3-Phenyl-1H-5-pyrazolylamine-based derivatives as potent and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3)

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 14; pp. 4654 - 4659
• Main Authors: Hsu, John T.-A., Yeh, Teng-Kuang, Yen, Shih-Chieh, Chen, Chiung-Tong, Hsieh, Shu-Yi, Hsu, Tsu, Lu, Cheng-Tai, Chen, Chun-Hwa, Chou, Ling-Hui, Chiu, Ching-Hui, Chang, Yun-I, Tseng, Ya-Ju, Yen, Kuei-Rong, Chao, Yu-Sheng, Lin, Wen-Hsing, Jiaang, Weir-Torn
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.07.2012; Elsevier
• Subjects: Acute myeloid leukemia; Amines - chemistry; Amines - pharmacology; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; FMS-like tyrosine kinase-3; growth retardation; Humans; Inhibitor; Internal tandem duplications; Medical sciences; Mice; Molecular Structure; neoplasms; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrazoles - chemistry; Receptor tyrosine kinase; Structure-Activity Relationship; structure-activity relationships; tyrosine; Xenograft Model Antitumor Assays; Receptor tyrosine kinase; FMS-like tyrosine kinase-3; Inhibitor; Internal tandem duplications; Acute myeloid leukemia; Signal transduction; Acute myelogenous leukemia; Enzyme; Transferases; Receptor protein-tyrosine kinase; Malignant hemopathy; Cancer
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.05.116

A new class of FLT3 inhibitors has been identified based on the 3-phenyl-1H-5-pyrazolylamine scaffold. The structure–activity relationships led to the discovery of two carbamate series, and some potent compounds within these two series exhibited better growth inhibition of FLT3-mutated MOLM-13 cells than FLT3 inhibitors sorafenib (2) and ABT-869 (3). In particular, compound 8d exhibited the ability to regress tumors in mouse xenograft model using MOLM-13 cells.