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.

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