning of the P2Y12 receptor, the molecular basis for ADP-induced platelet aggregation is seemingly complete. Two platelet-bound ADP receptors, P2Y1 and P2Y12, operate through unique pathways to induce and sustain platelet aggregation via the glycoprotein (GP)IIb-IIIa integrin. P2Y1 operates via a glycoprotein q (Gq) pathway, activates phospholipase C, induces platelet shape change and is responsible for intracellular calcium mobilisation. P2Y12 inhibits adenylyl cyclase through a glycoprotein i (Gi)-dependent pathway, and is the target of the clinically used thienopyridines, ticlopidine (Ticlid, F. Hoffman-La Roche) and clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Synthelabo). In addition, the receptor is targeted by the ADP analogue AR-C66096, which is currently in Phase IIb clinical trials, as well as other non-nucleoside-based preclinical leads.