title: Identification of novel inhibitors of the transforming growth factor beta1 (TGF-beta1) type 1 receptor (ALK5).
abstract: Screening of our internal compound collection for inhibitors of the transforming growth factor beta1 (TGF-beta1) type I receptor (ALK5) identified several hits. Optimization of the dihydropyrroloimidazole hit 2 by introduction of a 2-pyridine and 3,4-methylenedioxyphenyl group gave 7, a selective ALK5 inhibitor. With this information, optimization of the triarylimidazole hit 8 gave the selective inhibitor 14, which inhibits TGF-beta1-induced fibronectin mRNA formation while displaying no measurable cytotoxicity in the 48 h XTT assay.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA. james_f_callahan@gsk.com
authors.forename: James F
authors.initials: JF
authors.lastname: Callahan
authors.forename: Joelle L
authors.initials: JL
authors.lastname: Burgess
authors.forename: James A
authors.initials: JA
authors.lastname: Fornwald
authors.forename: Laramie M
authors.initials: LM
authors.lastname: Gaster
authors.forename: John D
authors.initials: JD
authors.lastname: Harling
authors.forename: Frank P
authors.initials: FP
authors.lastname: Harrington
authors.forename: Jag
authors.initials: J
authors.lastname: Heer
authors.forename: Chet
authors.initials: C
authors.lastname: Kwon
authors.forename: Ruth
authors.initials: R
authors.lastname: Lehr
authors.forename: A
authors.initials: A
authors.lastname: Mathur
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Olson
authors.forename: Joseph
authors.initials: J
authors.lastname: Weinstock
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Laping
mesh_terms: D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005353:Fibronectins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000096:biosynthesis; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D051900:Smad3 Protein; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005353:Fibronectins; D007093:Imidazoles; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human