Synthesis and structure–activity relationship of 6-arylureido-3-pyrrol-2-ylmethylideneindolin-2-one derivatives as potent receptor tyrosine kinase inhibitors

• Published in: Bioorganic & medicinal chemistry 2010-07, Vol.18 (13), p.4674-4686
• Main Authors: Khanwelkar, Rahul R., Chen, Grace Shiahuy, Wang, Hsiao-Chun, Yu, Chao-Wu, Huang, Chiung-Hua, Lee, On, Chen, Chih-Hung, Hwang, Chrong-Shiong, Ko, Ching-Huai, Chou, Nien-Tzu, Lin, Mai-Wei, Wang, Ling-mei, Chen, Yen-Chun, Hseu, Tzong-Hsiung, Chang, Chia-Ni, Hsu, Hui-Chun, Lin, Hui-Chi, Shih, Ying-Chu, Chou, Shuen-Hsiang, Tseng, Hsiang-Wen, Liu, Chih-Peng, Tu, Chia-Mu, Hu, Tsan-Lin, Tsai, Yuan-Jang, Chern, Ji-Wang
• Format: Article
• Language: English
• Subjects: Animals; Anticancer; Antineoplastic agents; Aurora Kinases; Binding Sites; Biological and medical sciences; Cell Line, Tumor; Computer Simulation; Drug Screening Assays, Antitumor; General aspects; Humans; Indoles - chemistry; Indoles - therapeutic use; Indoles - toxicity; Inhibitor; Leukemia, Myeloid - drug therapy; Medical sciences; Mice; Pharmacology. Drug treatments; Platelet-derived growth factor receptor; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - therapeutic use; Protein Kinase Inhibitors - toxicity; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Pyrroles - chemistry; Pyrroles - therapeutic use; Pyrroles - toxicity; Receptor tyrosine kinase; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors; Receptors, Platelet-Derived Growth Factor - metabolism; Structure-Activity Relationship; Transplantation, Heterologous; Urea - analogs & derivatives; Urea - chemistry; Urea - therapeutic use; Urea - toxicity; Vascular endothelial growth factor receptor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.05.021

A series of 6-ureido-substituted 3-pyrrolemethylidene-2-oxindole derivatives were synthesized and identified as potent inhibitors of the vascular endothelial growth factor receptor and platelet-derived growth factor receptor families of receptor tyrosine kinases. A series of new ureidoindolin-2-one derivatives were synthesized and evaluated as inhibitors of receptor tyrosine kinases. Investigation of structure–activity relationships at positions 5, 6, and 7 of the oxindole skeleton led to the identification of 6-ureido-substituted 3-pyrrolemethylidene-2-oxindole derivatives that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) families of receptor tyrosine kinases. Several derivatives showed potency against the PDGFR inhibiting both its enzymatic and cellular functions in the single-digit nanomolar range. Among them, compound 35 was a potent inhibitor against tyrosine kinases, including VEGFR and PDGFR families, as well as Aurora kinases. Inhibitor 36 (non-substituted on the pyrrole or phenyl ring) had a moderate pharmacokinetic profile and completely inhibited tumor growth initiated with the myeloid leukemia cell line, MV4-11, in a subcutaneous xenograft model in BALB/c nude mice.