RESUMEN
A series of (3R,4R)-pyrrolidine-3,4-dicarboxylic acid amides was investigated with respect to their factor Xa inhibitory activity, selectivity, pharmacokinetic properties, and ex vivo antithrombotic activity. The clinical candidate from this series, R1663, exhibits excellent selectivity against a panel of serine proteases and good pharmacokinetic properties in rats and monkeys. A Phase I clinical study with R1663 has been finalized.
Asunto(s)
Inhibidores del Factor Xa , Pirrolidinas/farmacología , Pirrolidinas/químicaRESUMEN
Starting from a hit identified by focused screening, 3-aminopyrrolidine factor Xa inhibitors were designed. The binding mode as determined by X-ray structural analysis as well as the pharmacokinetic behaviour of selected compounds is discussed.
Asunto(s)
Aminoquinolinas/farmacología , Antitrombina III/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Factor Xa/metabolismo , Aminoquinolinas/química , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacocinética , Antitrombina III/química , Antitrombina III/metabolismo , Antitrombina III/farmacocinética , Cristalografía por Rayos X , Factor Xa/química , Humanos , Modelos Moleculares , Conformación MolecularRESUMEN
The synthesis and in vitro structure-activity relationships (SAR) of a series of triazoles as A(2A) receptor antagonists is reported. This resulted in the identification of potent, selective and permeable 1,2,4-triazoles such as 42 for further optimization and evaluation in vivo.