Key result
PDE5 inhibitors like sildenafil, originally developed for cardiovascular disease, showed unimpressive cardiovascular responses but became widely used for erectile dysfunction.
Provides historical context on the discovery and development of PDE5 inhibitors, originally intended for cardiovascular disease but repurposed for erectile dysfunction.
was first discovered in the mid 1970s, not as a PDE but rather as a binding protein for cGMP. 1 Shortly thereafter, it became clear that this protein also had cGMP-selective PDE activity, and cGMP-binding to domains in the N-terminus (GAF domains) regulated its enzymatic activity. 2 PDE5 gained more attention in the mid 1980s when its role in modulating vascular tone was revealed. Pharmacologists at Pfizer considered it a potential drug for hypertension or coronary heart disease, which led to the development of UK-92,480 (sildenafil), a selective and potent PDE5 inhibitor. Although the desired cardiovascular responses were unimpressive, the phase I studies revealed a now-famous side effect that was quite popular among the trial participants. This ultimately led to development of PDE5 inhibitors for erectile dysfunction. 6] Limited functional analysis obtained largely under rest conditions suggested negligible effects.
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David A. Kass (2007) conducted an editorial in Hypertension or coronary heart disease. PDE5 inhibitors (sildenafil) was evaluated. PDE5 inhibitors like sildenafil, originally developed for cardiovascular disease, showed unimpressive cardiovascular responses but became widely used for erectile dysfunction.
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