2. Academic Validation
  3. Discovery of 4,7-Diamino-5-(4-phenoxyphenyl)-6-methylene-pyrimido[5,4- b]pyrrolizines as Novel Bruton's Tyrosine Kinase Inhibitors

Discovery of 4,7-Diamino-5-(4-phenoxyphenyl)-6-methylene-pyrimido[5,4- b]pyrrolizines as Novel Bruton's Tyrosine Kinase Inhibitors

  • J Med Chem. 2018 May 24;61(10):4608-4627. doi: 10.1021/acs.jmedchem.8b00441.
Yu Xue 1,  Peiran Song 2,  Zilan Song,  Aoli Wang 3,  Linjiang Tong,  Meiyu Geng 4 2,  Jian Ding 4 2,  Qingsong Liu 3,  Liping Sun 1,  Hua Xie 4,  Ao Zhang 4 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing 210009 , China.
  • 2 School of Life Science and Technology , ShanghaiTech University , Shanghai 201210 , China.
  • 3 High Magnetic Field Laboratory , Chinese Academy of Sciences , Hefei 230031 , China.
  • 4 College of Pharmacy , University of Chinese Academy of Sciences , Shanghai , China.
PMID: 29715023 DOI: 10.1021/acs.jmedchem.8b00441
Abstract

An alternative medicinal chemistry approach was conducted on Bruton's tyrosine kinase (Btk) inhibitor 1 (ibrutinib) by merging the pyrazolo[3,4- d]pyrimidine component into a tricyclic skeleton. Two types of compounds were prepared, and their biochemical activities on Btk as well as stereochemistry effects were determined. Structural optimization focusing on the reactive binding group to Btk Cys481 and on the metabolic site guided by metabolic study were conducted. 7S was identified as the most potent showing an IC50 value of 0.4 nM against Btk and 16 nM against BTK-dependent TMD8 cells. Compared to 1, 7S was slightly more selective with strong inhibition on the B-cell receptor signaling pathway. In a TMD8 cell-derived animal xenograft model, 7S showed a relative tumor volume of 5.3 at 15 mg/kg QD dosage that was more efficacious than 1 (RTV 6.6) at a higher dose of 25 mg/kg QD. All these results suggest 7S as a new Btk Inhibitor worthy of further profiling.

Figures