Drug discovery and development

Research and discovery

Pharmaceuticals are produced as a result of activities carried out by a complex array of public and private organizations that are engaged in the development and manufacture of drugs. As part of this process, scientists at many publicly funded institutions carry out basic research in subjects such as chemistry, biochemistry, physiology, microbiology, and pharmacology. Basic research is almost always directed at developing new understanding of natural substances or physiological processes rather than being directed specifically at development of a product or invention. This enables scientists at public institutions and in private industry to apply new knowledge to the development of new products. The first steps in this process are carried out largely by basic scientists and physicians working in a variety of research institutions and universities. The results of their studies are published in scientific and medical journals. These results facilitate the identification of potential new targets for drug discovery. The targets could be a drug receptor, an enzyme, a biological transport process, or any other process involved in body metabolism. Once a target is identified, the bulk of the remaining work involved in discovery and development of a drug is carried out or directed by pharmaceutical companies.

Contribution of scientific knowledge to drug discovery

Two classes of antihypertensive drugs serve as an example of how enhanced biochemical and physiological knowledge of one body system contributed to drug development. Hypertension (high blood pressure) is a major risk factor for development of cardiovascular diseases. An important way to prevent cardiovascular diseases is to control high blood pressure. One of the physiological systems involved in blood pressure control is the renin-angiotensin system. Renin is an enzyme produced in the kidney. It acts on a blood protein to produce angiotensin. The details of the biochemistry and physiology of this system were worked out by biomedical scientists working at hospitals, universities, and government research laboratories around the world. Two important steps in production of the physiological effect of the renin-angiotensin system are the conversion of inactive angiotensin I to active angiotensin II by angiotensin-converting enzyme (ACE) and the interaction of angiotensin II with its physiologic receptors, including AT1 receptors. Angiotensin II interacts with AT1 receptors to raise blood pressure. Knowledge of the biochemistry and physiology of this system suggested to scientists that new drugs could be developed to lower abnormally high blood pressure.

A drug that inhibited ACE would decrease the formation of angiotensin II. Decreasing angiotensin II formation would, in turn, result in decreased activation of AT1 receptors. Thus, it was assumed that drugs that inhibit ACE would lower blood pressure. This assumption turned out to be correct, and a class of antihypertensive drugs called ACE inhibitors was developed. Similarly, once the role of AT1 receptors in blood pressure maintenance was understood, it was assumed that drugs that could block AT1 receptors would produce antihypertensive effects. Once again, this assumption proved correct, and a second class of antihypertensive drugs, the AT1 receptor antagonists, was developed. Agonists are drugs or naturally occurring substances that activate physiologic receptors, whereas antagonists are drugs that block those receptors. In this case, angiotensin II is an agonist at AT1 receptors, and the antihypertensive AT1 drugs are antagonists. Antihypertensives illustrate the value of discovering novel drug targets that are useful for large-scale screening tests to identify lead chemicals for drug development.

Sources of compounds

Screening chemical compounds for potential pharmacological effects is a very important process for drug discovery and development. Virtually every chemical and pharmaceutical company in the world has a library of chemical compounds that have been synthesized over many decades. Historically, many diverse chemicals have been derived from natural products such as plants, animals, and microorganisms. Many more chemical compounds are available from university chemists. Additionally, automated, high-output, combinatorial chemistry methods have added hundreds of thousands of new compounds. Whether any of these millions of compounds have the characteristics that will allow them to become drugs remains to be discovered through rapid, high-efficiency drug screening.

Lead chemical identification

It took Paul Ehrlich years to screen the 606 chemicals that resulted in the development of arsphenamine as the first effective drug treatment for syphilis. From about the time of Ehrlich’s success (1910) until the latter half of the 20th century, most screening tests for potential new drugs relied almost exclusively on screens in whole animals such as rats and mice. Ehrlich screened his compounds in mice with syphilis, and his procedures proved to be much more efficient than those of his contemporaries. Since the latter part of the 20th century, automated in vitro screening techniques have allowed tens of thousands of chemical compounds to be screened for efficacy in a single day. In large-capacity in vitro screens, individual chemicals are mixed with drug targets in small, test-tube-like wells of microtiter plates, and desirable interactions of the chemicals with the drug targets are identified by a variety of chemical techniques. The drug targets in the screens can be cell-free (enzyme, drug receptor, biological transporter, or ion channel), or they can contain cultured bacteria, yeasts, or mammalian cells. Chemicals that interact with drug targets in desirable ways become known as leads and are subjected to further developmental tests. Also, additional chemicals with slightly altered structures may be synthesized if the lead compound does not appear to be ideal. Once a lead chemical is identified, it will undergo several years of animal studies in pharmacology and toxicology to predict future human safety and efficacy.

Taxol and the Pacific yew

As a member of the yew family, Taxaceae, the Pacific yew (Taxus brevifolia) has flat, evergreen needles and produces red, berrylike fruits. The toxicity of members of the yew family was described in ancient Greek literature. Indeed, the genus name Taxus derives from the Greek word toxon, which can be translated as toxin or poison. Pliny the Elder described people who died after drinking wine that had been stored in containers made from yew wood. Julius Caesar described how one of his enemies, Catuvolcus, poisoned himself using a yew plant. The early Japanese used yew plant parts to induce abortion and to treat diabetes, and Native Americans used yew to treat arthritis and fever. In part because of widespread historical accounts of the pronounced biological effects inherent in members of the yew family, samples of the Pacific yew were included in screens for potential anticancer drugs.

This screening process was initiated as a cooperative venture between the United States Department of Agriculture (USDA) and the National Cancer Institute (NCI) of the United States. Extracts from the Pacific yew were tested against two cancer cell lines in 1964 and found to have promising effects. After a sufficient quantity of the extract was prepared, the active compound, taxol, was isolated in 1969. In 1979 pharmacologist Susan Horwitz and her coworkers at Yeshiva University’s Albert Einstein College of Medicine reported a unique mechanism of action for taxol. In 1983 NCI-supported clinical trials with taxol were begun, and by 1989 NCI-supported clinical researchers at Johns Hopkins University reported very positive effects in the treatment of ovarian cancer. Also in 1989 the NCI reached an agreement with Bristol-Myers Squibb to increase production, supplies, and marketing of taxol. Taxol marketing for the treatment of ovarian cancer began in 1992. Bristol-Myers Squibb applied to trademark the name taxol, which became Taxol®, and the generic name became paclitaxel.

Initially, the sole source of taxol was the bark of the Pacific yew, native to the old-growth forests along the northwest coast of the United States and in British Columbia. This led to considerable public controversy. Environmental groups feared that harvesting of the yew would endanger its survival. It took the bark of between three and ten 100-year-old plants to make enough drug to treat one patient. There were also fears that harvesting the yew would lead to environmental damage to the area and could potentially destroy much of the habitat for the endangered spotted owl. After several years of controversy, Bristol-Myers Squibb adopted a semisynthetic process for making taxol. This process uses a precursor, which is chemically converted to taxol. The precursor is extracted from the needles (renewable biomass) of Taxus baccata, which is grown in the Himalayas and in Europe. Although there were some political controversies surrounding the discovery and development of taxol, the story of its development and marketing provides another example of how public and private enterprise can cooperate in the development of new discoveries and new drugs.