Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting a Unique Allosteric Pocket

Clinical
use of phosphodiesterase-5 (PDE5) inhibitors is limited
by several side effects due to weak isoform selectivity. Herein, a
unique allosteric pocket of PDE5 is identified by molecular modeling
and structural biology, which enables the discovery of highly selective
PDE5 inhibitors from natural product evodiamine (EVO). The crystal
structure of PDE5 with bound EVO derivative (S)-7e revealed that binding of (S)-7e to the novel
allosteric pocket induced dramatic conformation changes in the H-loop
with a maximum 24 Å movement of their Cα atoms. This movement
directly blocks the binding of substrate/inhibitors to the PDE5 active
site, which is different from all traditional PDE5 inhibitors such
as sildenafil, tadalafil, and vardenafil. These derivatives showed
>570-fold selectivity over PDE6C and PDE11A and achieved potent
efficacy
for the effective treatment of pulmonary hypertension in vivo.