1), which was one of the few drugs that had the properties of PDE inhibition; however, its drawback was its lack of selectivity and potency. Perhaps it was due to these reasons the developers of Zaprinast, May and Baker, never extended it commercially as an anti-allergy drug despite it being an effective vasodilator in vitro.
From early study of Zaprinast, it became clear to Campbell and Roberts the blueprint for success: to modify and build upon Zaprinast's ring structure, allowing tight binding to PDE's active site without excess, potency-hindering mechanisms. This was no easy feat since progress in pharmaceutical drugs at the time is achieved mostly through vigorous stages of trial and error. The team spent four arduous years exploring other ring systems, during which time they have came across several compounds; one of which is a called pyrazolopyrimidinone (Fig. 2). Pyrazolopyrimidinone's advantage over Zaprinast is its increased methyl groups, which significantly enhanced its affinity for PDE. This slight modification increased hydrophobic interactions between the compound and the hydrophobic pocket of PDE's active site and proved to be the crucial step leading to the final product.
The pyrazolopyrimidinone ring structure was further modified by substitution of a propyl group for a methyl group to further increase affinity and later addition of a sulphonamide group to reduce lipophilicity and increase solubility. In 1989, the team named the resulting compound sildenafil (Fig. 3). Through the entire course of its development, Sildenafil was filtered through approximately 1600 other compounds and was found to be the most promising candidate in fulfilling the initial goal of combating hypertension and angina. However, in true fashion of opportunists, unexpected results from years of phase trials persuaded the team to reinvent their expectation for sildenafil. Results showed the drug's activity in treating patients suffering from angina was badly overestimated.
