title: Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (volitinib) as a highly potent and selective mesenchymal-epithelial transition factor (c-Met) inhibitor in clinical development for treatment of cancer.
abstract: HGF/c-Met signaling has been implicated in human cancers. Herein we describe the invention of a series of novel triazolopyrazine c-Met inhibitors. The structure-activity relationship of these compounds was investigated, leading to the identification of compound 28, which demonstrated favorable pharmacokinetic properties in mice and good antitumor activities in the human glioma xenograft model in athymic nude mice.
authors.affiliation: Hutchison MediPharma Limited , Building 4, 720 Cai Lun Road, Zhangjiang Hi-Tech Park, 201203, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Jia
authors.forename: Guangxiu
authors.initials: G
authors.lastname: Dai
authors.forename: Jianyang
authors.initials: J
authors.lastname: Weng
authors.forename: Zhulin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.forename: Longxian
authors.initials: L
authors.lastname: Jiao
authors.forename: Yumin
authors.initials: Y
authors.lastname: Cui
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Ren
authors.forename: Shiming
authors.initials: S
authors.lastname: Fan
authors.forename: Jinghong
authors.initials: J
authors.lastname: Zhou
authors.forename: Weiguo
authors.initials: W
authors.lastname: Qing
authors.forename: Yi
authors.initials: Y
authors.lastname: Gu
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Sai
authors.forename: Weiguo
authors.initials: W
authors.lastname: Su
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011719:Pyrazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014227:Triazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011720:Pyrazoles; D014227:Triazines; C000593259:1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine; D000255:Adenosine Triphosphate; D019859:Proto-Oncogene Proteins c-met