Synthesis and biological evaluation of 2-amino-5-aryl-3-benzylthiopyridine scaffold based potent c-Met inhibitors

Dengyou Zhang; Xiaowei Zhang; Jing Ai; Yun Zhai; Zhongjie Liang; Ying Wang; Yi Chen; Chunpu Li; Fei Zhao; Hualiang Jiang; Meiyu Geng; Cheng Luo; Hong Liu

doi:10.1016/j.bmc.2013.07.032

Synthesis and biological evaluation of 2-amino-5-aryl-3-benzylthiopyridine scaffold based potent c-Met inhibitors

Bioorg Med Chem. 2013 Nov 1;21(21):6804-20. doi: 10.1016/j.bmc.2013.07.032. Epub 2013 Jul 31.

Authors

Dengyou Zhang¹, Xiaowei Zhang, Jing Ai, Yun Zhai, Zhongjie Liang, Ying Wang, Yi Chen, Chunpu Li, Fei Zhao, Hualiang Jiang, Meiyu Geng, Cheng Luo, Hong Liu

Affiliation

¹ State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.

PMID: 23993328
DOI: 10.1016/j.bmc.2013.07.032

Abstract

A series of 2-amino-N-benzylpyridine-3-carboxnamides, 2-amino-N-benzylpyridine-3-sulfonamides and 2-amino-3-benzylthiopyridines against c-Met were designed by means of bioisosteric replacement and docking analysis. Optimization of the 2-amino-3-benzylthiopyridine scaffold led to the identification of compound (R)-10b displaying c-Met inhibition with an IC50 up to 7.7nM. In the cytotoxic evaluation, compound (R)-10b effectively inhibited the proliferation of c-Met addictive human cancer cell lines (IC50 from 0.19 to 0.71μM) and c-Met activation-mediated cell metastasis. At a dose of 100mg/Kg, (R)-10b evidently inhibited tumor growth (45%) in NIH-3T3/TPR-Met xenograft model. Of note, (R)-10b could overcome c-Met-activation mediated gefitinib-resistance, which indicated its potential use for drug combination. Taken together, 2-amino-3-benzylthiopyridine scaffold was first disclosed and exhibited promising pharmacological profiles against c-Met, which left room for further exploration.

Keywords: 2-Amino-5-aryl-3-benzylthiopyridine; Receptor tyrosine kinase; c-Met.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / therapeutic use
Antineoplastic Agents / toxicity
Binding Sites
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Dogs
Drug Resistance, Neoplasm / drug effects
Half-Life
Humans
Madin Darby Canine Kidney Cells
Mice
Mice, Nude
Molecular Docking Simulation
NIH 3T3 Cells
Neoplasms / drug therapy
Phosphorylation / drug effects
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / toxicity
Protein Structure, Tertiary
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / metabolism
Pyridines / chemistry*
Pyridines / pharmacokinetics
Pyridines / toxicity
Rats
Signal Transduction / drug effects
Structure-Activity Relationship
Sulfonamides / chemistry
Sulfonamides / pharmacokinetics
Sulfonamides / toxicity
Transplantation, Heterologous

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyridines
Sulfonamides
Proto-Oncogene Proteins c-met
pyridine