2. Academic Validation
  3. Design, synthesis and biological evaluation of novel tetrahydroisoquinoline derivatives as potential PDE4 inhibitors

Design, synthesis and biological evaluation of novel tetrahydroisoquinoline derivatives as potential PDE4 inhibitors

  • Bioorg Med Chem Lett. 2015 Oct 15;25(20):4610-4. doi: 10.1016/j.bmcl.2015.08.043.
Gaopeng Song 1,  Dongsheng Zhao 2,  Dekun Hu 3,  Yasheng Li 3,  Hongwei Jin 4,  Zining Cui 5
Affiliations

Affiliations

  • 1 Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China; College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China.
  • 2 Department of Pharmacy, Quanzhou Medical College, Quanzhou 362100, China.
  • 3 Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China.
  • 4 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, 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.
PMID: 26320621 DOI: 10.1016/j.bmcl.2015.08.043
Abstract

The design, synthesis, and biological evaluation of new phosphodiesterase type 4 (PDE4) inhibitors, which possessed 7-(cyclopentyloxy)-6-methoxy 1,2,3,4-tetrahydroisoquinoline ring, were described. Compound 8 [(7-cyclopentyloxy)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)(4-hydroxy-3-methoxy-phenyl)methanone] showed the best inhibitory activity and good selectivity against PDE4B. The docking results showed that the catechol diether moiety of compound 8 played a key role to form integral hydrogen bonds with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4. Compound 8 would be great promise as a hit compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.

Keywords

7-(Cyclopentyloxy)-6-methoxy-1,2,3,4-tetrahydroisoquinoline derivatives; Molecular simulation; PDE4 inhibitor; SAR; Synthesis.

Figures