2. Academic Validation
  3. Synthesis, bioconversion, pharmacokinetic and pharmacodynamic evaluation of N-isopropyl-oxy-carbonyloxymethyl prodrugs of CZh-226, a potent and selective PAK4 inhibitor

Synthesis, bioconversion, pharmacokinetic and pharmacodynamic evaluation of N-isopropyl-oxy-carbonyloxymethyl prodrugs of CZh-226, a potent and selective PAK4 inhibitor

  • Eur J Med Chem. 2020 Jan 15;186:111878. doi: 10.1016/j.ejmech.2019.111878.
Jing Guo 1,  Tingting Wang 2,  Tianxiao Wu 1,  Kehan Zhang 3,  Wenbo Yin 1,  Mingyue Zhu 1,  Yu Pang 1,  Chenzhou Hao 1,  Zhonggui He 3,  Maosheng Cheng 1,  Yang Liu 1,  Jiang Zheng 4,  Jingkai Gu 2,  Dongmei Zhao 5
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 2 Research Institute of Translational Medicine, The First Bethune Hospital of Jilin University, Changchun, 130061, China; Research Center for Drug Metabolism, College of Life Science, Jilin University, Changchun, 130012, China.
  • 3 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China.
  • 4 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China; State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, 550025, China.
  • 5 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: medchemzhao@163.com.
PMID: 31757524 DOI: 10.1016/j.ejmech.2019.111878
Abstract

We have previously disclosed compound 3 (CZh-226), a potent and selective PAK4 Inhibitor, but its development was delayed due to poor oral pharmacokinetics. In an attempt to improve this issue, we synthesised a series of prodrugs by masking its terminal nitrogen of the piperazine moiety. Most synthesised prodrugs of 3 have low or no inhibition of PAK4 activity. The stability of synthetic prodrugs was evaluated in PBS, SGF, SIF, rat plasma and liver S9 fraction. Of these, prodrug 19 was not only stable under both acidic and neutral conditions but also could be quickly converted to parent drug 3 in rat plasma and liver S9 fraction. Such effective conversion into parent drug 3 was observed in rats, providing higher exposure of 3 compared to its direct administration. When given via oral route at daily doses of 25 and 50 mg/kg, the prodrug 19 was effective and well tolerated in mouse model of HCT-116 and B16F10.

Keywords

Antitumor; Bioavailability; Prodrug; Stability; p21-activated kinase 4.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-130628
    PAK4抑制剂
    PAK
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