Discovery of novel inhibitors of phosphodiesterase 4 with 1-phenyl-3,4-dihydroisoquinoline scaffold: Structure-based drug design and fragment identification

Yixian Liao; Xiuhua Jia; Yongmei Tang; Sumei Li; Yipeng Zang; Lei Wang; Zi-Ning Cui; Gaopeng Song

doi:10.1016/j.bmcl.2019.126720

Discovery of novel inhibitors of phosphodiesterase 4 with 1-phenyl-3,4-dihydroisoquinoline scaffold: Structure-based drug design and fragment identification

Bioorg Med Chem Lett. 2019 Nov 15;29(22):126720. doi: 10.1016/j.bmcl.2019.126720. Epub 2019 Oct 5.

Authors

Yixian Liao¹, Xiuhua Jia², Yongmei Tang³, Sumei Li⁴, Yipeng Zang³, Lei Wang³, Zi-Ning Cui⁵, Gaopeng Song⁶

Affiliations

¹ College of Materials and Energy, State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, 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 Department of Ophthalmology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
³ College of Materials and Energy, State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou 510642, China.
⁴ Department of Human Anatomy, School of Medicine, Jinan University, Guangzhou 510632, China.
⁵ Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China. Electronic address: ziningcui@scau.edu.cn.
⁶ College of Materials and Energy, State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou 510642, China. Electronic address: songgp1021@scau.edu.cn.

PMID: 31610942
DOI: 10.1016/j.bmcl.2019.126720

Abstract

Currently, it is in urgent need to develop novel selective PDE4 inhibitors with novel structural scaffolds to overcome the adverse effects and improve the efficacy. Novel 1-phenyl-3,4-dihydroisoquinoline amide derivatives were developed as potential PDE4 inhibitors based on the structure-based drug design and fragment identification strategy. A SARs analysis was performed in substituents attached in the C-3 side chain phenyl ring, indicating that the attachment of methoxy group or halogen atom substitution at the ortho-position of the phenyl ring was helpful to enhance both inhibitory activity toward PDE4B and selectivity. Compound 15 with excellent selectivity, exhibited the most potent inhibition in vitro and in vivo, which is a promising lead for development of a new class of selective PDE4 inhibitors.

Keywords: 1-Phenyl-3,4-dihydroisoquinoline; Selective PDE4B inhibitors; Structure-activity relationships; Synthesis.

Publication types

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

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Crystallography, X-Ray
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Isoquinolines / chemical synthesis
Isoquinolines / chemistry
Isoquinolines / pharmacology*
Models, Molecular
Molecular Structure
Phosphodiesterase 4 Inhibitors / chemical synthesis
Phosphodiesterase 4 Inhibitors / chemistry
Phosphodiesterase 4 Inhibitors / pharmacology*
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / antagonists & inhibitors
Tumor Necrosis Factor-alpha / metabolism

Substances

Amides
Isoquinolines
Phosphodiesterase 4 Inhibitors
Tumor Necrosis Factor-alpha
Cyclic Nucleotide Phosphodiesterases, Type 4