RESUMEN
Compound 1 (SNS-314) is a potent and selective Aurora kinase inhibitor that is currently in clinical trials in patients with advanced solid tumors. This communication describes the synthesis of prodrug derivatives of 1 with improved aqueous solubility profiles. In particular, phosphonooxymethyl-derived prodrug 2g has significantly enhanced solubility and is converted to the biologically active parent (1) following iv as well as po administration to rodents.
Asunto(s)
Compuestos de Fenilurea/química , Profármacos/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Tiazoles/química , Agua/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Aurora Quinasas , Masculino , Ratones , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/farmacología , Profármacos/farmacocinética , Profármacos/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Solubilidad , Tiazoles/farmacocinética , Tiazoles/farmacologíaRESUMEN
This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.