RESUMEN
The 4-(5-fluoro-6-methyl-pyridin-2-yl)-5-quinoxalin-6-yl-1H-imidazol-2-ylamine 3 is a potent and selective inhibitor of TGF-betaR1. Substitution of the amino group of 3 typically led to a slight decrease in the affinity for the receptor and in TGF-beta-inducted PAI-luciferase reporter activity. However, 2-acetamidoimidazoles were identified as attractive candidates for further optimization as a result of their significant activity combined to their superior pharmacokinetic profile.
Asunto(s)
Química Farmacéutica/métodos , Imidazoles/síntesis química , Imidazoles/farmacología , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Animales , Dominio Catalítico , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Luciferasas/metabolismo , Masculino , Modelos Biológicos , Conformación Molecular , Ratas , Ratas Sprague-DawleyRESUMEN
Lead identification by high-throughput screening of large compound libraries has been supplemented with virtual screening and focused compound libraries. To complement existing approaches for lead identification at Biogen Idec, a kinase-focused compound collection was designed, developed and validated. Two strategies were adopted to populate the compound collection: a ligand shape-based virtual screening and a receptor-based approach (structural interaction fingerprint). Compounds selected with the two approaches were cherry-picked from an existing high-throughput screening compound library, ordered from suppliers and supplemented with specific medicinal compounds from internal programs. Promising hits and leads have been generated from the kinase-focused compound collection against multiple kinase targets. The principle of the collection design and screening strategy was validated and the use of the kinase-focused compound collection for lead identification has been added to existing strategies.