1998: Sildenafil: Serendipitous PDE5 Discovery (1998)

Sildenafil (Viagra) reached the market in March 1998 after one of the most famous serendipitous
redirections in pharmaceutical history. Pfizer chemists at Sandwich, UK, originally synthesised
the compound in the late 1980s as a treatment for angina pectoris and hypertension. The rationale
was sound: nitric oxide (NO) relaxes vascular smooth muscle through cyclic GMP (cGMP), and
inhibiting phosphodiesterase type 5 (PDE5)—the enzyme that degrades cGMP—would sustain
vasodilation and reduce cardiac workload.

Early clinical trials were disappointing for angina. PDE5 inhibition provided only modest
antihypertensive effect and failed to differentiate from existing nitrates. However, male trial
participants repeatedly declined to return unused tablets at the end of studies and reported
improved erectile function as a side effect. Pfizer scientists recognised that corporal smooth
muscle in the penis is particularly rich in PDE5, making it exquisitely sensitive to cGMP
elevation: NO released from non-adrenergic, non-cholinergic neurons during sexual stimulation
drives penile erection, and PDE5 inhibition prolongs this effect.

The company pivoted the development programme entirely toward erectile dysfunction (ED), a
condition affecting an estimated 150 million men globally but treated almost exclusively by
psychotherapy or invasive prostheses. The Phase III programme was decisive: sildenafil produced
erections sufficient for intercourse in 70–80 % of men compared with 22 % on placebo. The FDA
approved the oral tablet in record time, and within weeks of launch it became the fastest-selling
drug in history.

Beyond ED, sildenafil's mechanism proved clinically important in a separate domain: pulmonary
arterial hypertension (PAH). PDE5 is highly expressed in pulmonary vascular smooth muscle; in
2005, the FDA approved sildenafil (branded Revatio) for PAH, where it reduces pulmonary vascular
resistance and improves exercise capacity.