Novel 2,4-Diarylaminopyrimidine Analogues (DAAPalogues) Showing Potent c-Met/ALK Multikinase Inhibitory Activities

  • ACS Med Chem Lett. 2014 Feb 8;5(4):304-8. doi: 10.1021/ml400373j.
Zhiqing Liu  1 ,  Jing Ai  1 ,  Xia Peng  1 ,  Zilan Song  1 ,  Kui Wu  2 ,  Jing Zhang  1 ,  Qizheng Yao  2 ,  Yi Chen  1 ,  Yinchun Ji  1 ,  Yanhong Yang  1 ,  Meiyu Geng  1 ,  Ao Zhang  1
Affiliations
  • 1. CAS Key Laboratory of Receptor Research, and Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences , Shanghai 201203, China.
  • 2. Department of Medicinal Chemistry, China Pharmaceutical University , Nanjing 210009, China.
PMID: 24900831 DOI: 10.1021/ml400373j
Abstract

By repurposing a typical dopamine D1/D5 receptor agonist motif, C1-substituted-N3-benzazepine or benzazecine, into the classical RTK inhibitor 2,4-diaminopyrimidine skeleton, a series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) were developed. Compounds 7 and 8a were identified possessing high potency against both c-Met and ALK kinases. Compound 8a displayed appreciable antitumor efficacy at the dose of 1 mg/kg in the ALK-driven BF3/EML4-ALK xenograft mice model.

Keywords
2,4-diarylaminopyrimidine analogues; C1-Substituted-N3-benzazepine; c-Met/ALK dual inhibitor; structure repurposing.