Rational design of conformationally constrained oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors

Gaopeng Song; Xiang Zhu; Junhua Li; Dekun Hu; Dongsheng Zhao; Yixian Liao; Juntong Lin; Lian-Hui Zhang; Zi-Ning Cui

doi:10.1016/j.bmc.2017.08.045

Rational design of conformationally constrained oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors

Bioorg Med Chem. 2017 Oct 15;25(20):5709-5717. doi: 10.1016/j.bmc.2017.08.045. Epub 2017 Sep 1.

Authors

Gaopeng Song¹, Xiang Zhu², Junhua Li³, Dekun Hu⁴, Dongsheng Zhao⁵, Yixian Liao⁶, Juntong Lin³, Lian-Hui Zhang⁴, Zi-Ning Cui⁷

Affiliations

¹ State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou 510642, China; College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China.
² Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
³ College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China.
⁴ State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou 510642, China; Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China.
⁵ Department of Pharmacy, Quanzhou Medical College, Quanzhou 362100, China.
⁶ State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou 510642, China; College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China; Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China.
⁷ State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou 510642, China; Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China. Electronic address: ziningcui@scau.edu.cn.

PMID: 28888661
DOI: 10.1016/j.bmc.2017.08.045

Abstract

Improvement of subtype selectivity of an inhibitor's binding activity using the conformational restriction approach has become an effective strategy in drug discovery. In this study, we applied this approach to PDE4 inhibitors and designed a series of novel oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as conformationally restricted analogues of rolipram. The bioassay results demonstrated the oxazolidinone-fused tetrahydroisoquinoline derivatives exhibited moderate to good inhibitory activity against PDE4B and high selectivity for PDE4B/PDE4D. Among these derivatives, compound 12 showed both the strongest inhibition activity (IC₅₀=0.60μM) as well as good selectivity against PDE4B and good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary SAR study showed that restricting the conformation of the catechol moiety in rolipram with the scaffold of oxazolidinone-fused tetrahydroisoquinoline could lead to an increase in selectivity for PDE4B over PDE4D, which was consistent with the observed docking simulation.

Keywords: Conformational restriction; Molecular simulation; PDE4 inhibitor; Synthesis; Tetrahydroisoquinoline derivatives.

Publication types

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

MeSH terms

Animals
Asthma / drug therapy
Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
Disease Models, Animal
Drug Design*
Humans
Inhibitory Concentration 50
Molecular Conformation
Molecular Docking Simulation
Phosphodiesterase 4 Inhibitors / chemical synthesis
Phosphodiesterase 4 Inhibitors / chemistry
Phosphodiesterase 4 Inhibitors / pharmacology
Phosphodiesterase 4 Inhibitors / therapeutic use
Pulmonary Disease, Chronic Obstructive / drug therapy
Rolipram / chemistry
Rolipram / pharmacology
Rolipram / therapeutic use
Sepsis / drug therapy
Structure-Activity Relationship
Tetrahydroisoquinolines / chemical synthesis*
Tetrahydroisoquinolines / chemistry
Tetrahydroisoquinolines / pharmacology*
Tetrahydroisoquinolines / therapeutic use

Substances

Phosphodiesterase 4 Inhibitors
Tetrahydroisoquinolines
Cyclic Nucleotide Phosphodiesterases, Type 4
Rolipram