Stewart Adams, the man who discovered ibuprofen
IT was about 2.30pm on Tuesday December 19, 1961, when there was a knock on the door.
A technician entered the office of Dr Stewart Adams at Boots' research laboratories in Nottingham with the latest data from ongoing trials.
They had produced a series of noughts. It was just what he wanted to see. This was good news.
The compound being tested against others, including aspirin, had successfully reduced or eliminated signs of any inflammation. This was the first indication that research, begun five years earlier, might pay off.
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It was to lead to the discovery of one of the world's most successful non-prescription drugs – ibuprofen.
Sitting at a dining table overlooking his garden towards fields beyond, Dr Adams has gathered some of his original papers from 50 years ago.
Among them is a paper dated March 5, 1956, headed "confidential".
Circulation of the paper included Dr Gordon Hobday, the future Sir Gordon Hobday, who was to become a future Boots chairman.
The paper was to mark the beginning of the search for a drug that would relieve rheumatoid arthritis, traditionally treated with large doses of aspirin pushed to the limit.
"The paper was the seminal document, setting out where I thought we should go, how we should do it," said Dr Adams. "No one knew the basis of rheumatoid arthritis. No one knew until 1970 how aspirin worked, a year after Boots began marketing ibuprofen."
Dr Adams had a hunch about which compounds to test and narrowed them down over five years.
If a compound was active, it was likely to be active for rheumatoid arthritis.
The project had begun in a house in Rutland Road, West Bridgford, now occupied by a day nursery.
Boots' research laboratories had moved there at the beginning of the war and stayed until the construction of what is today BioCity, in Pennyfoot Street, which became the Boots research and development facility in 1959.
Part of the research department in the Boots Island Street site was destroyed by German bombing, the rubble being pushed into the canal basin.
A group of compounds called carboxyls proved particularly interesting to Dr Adams' team. They looked in their chemical library for small molecules with a carboxyl group in them.
His colleague, John Nicholson, found a number, but one caught their attention. Dr Adams said: "The ones that were interesting were actually made of selective weedkiller for our agricultural division at Boots.
"One of those was the first one that proved to be active in the laboratory model. Of several hundred, we picked out the best, sent it for clinical trial – but it wasn't active in rheumatoid arthritis."
It was a major setback for Dr Adams and his colleagues, but they were undiminished in their determination.
"I altered the criteria, kept the model but added to it," he said. "John made some very minor alterations to the weedkillers Within a few weeks of a great disappointment, we found a new series of compounds that met the new criteria.
"It was quite lucky in a way and it buoyed us up.
"Of the newer group, three went on to clinical trials. They were all active but all failed because of toxicity.
"Two produced a rash, the third was marketed but had to be withdrawn because of an affect on the liver.
"So we were back without anything."
The researchers made a slight chemical modification to the three and moved into a new group of compounds, propionics, discovered by Boots.
"We found they were active in the tests.
"We had taken out a patent in January 1961 and made a lot more propionics to strengthen the patent. Ibuprofen was one of these and we turned it up on December 19, 1961."
That was 50 years ago yesterday.
At this point of the interview, Dr Adams reached into a pile of his papers, pulling out two sheets with numbers set out in columns.
Compound 1472 had produced little or no inflammation during a test carried out between 11.30am and 2.20pm.
A similar test was run two days later using the same compound, 1472. As modest doses were stepped up, there was still no or reduced inflammation.
As a scientist, Dr Adams had seen disappointments.
"I didn't react very much," he said. "We didn't know at that stage that this would be the job that we would choose.
"We had quite a number of other compounds which were also active as well as ibuprofen. So it didn't come out of the blue."
A number of compounds were examined and ibuprofen was discovered to be the least toxic. It is very difficult to overdose on it.
Drug development takes time and is expensive.
It was 30 months before ibuprofen became a product candidate at Boots.
The results of the first clinical trials came through in February, 1966, and it went on to the market as a prescription drug, Brufen, three years later for the treatment of rheumatic diseases.
Initially, Brufen sales started slowly. It had been marketed for rheumatic diseases at too low a dose. Boots was being cautious.
But the story doesn't stop there. Dr Adams discovered the drug was an analgesic and antipyretic, reducing pain and fever.
During the 1970s Boots tested it for further properties and ibuprofen was marketed for dental pain, period pain and headaches.
In 1983, it became the first drug to move from prescription only to over-the-counter.
Dr Adams was still unexcited. He said: "I am naturally a pessimist. As a scientist, you can march yourself up to the top of the hill just to fall off.
"But in 1984, we had got through the two toughest health authorities in the world."
The big smile arrived when ibuprofen was approved for sale over-the-counter by the Food and Drug Agency in the United States without the need for a doctor's prescription.
"That was when I felt we had made it," said Dr Adams.
He was feted across the States, ferried by smart limo from TV studio to TV studio for sofa interviews in New York and California.
This was the new drug which, designed to reduce inflammation in rheumatoid arthritis could be used to reduce pain and inflammation in other illnesses.
It was to rank alongside aspirin and paracetamol for its properties as an analgesic and is regarded as more effective.
Boots scientists had been taking Brufen for years for headaches and hangovers.
Ibuprofen was to make Boots and its shareholders a lot of money.
The drug is now well out of patent and is made by manufacturers around the world.
In the 12 months to September 2011, worldwide sales of straight ibuprofen were £2.4 billion.
But it is no longer made by Boots. Nurofen, the brand name of Boots' ibuprofen, was sold to Reckitt Benckiser five years ago.