Novel azulene-based derivatives as potent multi-receptor tyrosine kinase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 20; pp. 6129 - 6132
• Main Authors: Chen, Chih-Hung, Lee, On, Yao, Chung-Niang, Chuang, Meng-Yun, Chang, Yow-Lone, Chang, May-Hua, Wen, Yen-Fang, Yang, Wan-Hsu, Ko, Ching-Huai, Chou, Nien-Tzu, Lin, Mai-Wei, Lai, Chin-Pen, Sun, Chung-Yuan, Wang, Ling-mei, Chen, Yen-Chun, Hseu, Tzong-Hsiung, Chang, Chia-Ni, Hsu, Hui-Chun, Lin, Hui-Chi, Chang, Yu-Li, Shih, Ying-Chu, Chou, Shuen-Hsiang, Hsu, Yi-Ling, Tseng, Hsiang-Wen, Liu, Chih-Peng, Tu, Chia-Mu, Hu, Tsan-Lin, Tsai, Yuan-Jang, Chen, Ting-Shou, Lin, Chih-Lung, Chiou, Shu-Jiau, Liu, Chung-Cheng, Hwang, Chrong-Shiong
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.10.2010; Elsevier
• Subjects: Acute myeloid leukemia; AML; Animals; Antineoplastic agents; Antineoplastic Agents - blood; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Azulene; Azulenes - blood; Azulenes - chemistry; Azulenes - pharmacology; Azulenes - therapeutic use; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation; FLT-3; Flt3 protein; FMS-like tyrosine kinase 3; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; General aspects; Humans; Leukemia, Myeloid, Acute - drug therapy; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Pharmacology. Drug treatments; Rats; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - metabolism; AML; FLT-3; Azulene; FMS-like tyrosine kinase 3; Acute myeloid leukemia; Antineoplastic agent; Acute myelogenous leukemia; Intravenous administration; Nitrogen heterocycle; Lactam; Cytotoxicity; Azulene derivatives; Signal transduction; Structure activity relation; Bicyclic compound; Receptor protein-tyrosine kinase; Aromatic compound; Chemical synthesis; Tumor cell; Human; Aminoalcohol; Enzyme; Transferases; Rodentia; Oral administration; Enzyme inhibitor; Aminoether; Malignant hemopathy; In vitro; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Fluorine Organic compounds; Pharmacokinetics; Cancer
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.08.025

The discovery of a novel series of multi-receptor tyrosine kinase inhibitor is disclosed. A series of azulene-based derivatives were synthesized as potent inhibitors for receptor tyrosine kinases such as FMS-like tyrosine kinase 3 (FLT-3). Systematic side chain modification of prototype 1a was carried out through SAR studies. Analogue 22 was identified from this series and found to be one of the most potent FLT-3 inhibitors, with good pharmaceutical properties, superior efficacy, and tolerability in a tumor xenograft model.