Structure-Based Design of Novel Class II c-Met Inhibitors: 2. SAR and Kinase Selectivity Profiles of the Pyrazolone Series

被引：76

作者：

Liu, Longbin ^{[5
]}

Norman, Mark H. ^{[5
]}

Lee, Matthew ^{[2
]}

Xi, Ning ^{[5
]}

Siegmund, Aaron ^{[5
]}

Boezio, Alessandro A. ^{[3
]}

Booker, Shon ^{[5
]}

Choquette, Debbie ^{[3
]}

D'Angelo, Noel D. ^{[5
]}

Germain, Julie ^{[3
]}

Yang, Kevin ^{[5
]}

Yang, Yajing ^{[1
]}

Zhang, Yihong ^{[1
]}

Bellon, Steven F. ^{[4
]}

Whittington, Douglas A. ^{[4
]}

Harmange, Jean-Christophe ^{[3
]}

Dominguez, Celia ^{[5
]}

Kim, Tae-Seong ^{[5
]}

Dussault, Isabelle ^{[1
]}

机构：

[1] Amgen Inc, Dept Oncol Res, Thousand Oaks, CA 91320 USA

[2] Amgen Inc, Dept Mol Struct, Thousand Oaks, CA 91320 USA

[3] Amgen Inc, Dept Med Chem, Cambridge, MA 02142 USA

[4] Amgen Inc, Dept Mol Struct, Cambridge, MA 02142 USA

[5] Amgen Inc, Dept Med Chem, Thousand Oaks, CA 91320 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 05期

关键词：

GROWTH-FACTOR RECEPTOR; TYROSINE KINASE; SIGNALING PATHWAY; SCATTER-FACTOR; TARGET; CANCER; POTENT; IDENTIFICATION; DISCOVERY; METASTASIS;

D O I：

10.1021/jm201331s

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

As part of our effort toward developing an effective therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class II c-Met inhibitor, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1), was identified. Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2 proteins led to a novel strategy for designing more selective analogues of 1. Along with detailed SAR information, we demonstrate that the low kinase selectivity associated with class II c-Met inhibitors can be improved significantly. This work resulted in the discovery of potent c-Met inhibitors with improved selectivity profiles over VEGFR-2 and IGF-1R that could serve as useful tools to probe the relationship between kinase selectivity and in vivo efficacy in tumor xenograft models. Compound 59e (AMG 458) was ultimately advanced into preclinical safety studies.

引用

页码：1868 / 1897

页数：30

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