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

2009; Elsevier BV; Volume: 19; Issue: 8 Linguagem: Inglês

10.1016/j.bmcl.2009.02.087

1464-3405

Françoise Gellibert, Marie-Hélène Fouchet, Van Loc Nguyen, R. Wang, Gaël Krysa, A.-C. de Gouville, Stéphane Huet, N. Dodic,

Cancer-related gene regulation

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).