By Kevin She
2 Feb 2016
The majority of modern pharmaceutical drugs – outside of anti-infectives against multiple-drug resistant infections including combination anti-HIV and anti-tuberculosis regiments, and cancer chemotherapy cocktails – are typically composed of a single active small molecule along with excipients to aid in their formulation and fillers to aid in administering the drug, either to bulk up the final pill to a size that’s convenient to take or in carriers to facilitate the injection or the topical application of a single dose.
The reason behind single active small molecule drugs is that in many cases a single active small molecule is sufficient to be effective. Additional reasons probably lie in the way that drugs have been discovered and developed over the last few centuries, which themselves are a legacy of early investigations in medicinal and synthetic chemistry.
Bark from the cinchona tree, from which quinine is derived, was traditionally used by the people of Peru since antiquity to prevent shivering in low temperatures at high altitudes. After contact with Europeans, Jesuit priests in the 16th century became aware of the medicinal use of this tree bark not only to combat shivering but as an effective treatment for diarrhea. At the time malaria – caused by the Plasmodium parasite – was rampant in the North Mediterranean; the Jesuit brother Agostino Salumbrino sent samples of the bark to Rome as a treatment for the shivering symptoms of malaria. Unexpectedly quinine – later discovered to be the active small molecule in cinchona bark preparations – was effective in treating the cause of malaria as well as to prevent its development. While the exact mechanism of action is still unknown, it is likely that quinine disrupts Plasmodium parasites’ ability to break down heme, their major food source, leading to its accumulation and subsequent toxic effect on the parasite.
The late 18th century saw the transition of alchemy into the science of chemistry. Antoine Lavoisier, a French nobleman and chemist, published Traité élémentaire de chimie (Elementary Treatise on Chemistry) in 1789 and this is considered the first modern chemistry textbook. Important new theories presented in this work included the idea of the conservation of mass in chemical reactions, the concept of elements as substances that cannot be further broken down by chemical means, and that chemical compounds are composed of these elements all paved the way for the development of modern chemistry in contrast to the superstitions of alchemy. By the 19th century, interest burgeoned in the investigation of the composition and structure of all manner of natural compounds.
Figure 1 Thomas Jefferson’s Library Traité élémentaire de chimie
Among the first organic molecules to be purified and analyzed was quinine from chinchona bark in 1820 (Pelletier & Caventou 1820). It was found that the purified quinine compound was much more effective at treating malaria than crudely prepared chinchona bark. Apocryphally the “gin and tonic” was popularized during the East India Company’s excursions into colonial India. Quinine at the time was given in tonic form as a prophylaxis (preventative) and as a treatment for malaria. However, the tonic was extraordinarily bitter so gin, lime, and sugar was added to make it more palatable. Modern carbonated tonic water contains far less quinine than the original tonic and one would need to drink about 25 liters per day in order to achieve a prophylactic dose (Achan 2011).
Increasingly it was discovered that a single compound was usually responsible for the effects of natural medicines. Around the middle of the 19th century, attention turned from merely investigating the composition of natural compounds to the ability to make chemical compounds through synthesis from simpler compounds and elements.
Like cinchona, coca (Erythroxylon coca) is a plant native to South America and used by indigenous peoples as an anaesthetic and to enhance energy and strength. After European contact, coca was brought to Europe (it was heavily taxed!) and became widely popular. Cocaine, the active alkaloid in coca, was successfully isolated and characterized in 1860 (earning Albert Niemann his Ph.D for this endeavour), 40 years after quinine. It would be another 29 years before the art and science of chemical synthesis was advanced enough for cocaine to be synthesized. Despite the difficulty of synthesizing tropane alkaloids like cocaine (Humphry and O’Hagan 2001), it was the first recorded complex organic structure to ever be synthesized (Ladenberg 1889). Cocaine is a hell of a drug. It was also highly prized as an anesthetic that allowed the gradual development of modern surgical techniques and procedures that could otherwise not have been performed (Halsted 1885).
Shortly after quinine had been isolated and characterized, salicilin – a precursor of salicylic acid, and the active ingredient in willow bark – was also successfully isolated and characterized by Johann Andreas Buchner in 1828. By 1839 other groups had subsequently isolated salicilin and the salicylic acid form from a number of other plant species. In purified and concentrated form, salicylic acid was more effective than crude preparations; however, it caused digestive problems when large amounts were used including gastric irritation, bleeding, and diarrhea.
Although acetylsalicylic acid – the active ingredient in aspirin – had been serendipitously synthesized by several groups, it wasn’t until shortly before 1897 that the nascent field of rational drug development was directed towards salicylic acid, which was effective but was associated with undesirable side effects. In 1897 Bayer AG successfully developed a simple chemically modified salicin which turned out to be acetylsalicylic acid which showed a good anti-inflammatory and anti-pain profile with much less digestive upset.
Heroin largely follows a similar developmental trajectory. The use of opium, the crude dried latex collected from scored seed pods of the opium poppy (Papaver somniferum), has been in recorded use since around 1500 BCE and traces of Papaver somniferum has been found in multiple excavated Neolithic settlements dating to at least 4200 BCE. Traditionally, opium was taken orally as a lozenge or later as laudanum – opium dissolved in alcohol for use as a tincture or drink. Another preferred method of use and especially abuse was to heat opium pellets indirectly in an opium pipe whereupon the vapours are inhaled. One drawback of ingesting such crude preparations of opium was that it was often impossible to determine the potency of a preparation without first ingesting it. Aside from its narcotic, sedative, and pain relief properties, opium was an extraordinarily effective cough suppressant (antitussive). Incidentally, effective cough suppressants were remarkably in demand as tuberculosis infections and heavy smog from the use of coal and the industrial revolution was rampant at the time.
From left to right: Fresh latex expressed from scored seed pods from Papaver somniferum, Crest Brand laudanum bottle, opium pipe with picks and container of opium.
Given its usefulness and popularity, it isn’t surprising that there was interest in isolating and characterizing the active ingredient(s) in opium. Morphine, one of the major active ingredients in opium, was successfully isolated sometime around 1804 by Friedrich Sertürner and is considered to be the first isolation of a single active ingredient from a plant. The other major small molecule constituent naturally occurring in opium is codeine. One immediate advantage of having a purified extract was that a consistent dose could be administered and morphine was marketed commercially by Merck in 1827.
Morphine entered widespread use, and abuse, and was a significant medicine during the American Civil War when a then-unprecedented number of amputations were performed. Laudanum use persisted alongside morphine as a common adjunct therapy for tuberculosis as a cough suppressant and for pain relief, and when purified morphine was unavailable. However, it was found that morphine was more addictive than opium or alcohol and was quickly recognized as a health and social problem. Bayer AG sought to create a substitute drug with much lower addictive potential.
The acetylation of salicylic acid into acetylsalicylic acid (aspirin) is a relatively simple chemical reaction and significantly improved the safety profile of the drug. Bayer AG sought to investigate whether the acetylation of codeine in opium would similarly produce a new drug with all of the desirable qualities but with an improved safety profile, namely, a lower addictive potential. It is unknown whether Bayer AG was successful in acetylating, purifying, and testing acetylcodeine; however, they were able to produce and purify diacetylmorphine from opium – which would be named heroin, based on the German word heroisch meaning “heroic, strong” – and was brought to market in 1898. While diacetylmorphine was independently synthesized and even tested by C.R. Alder Write and F.M. Pierce in 1874, no further investigation or commercialization had been pursued at the time.
This relatively simple modification of morphine into heroin produced a drug that was more than two and a half times more potent than morphine, ten times more effective at cough suppression than codeine, and was heavily marketed as a safer and less addictive substance than morphine.
What about acetylcodeine? It turns out that it is one of the major impurities in modern illicitly (and poorly) manufactured heroin and would likely have been a side product in Bayer AG’s production of diacetylmorphine from opium feedstock. Acetylcodeine is somewhat less potent than codeine and considerably less potent than heroin. However, the convulsant effects of acetylcodeine are similar to heroin and when mixed with heroin is even more toxic at lower levels than codeine or heroin alone (O’Neal &al., 2001).
Figure 3 Pre-First World War Bayer heroin bottle
There is considerable irony in that Bayer AG sought to produce an analgesic that was less addictive than morphine, and ended up producing heroin. Furthermore, aspirin – acetylsalicylic acid – was almost ignored as the heads of Bayer AG were much more highly excited by the launch of heroin in 1898, a year after the synthesis of acetylsalicylic acid (aspirin) at the same company.
Development of many single small molecule drugs would follow this general pattern of discovering and isolating naturally occurring small molecules which is typically followed by experimental modification of the underlying molecule. Indeed, a vast constellation of drugs have been derived from the constituents of opium as well as cocaine. Many modern cancer chemotherapeutic drugs are based on modifications of existing drugs through both trial and error as well as by rational design (Patani & LaVoie 1996).
Between 1981 and 2002, 877 small molecule New Chemical Entities were introduced; about half of them were natural products or synthetics and semi-synthetics based on natural products. Since then, there has been a slow decline in new therapeutic small molecules based on natural products, in part due to the maturation of combinatorial chemistry, the development of better small molecule libraries (Koehn & Carter 2005), and the maturation of biologics; pharmaceutical therapeutics (pharmacotherapies) based on proteins or fragments of proteins (peptides). Increasing knowledge of human physiology and the etiology and pathophysiology of diseases – the cause of- and how- diseases progress – led to more sophisticated methods of drug discovery and development since the Victorian era. However, a renaissance for natural product based pharmacotherapies may be in the cards, especially as a source for novel antibiotics (Baltz 2007). Part 3 of this article sketches an outline of small molecule drug discovery and development.
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