Design of novel quinazoline derivatives and related analogues as potent and selective ALK5 inhibitors

Starting from quinazoline 3a, we designed potent and selective ALK5 inhibitors over p38MAP kinase from a rational drug design approach based on co-crystal structures in the human ALK5 kinase domain. The quinazoline 3d exhibited also in vivo activity in an acute rat model of DMN-induced liver fibrosis when administered orally at 5 mg/kg (bid).

Graphical abstractStarting from quinazoline 3a, we identified 3d a potent and selective ALK5 inhibitor over p38MAP kinase suitable for oral administration.Figure optionsDownload full-size imageDownload as PowerPoint slide