From Celecoxib to a Novel Class of Phosphodiesterase 5 Inhibitors: Trisubstituted Pyrazolines as Novel Phosphodiesterase 5 Inhibitors with Extremely High Potency and Phosphodiesterase Isozyme Selectivity

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 <b>d12</b> 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 <b>d12</b> only inhibited the full-length enzyme, suggesting a mechanism of enzyme inhibition distinct from sildenafil. The PDE5 inhibitory activity of compound <b>d12</b> was confirmed in cells using a cGMP biosensor assay. Oral administration of compound <b>d12</b> 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.