title: Design and optimization of a series of 1-sulfonylpyrazolo[4,3-b]pyridines as selective c-Met inhibitors.
abstract: c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo[4,3-b]pyridine 9 with improved DMPK properties was discovered. Further elaboration of π-π stacking interactions and solvent accessible polar moieties led to a series of highly potent and selective type I c-Met inhibitors. On the basis of in vitro and in vivo pharmacological and pharmacokinetics studies, compound 46 was selected as a preclinical candidate for further anticancer drug development.
authors: Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
authors: Yuchi
authors: Y
authors: Ma
authors: Guangqiang
authors: G
authors: Sun
authors: Danqi
authors: D
authors: Chen
authors: Xia
authors: X
authors: Peng
authors: Yue-Lei
authors: YL
authors: Chen
authors: Yi
authors: Y
authors: Su
authors: Yinchun
authors: Y
authors: Ji
authors: Jin
authors: J
authors: Liang
authors: Xin
authors: X
authors: Wang
authors: Lin
authors: L
authors: Chen
authors: Jian
authors: J
authors: Ding
authors: Bing
authors: B
authors: Xiong
authors: Jing
authors: J
authors: Ai
authors: Meiyu
authors: M
authors: Geng
authors: Jingkang
authors: J
authors: Shen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015195:Drug Design; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011725:Pyridines; D017228:Hepatocyte Growth Factor; D003577:Cytochrome P-450 Enzyme System; D019859:Proto-Oncogene Proteins c-met