Discovery and SAR study of c-Met kinase inhibitors bearing an 3-amino-benzo[d]isoxazole or 3-aminoindazole scaffold

Xiaolong Jiang; Hongyan Liu; Zilan Song; Xia Peng; Yinchun Ji; Qizheng Yao; Meiyu Geng; Jing Ai; Ao Zhang

doi:10.1016/j.bmc.2014.12.002

Discovery and SAR study of c-Met kinase inhibitors bearing an 3-amino-benzo[d]isoxazole or 3-aminoindazole scaffold

Bioorg Med Chem. 2015 Feb 1;23(3):564-78. doi: 10.1016/j.bmc.2014.12.002. Epub 2014 Dec 8.

Authors

Xiaolong Jiang¹, Hongyan Liu², Zilan Song³, Xia Peng², Yinchun Ji², Qizheng Yao⁴, Meiyu Geng², Jing Ai⁵, Ao Zhang⁶

Affiliations

¹ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
² Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: qz_yao@yahoo.com.cn.
⁵ Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jai@simm.ac.cn.
⁶ CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: aozhang@simm.ac.cn.

PMID: 25537530
DOI: 10.1016/j.bmc.2014.12.002

Abstract

A series of 3-amino-benzo[d]isoxazole-/3-aminoindazole-based compounds were designed, synthesized and pharmacologically evaluated as tyrosine kinase c-Met inhibitors. The SAR study was conducted leading to identification of nine compounds (8d, 8e, 12, 28a-d, 28h and 28i) with IC50s less than 10nM against c-Met. Compound 28a stood out as the most potent c-Met inhibitor displaying potent inhibitory effects both at enzymatic (IC50=1.8 nM) and cellular (IC50=0.18 μM on EBC-1 cells) levels. In addition, 28a had a relatively good selectivity compared to a panel of our in-house 14 RTKs.

Keywords: 3-Amino-benzo[d]isoxazole; 3-Aminoindazole; Inhibitor; Non-small cell lung cancer; c-Met kinase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Drug Discovery
Isoxazoles / chemistry*
Isoxazoles / pharmacology*
Molecular Docking Simulation
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Isoxazoles
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-met