Design, synthesis and structure-activity relationship of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure as multi-target inhibitors against receptor tyrosine kinase
- Bioorg Med Chem. 2018 Sep 1;26(16):4735-4744. doi: 10.1016/j.bmc.2018.08.013.
- 1. Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
- 2. National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu 210023, China. Electronic address: [email protected].
- 3. Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China. Electronic address: [email protected].
Inspired by that the multi-target inhibitors against Receptor Tyrosine Kinases (RTKs) have significantly improved the effect of clinical treatment for Cancer, and based on the chemical structure of Linifanib (ABT-869, Abbott), two series of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure were designed and synthesized as multi-target inhibitors against RTKs. The preliminary biological evaluation showed that several compounds exhibited comparable potency with Linifanib. Compound S21 was identified as the most potent inhibitor against Fms-like tyrosine kinase 3 (Flt-3), kinase insert domain containing receptor (KDR) and platelet-derived growth factor receptor β (PDGFR-β) with its IC50 values were 4 nM, 3 nM and 8 nM respectively, it also showed potent inhibitory activities against several Cancer cells.