Phosphodiesterases (PDEs) are a superfamily of enzymes which catalyze the hydrolysis of cAMP and/or cGMP and are targets of interest for cardiovascular diseases. We sought to identify subtype-specific inhibitors using Valo’s DEL platform. The DEL sections interrogated several target forms of each subtype and included competition selections with a known PDE-binder to enable profiling of active site binders. Through the informatic analysis of the selection data, we deprioritized structural clusters that showed pan-subtype enrichment and only focused on subtype-specific clusters. These efforts yielded numerous structurally distinct series with >1,000-fold inhibition selectivity for nearly all compounds and with a hit rate of 75% (IC50 < 1 μM).