Rationalization of Medicinal Chemistry Sebastian Zagler

Introduction

Medicinal chemistry refers to the design, synthesis, and testing of compounds in the search for new drugs. Since the foundation of modern medicinal chemistry in the late 1800s, greater knowledge and many advancements have made the field more systematic and precise, through the process George Ritzer describes as rationalization. Rationalization is the transformation of industries and occupations and professions to become more efficient, calculable, predictable, and controlled. In this page, I will examine the history of the field of medicinal chemistry and specifically antibiotic development through the lens of rationalization and what it means for the industry, its workers, and society as a whole.

Modern Medicinal Chemistry

This changed in the 1800s when modern medicinal chemistry came about. The 1800s brought huge advancements to medicine and science, such as germ theory which more accurately described the nature and transmission of disease-causing pathogens. Developments in chemistry also continued allowing the purification and isolation of natural products such as salicin from aspirin in 1828. Over the course of the century, facilitated by a greater understanding of cellular functions and microscopes, chemists began looking for and testing more systematically potential isolated and novel drug compounds.

Salvarsan, the first Magic Bullet

In his search for a magic bullet, Ehrlich set his sights on syphilis, a widespread and chronic bacterial illness. He and his team pioneered the more modern drug development process with greater efficiency and systematic study. The bacterium causing syphilis is a spirochete, known to be similar to the parasitic trypanosomes. Trypanosomes had been targeted previously using arsenical compounds, laying the groundwork for Ehrlich’s search for the magic bullet [7].

The subsequent process closely mirrors later hit identification strategies. With the target identified and an understanding of what worked for similar targets, a broader screen was conducted. Together with his lab, Ehrlich first synthesized hundreds of arsenical compounds. Research assistant Sahachiro Hata realized how to infect rabbits with syphilis, and began inoculating hundreds with each syphilis and then injecting each arsenical compound. In 1909, on compound number 606, they received a hit. The compound, later dubbed Salvarsan was the first magic bullet, and its discovery would transform medicine.

Ehrlich had successfully pioneered the modern process of drug discovery by using systematic screening techniques. This was continued in clinical trials where 65,000 samples of Salvarsan were provided for free to demonstrate the drug’s effectiveness. Based on his work on Salvarsan, many more 'magic bullets' or chemotherapies were discovered, including Penicillin and entire classes of antibiotics, leading to vast improvements in healthcare, quality-of-life, and life expectancies in the 1900s.

High-throughput synthesis and screening

Perhaps one of the most important in transforming the pharmaceutical industry is the introduction of high-throughput techniques in the late 1900s, allowing for the synthesis and screening of large numbers of compounds [10]. Whereas before, compounds were discovered by chance or through an iterative synthetic process, now compounds are synthesized broadly on a huge scale. Large chemical suppliers compile compound libraries of hundreds of thousands to over a million different compounds to provide labs around the world with potential drug compounds. The best compounds are identified as “hits” using automated screening in which robots and computers can analyze the binding of the drug compound to its intended target. The compounds are quantitatively ranked and the best are then selected for further testing. This process can be very attractive to pharmaceutical companies because it is quantitative and calculable and controlled and automated. It also prevents the need for early testing against animal or human models.

The Changing Role of the Medicinal Chemist

While some aspects of the occupation have remained similar for the last 100 years, such as the high education level required for chemists and the approximate number of people employed in the position, the work of the medicinal chemist has become more structured and controlled from the early days of medicinal chemistry. With many of the low-hanging fruit of drug compounds already taken, chemists have seen less success with haphazard approaches. Instead, quantitative techniques take a central role, with chemists in early-stage drug development first identifying a target and then following a well-defined pathway of narrowing down candidate compounds. Calculability and predictability are valued, with chemists and drug companies opting to throw hundreds of thousands of compounds at a target to see what sticks before going toward animal models and large expensive clinical trials. These screens are enabled by automated and controlled robotic systems, which chemists control and evaluate data from using computers. Most data are quantified too, with scoring functions instead of chemical properties often used to more easily compare and rank compounds.

Stricter regulations and a higher bar for new drug compounds result in fewer animal and human studies. Where Ehrlich tested compounds directly on rabbits and soon after on humans with often very toxic but sometimes surprising results, chemists today rarely take such risks. While newer methods for drug development might result in more calculable data and more predictable and safe results, recent data suggest they have not achieved greater efficiency.

Picked off low-hanging fruit

One reason why drug development has become more difficult is that many important and effective drugs already exist. Drugs like aspirin, for which precursors have been used by humans for thousands of years and have been approved for many decades are proven to work and well-understood. A drug is less likely to be developed to solve a problem that is already mostly solved, even if such a drug could produce marginally better results, an effect some researchers describe as the “better than The Beatles effect,” meaning that if all new music had to be better than The Beatles, very few new songs would be produced [12]. Instead, researchers and companies must set their sights on new diseases and targets which might be less known, important, or affect a smaller number of people to avoid producing a drug that essentially already exists. This increases the cost and difficulty of developing new drugs.

Less favorable risk and reward

This brings up an important point that producing new drugs, especially antibiotics, has become much less economically favorable. Simply showing that a compound is promising is no longer enough since extensive testing is required for a company before a drug can be approved and profits can be made. This process is risky and expensive, and only large companies have the capital to push a drug through both the drug development pipeline and the complex regulatory pipeline that follows.

Demand for many new drugs is also low. Since most important drugs already have solutions, as discussed above, this means researchers must set their sights on more obscure targets and rarer diseases. With fewer people using new drugs, a company becomes much less likely to get sufficient return on their investments and the prices of new drugs will increase. This is especially true for antibiotics. As antibiotic resistance grows, regulators urge them to be used very sparingly to ensure they will continue to be effective against drug-resistant pathogens. When the patent on such compounds expires, cheap generics further cut into the profits of the original developer.

The result is that fewer companies can afford to carry out drug development and the total number of new drugs per dollar spent, especially among antibiotics has decreased sharply (from 30 antibiotic approvals in the 1980s to 7 from 2000 to 2009). This is incredibly concerning as antibiotic resistance and deaths from drug-resistant pathogens become more common.

Reversing Eroom’s Law

Although Eroom’s Law was observed from 1950 to 2010, in the past decade we have experienced what appears to be a reversal in Eroom’s Law [15]. The reasons for this are not exactly clear yet, but there are some theories as to why. One theory is that new technologies, such as the greater understanding of human genetic data have tipped the balance back into the favor of drug development. Genetic data also helps diagnose and target rare genetic diseases which are the focus of many drug companies currently. Finally, the regulatory system has become less strict, a kind of counter-rationalization, where the threshold for efficiency and predictability was lowered for novel treatments of rare diseases to make it more likely for drugs to be approved where there was no other alternative. The rate of the introduction of new antibiotics also increased during the 2010s, with 15 new antibiotics approved over 7 in the previous decade.

The pharmaceutical industry also showed great efficiency during the covid-19 pandemic, producing several vaccines with completely new technologies and many antivirals coming to market in under 2 years of development. This unheard-of rate of progress was facilitated by new technologies and approaches and relaxation of stringent regulations shows that the pharmaceutical industry can still be productive given the right conditions. The counter-rationalization and relaxation of regulatory bodies as well as the important return of mass human and animal testing helped facilitate these successes, and present a solution to ensure the productivity of the pharmaceutical industry and its workers.