title: Discovery of potent and selective 8-fluorotriazolopyridine c-Met inhibitors.
abstract: The overexpression of c-Met and/or hepatocyte growth factor (HGF), the amplification of the MET gene, and mutations in the c-Met kinase domain can activate signaling pathways that contribute to cancer progression by enabling tumor cell proliferation, survival, invasion, and metastasis. Herein, we report the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity. Optimization of the 8-fluorotriazolopyridine scaffold through the combination of structure-based drug design, SAR studies, and metabolite identification provided potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.
authors.affiliation: Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Peterson
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Teffera
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
authors.forename: David
authors.initials: D
authors.lastname: Bauer
authors.forename: Steven F
authors.initials: SF
authors.lastname: Bellon
authors.forename: Alessandro
authors.initials: A
authors.lastname: Boezio
authors.forename: Christiane
authors.initials: C
authors.lastname: Boezio
authors.forename: Martin A
authors.initials: MA
authors.lastname: Broome
authors.forename: Deborah
authors.initials: D
authors.lastname: Choquette
authors.forename: Katrina W
authors.initials: KW
authors.lastname: Copeland
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dussault
authors.forename: Richard
authors.initials: R
authors.lastname: Lewis
authors.forename: Min-Hwa Jasmine
authors.initials: MH
authors.lastname: Lin
authors.forename: Julia
authors.initials: J
authors.lastname: Lohman
authors.forename: Jingzhou
authors.initials: J
authors.lastname: Liu
authors.forename: Michele
authors.initials: M
authors.lastname: Potashman
authors.forename: Karen
authors.initials: K
authors.lastname: Rex
authors.forename: Roman
authors.initials: R
authors.lastname: Shimanovich
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: Karina R
authors.initials: KR
authors.lastname: Vaida
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D055808:Drug Discovery; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014018:Tissue Distribution; D014230:Triazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000598574:5-(8-fluoro-3-(1-(3-(2-methoxyethoxy)quinolin-6-yl)ethyl)(1,2,4)triazolo(4,3-a)pyridin-6-yl)-3-methylisoxazole; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D014230:Triazoles; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met