RESUMEN
An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure-activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ-PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Descubrimiento de Drogas/métodos , Inhibidores de las Quinasa Fosfoinosítidos-3/síntesis química , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/enzimología , Femenino , Humanos , Isoenzimas , Ratones , Simulación del Acoplamiento Molecular , Células PC-3 , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacocinética , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Células RAW 264.7 , Ratas Sprague-Dawley , Ratas WistarRESUMEN
HGF/c-Met signaling has been implicated in human cancers. Herein we describe the invention of a series of novel triazolopyrazine c-Met inhibitors. The structure-activity relationship of these compounds was investigated, leading to the identification of compound 28, which demonstrated favorable pharmacokinetic properties in mice and good antitumor activities in the human glioma xenograft model in athymic nude mice.