title: Discovery and optimization of a potent and selective triazolopyridinone series of c-Met inhibitors.
abstract: Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of a structurally diverse series of carbon-linked quinoline triazolopyridinones, which demonstrates nanomolar inhibition of c-Met kinase activity. This novel series of inhibitors exhibits favorable pharmacokinetics as well as potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.
authors.affiliation: Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. aboezio@amgen.com
authors.forename: Christiane M
authors.initials: CM
authors.lastname: Bode
authors.forename: Alessandro A
authors.initials: AA
authors.lastname: Boezio
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
authors.forename: Steven F
authors.initials: SF
authors.lastname: Bellon
authors.forename: Loren
authors.initials: L
authors.lastname: Berry
authors.forename: Martin A
authors.initials: MA
authors.lastname: Broome
authors.forename: Deborah
authors.initials: D
authors.lastname: Choquette
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dussault
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lewis
authors.forename: Min-Hwa Jasmine
authors.initials: MH
authors.lastname: Lin
authors.forename: Karen
authors.initials: K
authors.lastname: Rex
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: Yajing
authors.initials: Y
authors.lastname: Yang
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C553307:HGF protein, mouse; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011804:Quinolines; D014230:Triazoles; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met