title: Discovery of a series of 2-(1H-pyrazol-1-yl)pyridines as ALK5 inhibitors with potential utility in the prevention of dermal scarring.
abstract: A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFβ receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFβ induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.
authors.affiliation: Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA. mark.boys@arraybiopharma.com
authors.forename: Mark L
authors.initials: ML
authors.lastname: Boys
authors.forename: Feng
authors.initials: F
authors.lastname: Bian
authors.forename: James B
authors.initials: JB
authors.lastname: Kramer
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Chio
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Ren
authors.forename: Huifen
authors.initials: H
authors.lastname: Chen
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Barrett
authors.forename: Karen E
authors.initials: KE
authors.lastname: Sexton
authors.forename: Donna M
authors.initials: DM
authors.lastname: Iula
authors.forename: Gary F
authors.initials: GF
authors.lastname: Filzen
authors.forename: Maria N
authors.initials: MN
authors.lastname: Nguyen
authors.forename: Paul
authors.initials: P
authors.lastname: Angell
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Downs
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wang
authors.forename: Neil
authors.initials: N
authors.lastname: Raheja
authors.forename: Edmund L
authors.initials: EL
authors.lastname: Ellsworth
authors.forename: Stephen
authors.initials: S
authors.lastname: Fakhoury
authors.forename: Larry D
authors.initials: LD
authors.lastname: Bratton
authors.forename: Paul R
authors.initials: PR
authors.lastname: Keller
authors.forename: Richard
authors.initials: R
authors.lastname: Gowan
authors.forename: Elena M
authors.initials: EM
authors.lastname: Drummond
authors.forename: Samarendra N
authors.initials: SN
authors.lastname: Maiti
authors.forename: Mostofa A
authors.initials: MA
authors.lastname: Hena
authors.forename: Leroy
authors.initials: L
authors.lastname: Lu
authors.forename: Patrick
authors.initials: P
authors.lastname: McConnell
authors.forename: John D
authors.initials: JD
authors.lastname: Knafels
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Thanabal
authors.forename: Fang
authors.initials: F
authors.lastname: Sun
authors.forename: Diane
authors.initials: D
authors.lastname: Alessi
authors.forename: Ann
authors.initials: A
authors.lastname: McCarthy
authors.forename: Erli
authors.initials: E
authors.lastname: Zhang
authors.forename: Barry C
authors.initials: BC
authors.lastname: Finzel
authors.forename: Sneha
authors.initials: S
authors.lastname: Patel
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ciotti
authors.forename: Rone
authors.initials: R
authors.lastname: Eisma
authors.forename: N A
authors.initials: NA
authors.lastname: Payne
authors.forename: Richard B
authors.initials: RB
authors.lastname: Gilbertsen
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Kostlan
authors.forename: David J
authors.initials: DJ
authors.lastname: Pocalyko
authors.forename: Deepak S
authors.initials: DS
authors.lastname: Lala
mesh_terms: D000818:Animals; D002921:Cicatrix / Q000517:prevention & control*; D055808:Drug Discovery; D008958:Models, Molecular; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D012867:Skin / Q000187:drug effects*
chemical_list: D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625843:Tgfbr1 protein, rat