title: Design of novel quinazoline derivatives and related analogues as potent and selective ALK5 inhibitors.
abstract: 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 5mg/kg (bid).
authors.affiliation: GlaxoSmithKline, Les Ulis, France. francoise.gellibert@gsk.com
authors.forename: F
authors.initials: F
authors.lastname: Gellibert
authors.forename: M-H
authors.initials: MH
authors.lastname: Fouchet
authors.forename: V-L
authors.initials: VL
authors.lastname: Nguyen
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.forename: G
authors.initials: G
authors.lastname: Krysa
authors.forename: A-C
authors.initials: AC
authors.lastname: de Gouville
authors.forename: S
authors.initials: S
authors.lastname: Huet
authors.forename: N
authors.initials: N
authors.lastname: Dodic
mesh_terms: D029404:Activin Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D029404:Activin Receptors; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625843:Tgfbr1 protein, rat