Discovery of a potent tyrosine kinase AXL inhibitor bearing the 3-((2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)amino)pyrazine core

• Published in: Bioorganic & medicinal chemistry letters Vol. 29; no. 6; pp. 836 - 838
• Main Authors: Wang, Yueliang, Xing, Li, Ji, Yinchun, Ye, Jiqing, Dai, Yang, Gu, Wangting, Ai, Jing, Song, Zilan
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.03.2019; Elsevier
• Subjects: Aniline Compounds - chemistry; Aniline Compounds - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; AXL Kinase; Benzazepines - chemical synthesis; Benzazepines - pharmacokinetics; Benzazepines - pharmacology; Cancer; Cell Line, Tumor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Discovery; Life Sciences & Biomedicine; Mice; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Pyrazine; Pyrazines - chemical synthesis; Pyrazines - chemistry; Pyrazines - pharmacokinetics; Pyrazines - pharmacology; Rats, Sprague-Dawley; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Science & Technology; AXL Kinase; Pyrazine; Cancer; RECEPTOR; EXPRESSION; MET; FAMILY
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2019.01.018

[Display omitted] •AXL has been a promising therapeutic target for cancers.•A side-chain ring closure medicinal chemistry approach was conducted.•15c bearing the 3-((2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)amino)pyrazine core was found to be most potent.•15c exhibited high anti-proliferative activity with IC50 values of 0.3 nM.•15c showed acceptable PK properties with the oral bioavailability of 24.8%. Starting from the recently launched FLT3/AXL multi-targeted inhibitor Gilteritinib (5), we conducted a side-chain ring closure medicinal chemistry approach leading to the identification of compound 15c as a highly potent AXL inhibitor in the biochemical and cellular anti-proliferative assays, with IC50 values of 1.2 and 0.3 nM, respectively. Compared with the reference compound 5, our new discovered AXL inhibitor 15c is more potent in both assays.