1909

Salvarsan

Paul Ehrlich (1854–1915), Sahachiro Hata (1873–1938), Alfred Bertheim (1879–1914)

German physician Paul Ehrlich is considered the father of modern medicinal chemistry, and salvarsan (arsphenamine) is the prototype of all the drug development efforts that have come since. Ehrlich and his colleagues Sahachiro Hata (a Japanese bacteriologist) and Alfred Bertheim (a German inorganic chemist) were searching for compounds that would be more poisonous to disease organisms than to humans. They hoped to improve on a toxic, abandoned arsenic drug (atoxyl) created to kill trypanosomes (the parasites that caused sleeping sickness) that had, tragically, permanently blinded as many as 2 percent of the patients who had tried it. If a wide variety of organic arsenic compounds could be prepared and tested, Ehrlich thought, some useful relationship might arise to separate the activity from the toxicity.

This was the first organized search for such a structure-activity relationship (SAR), still the key step in all medicinal chemistry research programs. In 1909, the 606th compound they tried, arsphenamine, was not effective against the trypanosomes, but it proved very useful against syphilis bacteria. Until then, syphilis had been treated for the most part with mercury salts, which killed the bacteria but at grave risk to the patient. Compound 606, later branded as Salvarsan, was used on humans much sooner than any drug is in the modern era, and with far less testing. It still presented the risk of serious side effects, but nothing like the mercury treatment (or like untreated syphilis, for that matter). It was a frontline therapy for over thirty years.

It was also a difficult compound to administer. Like many organoarsenic compounds, it was unstable in air, and had to be quickly dissolved in sterile water and injected. To address this problem, Ehrlich and Hata developed another easier-to-handle compound, but it was not quite as effective. They were the first medicinal chemists to discover that many trade-offs of this sort were waiting for drug researchers. Getting all the properties you’d like into one molecule is not easy, but it was Ehrlich and his team who showed that it was possible at all, leading the way for the generations of drug researchers who followed.

A Salvarsan treatment kit from 1912, containing the drug and all the equipment needed to prepare it for injection.