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

Bioorg Med Chem. 2010 Jul 1;18(13):4674-86. doi: 10.1016/j.bmc.2010.05.021.

Rahul R Khanwelkar ¹, Grace Shiahuy Chen, Hsiao-Chun Wang, Chao-Wu Yu, Chiung-Hua Huang, On Lee, Chih-Hung Chen, Chrong-Shiong Hwang, Ching-Huai Ko, Nien-Tzu Chou, Mai-Wei Lin, Ling-Mei Wang, Yen-Chun Chen, Tzong-Hsiung Hseu, Chia-Ni Chang, Hui-Chun Hsu, Hui-Chi Lin, Ying-Chu Shih, Shuen-Hsiang Chou, Hsiang-Wen Tseng, Chih-Peng Liu, Chia-Mu Tu, Tsan-Lin Hu, Yuan-Jang Tsai, Ji-Wang Chern

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Affiliation

1 School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.

PMID: 20570526 DOI: 10.1016/j.bmc.2010.05.021

Abstract

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.

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