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

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.
Gaopeng Song 1,  Xiang Zhu 2,  Junhua Li 3,  Dekun Hu 4,  Dongsheng Zhao 5,  Yixian Liao 6,  Juntong Lin 3,  Lian-Hui Zhang 4,  Zi-Ning Cui 7
Affiliations

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.

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