Drug Discovery and Development: The Road from an Idea to Promoting Human Health

We are almost where we need to be to grasp the tales of drug discovery that make up the final seven chapters of this book. The three previous chapters have laid the necessary scientific foundation. Here is my take on what you still need to know to understand drug discovery and development: the process of getting from an idea to a product that meets a medical need—from the laboratory to the bedside. We begin with a look at the process from 35,000 feet. Realize one thing at the outset: there is more than one way of getting from an idea to approval of a new drug for use in human medicine. The process described in this chapter captures the essential features of getting this done. However, each drug discovery effort poses specific problems, and getting around them may have an effect on the actual process followed. Nonetheless, what is described here is well worth understanding. Imagine running a maze that may have more than two dimensions, a huge number of entry points, and a very small number of exits or perhaps no exit at all, depending on your entry point. Have a look at Figure 5.1 to get the idea. You can see the external features but have no clue what awaits you inside. You can wander in this maze for a long time without getting very far. This pretty well symbolizes what happens during a lot of drug discovery projects. In target-based drug discovery, described in the next section, each entry point in the maze corresponds to a molecule chosen as a starting place to begin work. Most of these entry points are dead ends. No matter what you do or how hard you try, the only exit from the maze is the place you entered—nothing gained. The journey may be long, there may be encouraging signs along the way, but at the end of the day, you are back where you started.

Basic Research, Snake Venoms, and ACE Inhibitors: Ondetti, Cushman, and Patchett

On April 6, 1981, the U.S. FDA approved a molecule captopril for the treatment of elevated blood pressure, otherwise known as hypertension. This action marked the beginning of a major change in the treatment of high blood pressure and, later, congestive heart failure, diabetic kidney damage, postheart attack management, and stroke prevention. The health of millions of people worldwide has been sustained or restored through the use of captopril and its pharmaceutical relatives. Captopril is the product of research and development work at the Squibb Institute for Medical Research, at the time a branch of Squibb Pharmaceuticals, now Bristol-Myers Squibb. Captopril was marketed worldwide under the trade name Capoten. Its patent life has long since expired and it is available as a generic drug. Captopril is remarkable for two reasons. First, it is the pioneer drug in a new class of treatments for high blood pressure and other cardiovascular problems. This new class is known as ACE inhibitors. ACE is the chemical acronym for angiotensin converting enzyme. The names of enzymes reflect an effort to describe what they do, and the names are often complicated. Later, I explain what ACE does, and perhaps the name will make sense then. In the meantime, ACE will have to do. Second, captopril was among the first drugs approved for use in clinical medicine discovered by a process of rational drug design, as opposed to a more-or-less random hunt for molecules having promise of use in human medicine. The discovery of captopril followed the earlier work of James Black, Gertrude Elion, and George Hitchings, pioneers in the formulation of the principles of drug design and treatment. They shared the Nobel Prize for Medicine or Physiology in 1988. The goal of this chapter is to pull together the various threads of the story of ACE inhibitors and weave a revealing fabric. Physicians have been measuring blood pressure for a lot longer than they have had effective means to deal with excursions beyond the normal range.

The Small Molecules of Life

All life on Earth is unified. Life may have flickered into being, only to be subsequently extinguished, many times during the early days of our planet’s evolution. But on exactly one occasion, life on Earth did arise and persist. Every living organism is a descendent of that life. We are all hatched from the same primeval egg. The universal roles of the big molecules of life—proteins and nucleic acids—reflect this unique origin. The genetic code that links the language of nucleic acids to that of proteins is universal throughout the amazing diversity of living organisms. Protein relatives serve the same or similar functions in living organisms from wheat to humans. We are going to have a closer look at the proteins as we move forward: protein structure in chapter 3, protein function in chapter 4, and proteins as targets for drug discovery in chapters 6 through 12. This is not to argue that there are no differences among the molecules of life. Clearly, there are. For example, bacteria are isolated from their environment by a surrounding cell wall. There is no related structure in mammalian cells. We take advantage of these differences to sustain and restore human health. For example, many antibiotics act by preventing construction of bacterial cell walls. We will see two examples in what follows: Primaxin and fludalanine. The unity of life extends to the small molecules of life as well. There is compelling similarity among the small molecules that carry out critical functions of life. Adenosine triphosphate (ATP) is the universal energy currency of life; molecules that transmit messages from one nerve cell to another are shared between sea snails and humans. Molecules on the routes of metabolic pathways are much the same in fruit flies and flying bats, and on and on.

Diabetes Breakthroughs: Januvia and Janumet

I do not recommend this, but let’s just suppose that for breakfast you had a waffle drenched in maple syrup, a large glass of orange juice, and coffee with two teaspoons of sugar. What happens next? Your breakfast is full of carbohydrates. The waffle contains complex carbohydrates (starches) from the flour, and the orange juice, syrup, and sugared coffee contain simple carbohydrates (sugars). The sugar in orange juice and syrup is mostly fructose, and that in your coffee is sucrose. In the intestines, the starches are slowly broken down into the sugar glucose; the sucrose is split into equal amounts of glucose and fructose. The fructose can be converted to glucose in the liver. The sugars from the orange juice, syrup, and coffee enter the blood quickly; those from the starches in the waffle enter more slowly. However, they all act to increase blood glucose levels. A basic principle of human physiology is summed up in one word—homeostasis, which simply means that when the normal metabolic status of the human body is changed in some way, the body responds by restoring normality. When something changes, the body fights back to eliminate or minimize the change. This is what happens when blood glucose is elevated in response to a meal. Here is how. The pancreas is a medium-size organ in the abdomen that secretes enzymes into the gut to aid in digestion, and endocrine hormones into the bloodstream to control some aspects of metabolism. The pancreas responds to sugar entering the bloodstream by secreting the peptide hormone insulin into the circulation. Insulin is made in specialized cells of the pancreas known as the beta cells of the islets of Langerhans. Insulin has a critical role in the regulation of blood glucose levels. Acting through its receptor, insulin causes glucose in the blood to be taken up by muscle and fat cells, reducing the blood glucose level.

Fludalanine: Nice Try But No Hallelujah

It is time that we experienced a tale of failure. As I have stated repeatedly, most drug discovery efforts fail. Choice of the wrong target dooms the effort from the start. Screening may fail to turn up actives, and molecular design may do no better. Given active molecules, medicinal chemistry efforts to improve properties may fail. Senior management’s heavy hand may terminate a promising effort. If one gets as far as development, a safety or efficacy issue may derail the project. Then, too, competitors may outrun you or financial support may dry up. There are many ways to fail, not so many to succeed. All five stories told so far have been successes: finasteride, ACE inhibitors, statins, imipenem/cilastatin, and the avermectins. Chapter 12 provides another example of a success: the gliptins. In this chapter, however, I pull together the threads of a failure: fludalanine. It is the most interesting failed drug discovery story that I know. There is much to learn from it, particularly about problem solving. It has a couple of surprises. By way of background, Merck had set its mind on finding an effective orally active antibiotic, driven in substantial part by the insistence of Max Tishler, Merck’s determined head of research. Orally active antibiotics are attractive. A patient with a bacterial infection may be treated in the hospital with an oral or a parenteral agent, one given by injection or inhalation. An injectable antibiotic may be given intravenously, intramuscularly, or subcutaneously. However, when the patient has been released from the hospital and sent home, it is convenient to have an antibiotic that can be taken by mouth, a tablet or capsule, for continued action against the infection. Ideally, an antibiotic should be available in both a parenteral (intravenous, intramuscular, or subcutaneous) formulation and an orally active formulation. In this way, the patient can be maintained on the same antibiotic when returning home from the hospital. Merck was having trouble meeting its objective.

Statins: Protection Against Heart Attacks and Strokes—Hallelujah!

Cholesterol! This may be the single most famous (or infamous) small molecule of life. Most people view it as a threat to good health and even to life itself. We search for foods that are cholesterol free or at least low in cholesterol. We use them in efforts to achieve a low-cholesterol diet. Our primary care physicians measure our blood cholesterol levels routinely and report the news, good and bad. If the level is high, they recommend a better diet (that is, one lower in cholesterol and saturated fat), more exercise, and perhaps weight reduction. If those measures fail to get the cholesterol level where it should be, it is highly likely that therapy with a cholesterol-lowering drug will be recommended. The drug will usually fall into a class known as statins. Statins are among the most frequently prescribed drugs in the world. The first statin approved for marketing by the FDA in the United States was lovastatin (Mevacor), which happened in 1987. Lovastatin was followed into clinical practice by pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor), cerivastatin (Baychol), pitivastatin (Livalo), and rosuvastatin (Crestor). There are a lot of options from which to choose among the statins. The story of how statins were discovered and developed is pretty amazing. The tale focuses on cholesterol in its several dimensions—what it is, how it is made, how its levels are regulated, the health consequences that may ensue when proper regulation fails, and how statins act to restore that regulation. The task of this chapter is to tell the tale. The focal point is cholesterol. So that is where we begin. There are two sides to most stories, which is certainly the case for cholesterol. Although what we hear about cholesterol is mostly negative (isn’t there some way to get rid of this stuff?), the fact is, we cannot live without it and there are three reasons why. First, cholesterol is an essential component of all our membranes.

Finasteride: The Gary and Jerry Show

Way back in chapter 1, I told the story of how I jumped from the world of academic science, which I understood, to that of drug discovery and development, which I did not. So I knew there was a lot of learning to do on my part if I was to contribute anything to Merck Research (and continue to find a way to feed my family), although I underestimated the extent of my ignorance. Here is the way it started. I showed up for work at Merck Research on January 3, 1979, and met with Ralph Hirschmann, my boss, in his office to get a sense of his expectations and my marching orders. Among other things, he informed me that the benign prostatic hyperplasia (BPH) project was among my responsibilities. At that point, I began to understand just how much I needed to learn. The BPH project had been under way for some years at the time I joined Merck. Coming in, I knew a lot of general biochemistry and physical organic chemistry. I knew less about human physiology and less than that about human diseases and medicine. Among areas of my ignorance was the disease BPH, for which I was now responsible on the biology side. Later, I became the BPH preclinical team leader. BPH is medicine’s shorthand for benign prostatic hyperplasia, the benign growth of the prostate gland in aging men. Hyperplasia refers to an increased number of cells in an organ, with consequent increase in organ size, as a result of too-frequent cell division. BPH stands in contrast to the malignant growth of the prostate gland—prostatic carcinoma—a potentially life-threatening cancer. BPH is not life-threatening, but it is surely a condition that compromises the quality of life of men who have it. Lets get started by having a look at what goes wrong. In normal young men, the prostate gland has a volume of about 20 mL and is roughly the size of a walnut.

Proteins Perform Multiple Functions: Enzymes, Receptors, Ion Channel Proteins

As emphasized in the preceding chapter, there are an unimaginably large number of possible protein structures based on the sequence of amino acids along the amino acid chain. Through the process of evolution, nature has chosen a minute fraction of them to create proteins that provide for the necessities of life. Among all the functions that proteins serve in living organisms, I focus on the three that relate most directly to my tales of drug discovery: catalysis, information transfer, and control of the intracellular milieu. These functions are served by, respectively, enzymes, receptors, and ion channel proteins. I spend most of the time discussing enzymes, because most of the stories in the later chapters focus on enzymes. There are occasions when I refer to receptors and ion channels, as well, but because enzymes are the stars of the stories, let’s start there. Chemical reactions are processes during which one or more molecules are converted into different ones. Chemical reactions involve breaking and forming of the chemical bonds that hold atoms together in molecules. Certain chemical bonds in the starting molecules (the reactants) are broken, followed by the formation of new ones, leading to the end products. All the atoms in the reactants are found in the products; they are just rearranged. A simple example is provided by diamond and graphite. Diamond is brilliant and the hardest natural substance known; graphite is black and very soft. Yet, both diamond and graphite are composed entirely of carbon atoms. The carbon atoms are linked differently by the chemical bonds holding them together, yielding substances with very different properties. It may surprise you to know that graphite is actually very slightly more stable than diamond. So if we wait long enough, the chemical reaction . . . Diamond → Graphite . . . might be expected to occur. However, do not search for evidence of black dots in your wedding diamond. This may be the slowest chemical reaction of all and may take longer than the age of the universe to get anywhere.

Proteins: Molecular Wonders in Three Dimensions

I grew up in a solid middle-class family, largely of German descent, in a city of modest size in central Nebraska. Like a lot of such families, our diet was based on meat and potatoes. It was an unwritten but religiously observed law in our home that two meals each day would include both meat and potatoes. The meat was turkey twice a year, ham on occasion, chicken or pork from time to time, but mostly beef. The potatoes were usually boiled or boiled potatoes subsequently sliced and fried. My brother and I also drank a lot of whole milk, at least a quart a day each and frequently more (skim milk was available, but no one gave much thought to “reduced fat” or “low fat” milk back in those days). On farms, a lot of people just drank what the cows had on tap. Between the meat, potatoes, and the whole milk, we got a lot of protein in our diet, which is good; we also got a lot of saturated fat in our diet and that is not so good. Adequate protein in our diet is essential for good health. Proteins in our diet break down to provide essential amino acids. Amino acids are the building blocks of proteins. The amino acids that are essential in our diet are those that our bodies cannot make or cannot make in adequate quantity for optimal health. For dietary proteins, two things matter: amount and quality. The amount of protein is a simple quantitative matter; it is measured in grams per day. The amount you need depends on several factors: your gender, age, size, level of exercise and other physical activity, and whether you are pregnant or lactating, for example. The quality of protein is not so easy to evaluate. Getting the essential amino acids in your diet is more important than getting the others. The highest quality proteins are those that contain an abundance of all the essential amino acids. Meats and dairy products are among the best sources of high-quality proteins.

Seduced by Drug Discovery

In autumn 1978, a gentleman scientist named Ralph Hirschmann changed my life. At the time, Ralph was a 56-year-old chemist who had just been promoted to senior vice-president for basic research in chemistry in the Merck Research Laboratories of Merck and Company, a large and—in the opinion of many—the best pharmaceutical house in the world at that time. Ralph had spent his entire professional career at Merck, starting in 1950, and he had a substantial list of scientific accomplishments to his credit. One of these stood out above all others: the laboratory synthesis of a really big molecule. The focal point of chemistry is the molecule. Linking together atoms of the elements hydrogen, oxygen, and carbon, for example, with chemical bonds (think electron glue) creates molecules. There are a lot of different molecules on planet Earth—perhaps a hundred million—some assembled by living organisms and others made in chemistry labs. Some are very small, just two or three atoms linked together. The principal components of our atmosphere—nitrogen and oxygen—are examples. Nitrogen gas consists of two nitrogen atoms (N) linked together: N2. Likewise, oxygen gas is composed of two oxygen atoms (O) linked together: O2. Water provides a slightly more complex example. Two hydrogen atoms (H) are linked to an oxygen atom, H-O-H, more commonly written as H2O. Others are really big and contain thousands of atoms. This is where Ralph comes in. The outstanding achievement for which Ralph gained fame in the arcane world of chemistry was the total laboratory synthesis of a protein—known as ribonuclease S—completed in 1969. A word of warning here: chemistry is full of long words such as ribonuclease that are difficult to spell, difficult to pronounce, and have meaning only to a chemist. There is nothing that I can do about that, so get used to it. Proteins are big molecules—thousands of atoms. The work that Ralph did was in collaboration with another chemist at Merck—Bob Denkewalter.