Structure-based design and structure-activity relationships of 1, 2, 3, 4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors. Issue 7 (15th April 2018) - Liao, Yixian
Graphical abstract: Abstract: This paper describes our medicinal chemistry efforts on 7-(cyclopentyloxy)-6-methoxy1, 2, 3, 4-tetrahydroisoquinoline scaffold: design, synthesis and biological evaluation using conformational restriction approach and bioisosteric replacement strategy. Biological data revealed that the majority of the synthesized compounds of this series displayed moderate to potent inhibitory activity against PDE4B and strong inhibition of LPS-induced TNF α release. Among them, compound19 exhibited the strongest inhibition against PDE4B with an IC50 of 0.88 µM and 21 times more potent selectivity toward PDE4B over PDE4D when compared to rolipram. A primary structure-activity relationship study showed that the attachment of CH3 O group or CF3 O group to the phenyl ring at the para- position was helpful to enhance the inhibitory activity against PDE4B. Moreover, sulfonamide group played a key role in improving the inhibitory activity against PDE4B and subtype selectivity. In addition, the attachment of the additional rigid substituents at the C-3 position of 1, 2, 3, 4-tetrahydroisoquinoline ring was favored to subtype selectivity, which was consistent well with the observed docking simulation.