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

Jing Guo; Tingting Wang; Tianxiao Wu; Kehan Zhang; Wenbo Yin; Mingyue Zhu; Yu Pang; Chenzhou Hao; Zhonggui He; Maosheng Cheng; Yang Liu; Jiang Zheng; Jingkai Gu; Dongmei Zhao

doi:10.1016/j.ejmech.2019.111878

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. Epub 2019 Nov 14.

Authors

Jing Guo¹, Tingting Wang², Tianxiao Wu¹, Kehan Zhang³, Wenbo Yin¹, Mingyue Zhu¹, Yu Pang¹, Chenzhou Hao¹, Zhonggui He³, Maosheng Cheng¹, Yang Liu¹, Jiang Zheng⁴, Jingkai Gu², Dongmei Zhao⁵

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HCT116 Cells
Humans
Liver / chemistry
Liver / metabolism
Male
Melanoma, Experimental / drug therapy
Melanoma, Experimental / metabolism
Melanoma, Experimental / pathology
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Piperazines / chemical synthesis
Piperazines / chemistry
Piperazines / pharmacology*
Prodrugs / chemical synthesis
Prodrugs / chemistry
Prodrugs / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Rats
Rats, Wistar
Structure-Activity Relationship
p21-Activated Kinases / antagonists & inhibitors*
p21-Activated Kinases / metabolism

Substances

Antineoplastic Agents
Piperazines
Prodrugs
Protein Kinase Inhibitors
PAK4 protein, human
p21-Activated Kinases