Enhancing the cellular anti-proliferation activity of pyridazinones as c-met inhibitors using docking analysis

• Published in: European journal of medicinal chemistry 2015-05, Vol.95, p.302-312
• Main Authors: Xing, Weiqiang, Ai, Jing, Jin, Shiyu, Shi, Zhangxing, Peng, Xia, Wang, Lang, Ji, Yinchun, Lu, Dong, Liu, Yang, Geng, Meiyu, Hu, Youhong
• Format: Article
• Language: English
• Subjects: Anticancer; c-Met inhibitor; Cell Line, Tumor; Cell Proliferation - drug effects; Docking study; Drug Design; Humans; Molecular Docking Simulation; Protein Conformation; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - chemistry; Proto-Oncogene Proteins c-met - metabolism; Pyridazines - chemistry; Pyridazines - metabolism; Pyridazines - pharmacology; Pyridazinone; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.03.041

A series of 2, 6-disubstituted pyridazinone derivatives were evaluated and optimized for their c-Met inhibitory activity in enzyme and cellular assay. An analysis of the SAR results arising from computer modeling analysis of members of the library led to the proposal that in order to obtain optimal inhibitory activity in cellular systems the lipophilic/hydrophilic properties of individual structural fragments in the inhibitors need to match those of corresponding binding pockets in the enzyme. Guided by this proposal, the quinoline-pyridazinone 8a, containing hydrophobic 6-indolyl pyridazinone and quinoline moieties along with a hydrophilic morpholine terminal group, was designed and synthesized. The results of studies with this substance showed that it is a selective c-Met inhibitor with both a high enzyme inhibition IC50 value of 4.2 nM and a high EBC-1 cell proliferation inhibition IC50 value of 17 nM. A series of 2, 6-disubstituted pyridazinones were optimized for the c-Met activity. By an analysis of the SAR results, the quinoline-pyridazinone 8a was achieved as a selective c-Met inhibitor. [Display omitted] •A series of 2, 6-disubstituted pyridazinone derivatives were evaluated and optimized for c-Met inhibitory activity.•An analysis of the SAR results arising from computer modeling analysis was investigated.•The properties of fragments in the inhibitors need to match the binding pockets for cellular activity was proposed.•6-Indolylpyridazinone-quinoline 8a as a selective c-Met inhibitor with both potent enzyme and cellular activity was achieved.