title: Discovery of novel c-Met kinase inhibitors bearing a thieno[2,3-d]pyrimidine or furo[2,3-d]pyrimidine scaffold.
abstract: A series of thieno[2,3-d]pyrimidines and furo[2,3-d]pyrimidines were synthesized and evaluated for the c-Met inhibition. Thieno[2,3-d]pyrimidine 6b stood out as the most potent showing an IC(50) of 35.7 nM. This compound displayed high inhibitory effect on cell proliferation in BaF3-TPR-Met cells and showed high selectivity for c-Met family against other 14 tested kinases. However, compound 6b was found ineffective in the c-Met-dependent U-87MG human gliobastoma xenograft model that may be relevant to its poor PK profile.
authors.affiliation: Synthetic Organic and Medicinal Chemistry Laboratory (SOMCL), State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ailing
authors.initials: A
authors.lastname: Zhao
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.forename: Yuanxiang
authors.initials: Y
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.forename: Ao
authors.initials: A
authors.lastname: Zhang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D005909:Glioblastoma / Q000188:drug therapy; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014183:Transplantation, Heterologous
chemical_list: C561755:N-(3-fluoro-4-(5-phenylthieno(2,3-d)pyrimidin-4-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013876:Thiophenes; D019859:Proto-Oncogene Proteins c-met; C030986:pyrimidine