| 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. | |
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MedLine Citation:
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PMID: 23188156 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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 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. |
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Authors:
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Yong Wang; Zhong-Liang Xu; Jing Ai; Xia Peng; Jian-Ping Lin; Yin-Chun Ji; Mei-Yu Geng; Ya-Qiu Long |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-11-28 |
Journal Detail:
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Title: Organic & biomolecular chemistry Volume: - ISSN: 1477-0539 ISO Abbreviation: Org. Biomol. Chem. Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-11-28 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101154995 Medline TA: Org Biomol Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China. yqlong@mail.shcnc.ac.cn mygeng@mail.shcnc.ac.cn. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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