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

• Published in: Organic & biomolecular chemistry 2013-03, Vol.11 (9), p.1545-1562
• Main Authors: Wang, Yong, Xu, Zhong-Liang, Ai, Jing, Peng, Xia, Lin, Jian-Ping, Ji, Yin-Chun, Geng, Mei-Yu, Long, Ya-Qiu
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Dose-Response Relationship, Drug; Drug Design; Mice; Models, Molecular; Molecular Structure; Naphthyridines - chemical synthesis; Naphthyridines - chemistry; Naphthyridines - pharmacology; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - metabolism; Structure-Activity Relationship
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c2ob26710a

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 1 H -imidazo[4,5- h ][1,6]naphthyridin-2(3 H )-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 1 H -imidazo[4,5- h ][1,6]naphthyridin-2(3 H )-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. A new class of c-Met inhibitors were designed and discovered based on the 1,6-naphthyridine scaffold by constraining the 7,8-positions into a urea functionality.