title: Investigation on the 1,6-naphthyridine motif: discovery and SAR study of 1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one-based c-Met kinase inhibitors.
abstract: The 1,6-naphthyridine motif is a multivalent scaffold in medicinal chemistry presenting various bioactivities when properly substituted. By incorporating a cyclic urea pharmacophore into the 1,6-naphthyridine framework through conformationally constraining the 7,8-positions, the resulting 1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one was identified as a new class of c-Met kinase inhibitor. A comprehensive SAR study indicated that an N-1 alkyl substituent bearing a terminal free amino group, a hydrophobic substituted benzyl group at the N-3 position and the tricyclic core were essential for retaining effective Met inhibition of the 1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one chemotype. Further introduction of a 4'-carboxamide phenoxy group at the C-5 position significantly improved the potency. The best c-Met kinase inhibitory activity was exemplified by 2t with an IC(50) = 2.6 μM, which also displayed effective inhibition against TPR-Met phosphorylation and the proliferation of the BaF3-TPR-Met cells at low micromolar concentrations.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P R China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhong-Liang
authors.initials: ZL
authors.lastname: Xu
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.forename: Xia
authors.initials: X
authors.lastname: Peng
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Lin
authors.forename: Yin-Chun
authors.initials: YC
authors.lastname: Ji
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Geng
authors.forename: Ya-Qiu
authors.initials: YQ
authors.lastname: Long
mesh_terms: D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C584188:1H-imidazo(4,5-h)(1,6)naphthyridin-2(3H)-one; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met