RESUMEN
2,4-Diaryl-2,5-dihydropyrroles have been discovered to be novel, potent and water-soluble inhibitors of KSP, an emerging therapeutic target for the treatment of cancer. A potential concern for these basic KSP inhibitors (1 and 2) was hERG binding that can be minimized by incorporation of a potency-enhancing C2 phenol combined with neutral N1 side chains. Aqueous solubility was restored to these, and other, non-basic inhibitors, through a phosphate prodrug strategy.
Asunto(s)
Canales de Potasio Éter-A-Go-Go/metabolismo , Cinesinas/antagonistas & inhibidores , Profármacos , Pirroles/síntesis química , Pirroles/farmacología , Animales , Área Bajo la Curva , Perros , Unión Proteica , Pirroles/metabolismo , Pirroles/farmacocinética , Ratas , Solubilidad , Huso Acromático/química , AguaRESUMEN
The evolution of 2,4-diaryl-2,5-dihydropyrroles as inhibitors of KSP is described. Introduction of basic amide and urea moieties to the dihydropyrrole nucleus enhanced potency and aqueous solubility, simultaneously, and provided compounds that caused mitotic arrest of A2780 human ovarian carcinoma cells with EC(50)s<10nM. Ancillary hERG activity was evaluated for this series of inhibitors.