Structure-based design and structure-activity relationships of 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors

Yixian Liao; Yiming Guo; Sumei Li; Lei Wang; Yongmei Tang; Tianmiao Li; Weihao Chen; Guohua Zhong; Gaopeng Song

doi:10.1016/j.bmcl.2018.02.056

Structure-based design and structure-activity relationships of 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors

Bioorg Med Chem Lett. 2018 Apr 15;28(7):1188-1193. doi: 10.1016/j.bmcl.2018.02.056. Epub 2018 Mar 6.

Authors

Yixian Liao¹, Yiming Guo², Sumei Li³, Lei Wang², Yongmei Tang², Tianmiao Li², Weihao Chen², Guohua Zhong⁴, Gaopeng Song⁵

Affiliations

¹ College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China; Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China.
² College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China.
³ Department of Human Anatomy, School of Medicine, Jinan University, Guangzhou 510632, China.
⁴ Key Laboratory of Crop Integrated Pest Management in South China, Ministry of Agriculture, P. R. China, and Lab of Insect Toxicology, South China Agricultural University, Guangzhou 510642, China. Electronic address: guohuazhong@scau.edu.cn.
⁵ College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China. Electronic address: vinsin1021@126.com.

PMID: 29545101
DOI: 10.1016/j.bmcl.2018.02.056

Abstract

This paper describes our medicinal chemistry efforts on 7-(cyclopentyloxy)-6-methoxy1,2,3,4-tetrahydroisoquinoline scaffold: design, synthesis and biological evaluation using conformational restriction approach and bioisosteric replacement strategy. Biological data revealed that the majority of the synthesized compounds of this series displayed moderate to potent inhibitory activity against PDE4B and strong inhibition of LPS-induced TNFα release. Among them, compound 19 exhibited the strongest inhibition against PDE4B with an IC₅₀ of 0.88 µM and 21 times more potent selectivity toward PDE4B over PDE4D when compared to rolipram. A primary structure-activity relationship study showed that the attachment of CH₃O group or CF₃O group to the phenyl ring at the para-position was helpful to enhance the inhibitory activity against PDE4B. Moreover, sulfonamide group played a key role in improving the inhibitory activity against PDE4B and subtype selectivity. In addition, the attachment of the additional rigid substituents at the C-3 position of 1,2,3,4-tetrahydroisoquinoline ring was favored to subtype selectivity, which was consistent well with the observed docking simulation.

Keywords: PDE4 inhibitors; Structure-activity relationship; Synthesis; Tetrahydroisoquinoline derivatives.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
Dose-Response Relationship, Drug
Drug Design*
Humans
Lipopolysaccharides / antagonists & inhibitors
Lipopolysaccharides / pharmacology
Molecular Docking Simulation
Molecular Structure
Phosphodiesterase 4 Inhibitors / chemical synthesis
Phosphodiesterase 4 Inhibitors / chemistry
Phosphodiesterase 4 Inhibitors / pharmacology*
Structure-Activity Relationship
Tetrahydroisoquinolines / chemical synthesis
Tetrahydroisoquinolines / chemistry
Tetrahydroisoquinolines / pharmacology*
Tumor Necrosis Factor-alpha / antagonists & inhibitors
Tumor Necrosis Factor-alpha / metabolism

Substances

Lipopolysaccharides
Phosphodiesterase 4 Inhibitors
Tetrahydroisoquinolines
Tumor Necrosis Factor-alpha
1,2,3,4-tetrahydroisoquinoline
Cyclic Nucleotide Phosphodiesterases, Type 4
PDE4B protein, human