The angina file at Sandwich
Nitrates were already in wide use for angina. The Sandwich team wanted another way into the same nitric-oxide pathway, downstream, by inhibiting the enzyme that breaks down cyclic GMP. In 1986 Pfizer formed a project team at Sandwich to develop a selective PDE5 inhibitor and to test it in animals before any volunteer ever saw a dose. UK-92,480 came out of that chemistry. The review records an IC50 of 3.5 nM against PDE5 from human platelets, which is a lab potency figure, not a tablet strength.
Wikipedia's history section says the compound was synthesized in 1989 by chemists led by Simon Campbell, at the Sandwich facility, and that the first clinical trials were at Morriston Hospital in Swansea. The 2006 review cites a Campbell essay in its references and, in the milestone prose, does not put his name or that hospital on the timeline. This note follows the review for the years and leaves Campbell and Morriston as encyclopedia claims we did not re-check in a lab notebook.
Why a three-times-a-day heart pill stalled
In 1991, studies in healthy volunteers started. Single doses of UK-92,480 up to 200 mg were given. The plasma half-life was relatively short, about four hours. At doses of 150 mg and higher, volunteers reported transient disturbances in colour vision. An intravenous study in people who already had angina showed a moderate vasodilatory effect. A separate volunteer study found that UK-92,480 augmented the vasodilatory and antihypertensive effects of glyceryl trinitrate. The practical consequence in the review is blunt: the compound would have to be contraindicated in patients taking nitrates, unless someone could show a safe way to give both.
By mid-1993, UK-92,480 was looking less promising as a new treatment for angina pectoris. Chronic angina would have needed dosing at least three times per day because the half-life was short. That is a different problem from "the chest pain numbers were a bit dull." The nitrate clash and the dosing clock were already on the page before anyone rebuilt the file around erections.
Those 150 mg and 200 mg doses are Phase I research doses. They are not the as-needed erectile-dysfunction start. Timing, food, and the once-a-day limit are on the how to take sildenafil note.
From a side-effect line to an ED study
In 1992, several multiple-dose studies in healthy volunteers looked at kinetics, effects, and tolerance. Some volunteers also reported penile erections as a side effect. At first that was not treated as the main finding. The review says cardiovascular indications stayed the focus through 1992 and 1993, because the reports came after only several days of dosing.
The turn is dated. The decision to run pilot studies in erectile dysfunction was supported by erections being a common side effect in the multiple-dose Phase I study, and by newer work on nitric oxide in penile erection. The Pfizer team postulated that blocking the breakdown of cyclic GMP would prolong the vascular response in the penis only during sexual stimulation. In late 1993 the first clinical study in patients with ED was undertaken. A Rigiscan device, with loops at the base and tip of the penis, recorded girth and hardness while the men were sexually stimulated, so the clinic did not have to pretend an erection could be scored in a quiet chair with no stimulus. By mid-1994, two studies had shown that single doses of sildenafil enhanced erectile responses to sexual stimulation.
The September 1998 BMJ piece that leads this search says sildenafil was first discovered by accident, as a treatment for erectile dysfunction related to diabetes and some vascular disorders, and that the drug alone does not cause an erection: sexual stimulation is still required. The review's account is a side effect that was logged, then a deliberate change of indication. The stimulation rule is the part both accounts share, and it is still the rule on the tablet.
What David Brown told the Guardian in 2023
David Brown, a former Pfizer medicinal chemist, spoke to the Guardian before a BBC drama about the early volunteers. He said that by 1993 Pfizer had all but decided to abandon the programme. He described a study at a clinic in Merthyr Tydfil, south Wales, and said the men were paid £300 to stay overnight. His line, as the paper prints it: he does not think there would be a drug around if that one miner had not put his hand up. The Guardian also says Viagra was launched commercially in 1998.
The 2006 review, with Osterloh as co-author, does not name Merthyr Tydfil, a payment, or a miner. It places erection reports in the 1992 multiple-dose volunteer studies and the first patient study in late 1993. Brown's interview is his later telling, published on 2 December 2023. It is worth reading as a named recollection. It is not a substitute for the year-by-year account in the review. A Guardian interview can carry a scene the review never wrote down.
March 1998, and a later pulmonary approval
US approval for erectile dysfunction is March 1998 in the review, and the BMJ notes that the pills were available in the United States from that March. An American Chemical Society blog in the same search says Pfizer filed a patent on sildenafil citrate in 1994 and that the FDA approved the drug for erectile dysfunction in 1998. Wikipedia's history section also discusses a 1996 patent and a 1992 cardiovascular filing. This note does not choose a patent year when secondary histories disagree.
In 2005 the FDA and the EMEA approved sildenafil for pulmonary arterial hypertension. That approval is a second life for the same molecule, under a different prescription. It does not supply an erectile-dysfunction dose, and this history does not borrow a pulmonary schedule. What the ED trials actually measured is the sildenafil clinical trials note. Imprint checks and the online-pharmacy questions sit on the sildenafil medicine note.
The Springer chapter listed for this question did not open. A drugstore feature, a news essay, a publisher abstract, and a pharmacy blog in the same results were not used for dates. The years above come from the 2006 review. The miner scene comes only from Brown's interview.
Julian Frost is the PDE5 signer. The margin disclaimer is the limit of a reading note. Talk with your own clinician before you treat a discovery story as a dosing plan.