title: Design, synthesis and optimization of 7-substituted-pyrazolo[4,3-b]pyridine ALK5 (activin receptor-like kinase 5) inhibitors.
abstract: A series of potent ALK5 inhibitors were designed using a SBDD approach and subsequently optimized to improve drug likeness. Starting with a 4-substituted quinoline screening hit, SAR was conducted using a ALK5 binding model to understand the binding site and optimize activity. The resulting inhibitors displayed excellent potency but were limited by high in vitro clearance in rat and human microsomes. Using a scaffold morphing strategy, these analogs were transformed into a related pyrazolo[4,3-b]pyridine series with improved ADME properties.
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States. Electronic address: mark.sabat@takedasd.com.
authors.forename: Mark
authors.initials: M
authors.lastname: Sabat
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Haixia
authors.initials: H
authors.lastname: Wang
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Nick
authors.initials: N
authors.lastname: Scorah
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: J David
authors.initials: JD
authors.lastname: Lawson
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Joy
authors.initials: J
authors.lastname: Atienza
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Ruhi
authors.initials: R
authors.lastname: Kamran
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Hixon
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Dougan
mesh_terms: D002460:Cell Line; D006801:Humans; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; 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; D011720:Pyrazoles; 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
keywords: ALK5 activin-like kinase 5