Clinical studies with our male erectile dysfunction medicine, sildenafil, identified several additional indications for PDE5 inhibitors. Since these include disease indications requiring chronic treatment and/or single dose daily dosing in order to be competitive, we sought novel agents with an excellent safety profile, and in particular, no potential for off-target activity against other PDE family members.We were able to identify a second generation PDE5 agent meeting these requirement based on a HTSâ derived series. Key elements in discovery were the focus on physicochemistry and pharmacokinetics throughout the programme, together with the use of co-crystal structure data to guide design and identification of a parallel chemistry amenable, wide synthetic scope template. These elements enabled rapid discovery of a proprietary lead 3 with inherently good physicochemistry, a novel aminopyridine pharmacophore and PDE6 selectivity. Further optimisation provided advanced acidic, neutral and basic leads. Finally, a potent and selective acidic clinical candidate 13 with low clearance and an outstanding safety profile was identified. The excellent pre-clinical profile derived from our property-based strategy has successfully translated to once daily oral pharmacokinetics in man.