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

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. (C) 2015 Elsevier Ltd. All rights reserved.Special Fund for the Research and Construction of Public Service Ability in Guangdong Province, China [2014A020210019]; National Key Project for Basic Research (973 Program) [2015CB150600]; Pearl River S&T Nova Program of Guangzhou [201506010029]; National Natural Science Foundation of China [21202047, 31570122]; Specialty and Innovation Project from the Department of Education in Guangdong Province, China [2014KTSCX031]SCI(E)PubMedARTICLEziningcui@scau.edu.cn204610-46142