Abstract:
A ligand-based approach involving systematic
modifications of a trisubstituted pyrazoline scaffold derived from
the COX2 inhibitor, celecoxib, was used to develop novel PDE5
inhibitors. Novel pyrazolines were identified with potent PDE5
inhibitory activity lacking COX2 inhibitory activity. Compound
d12 was the most potent with an IC50 of 1 nM, which was three
times more potent than sildenafil and more selective with a
selectivity index of >10,000-fold against all other PDE isozymes.
Sildenafil inhibited the full-length and catalytic fragment of PDE5,
while compound d12 only inhibited the full-length enzyme,
suggesting a mechanism of enzyme inhibition distinct from
sildenafil. The PDE5 inhibitory activity of compound d12 was
confirmed in cells using a cGMP biosensor assay. Oral
administration of compound d12 achieved plasma levels >1000-fold higher than IC50 values and showed no discernable toxicity
after repeated dosing. These results reveal a novel strategy to inhibit PDE5 with unprecedented potency and isozyme selectivity.
