36.1 The Development of Drugs Presents Huge Challenges

Most drugs act by binding to enzymes or receptors and modulating their activities. To be effective, drugs must bind to these targets with high affinity and specificity. However, compounds with the desired affinity and specificity do not necessarily make suitable drugs. Most compounds are poorly absorbed or rapidly excreted from the body or they are modified by metabolic pathways that target foreign compounds. Consequently, when taken orally, these compounds do not reach their targets at appropriate concentrations for a sufficient period of time. A drug’s properties related to its absorption, distribution, metabolism, and excretion are called ADME properties. Oral bioavailability is a measure of a drug’s ability to be absorbed; it is the ratio of the peak concentration of a compound given orally to the peak concentration of the same dose directly injected. The structure of a compound can affect its bioavailability in complicated ways, but generalizations called Lipinski’s rules provide useful guidelines. Drug-metabolism pathways include oxidation by cytochrome P450 enzymes (phase I metabolism) and conjugation to glutathione, glucuronic acid, and sulfate (phase II metabolism). A compound may also not be a useful drug because it is toxic, either because it modulates the target molecule too effectively or because it also binds to proteins other than the target. The liver and kidneys play central roles in drug metabolism and excretion.

36.2 Drug Candidates Can Be Discovered by Serendipity, Screening, or Design

Many drugs have been discovered by serendipity—that is, by chance observation. The antibiotic penicillin is produced by a mold that accidentally contaminated a culture dish, killing nearby bacteria. Drugs such as chlorpromazine and sildenafil were discovered to have beneficial, but unexpected, effects on human physiology. The cholesterol-lowering statin drugs were developed after large collections of compounds were screened for potentially interesting activities. Combinatorial chemistry methods have been developed to generate large collections of chemically related yet diverse compounds for screening. In some cases, the three-dimensional structure of a drug target is available and can be used to aid the design of potent and specific inhibitors. Examples of drugs designed in this manner are the HIV protease inhibitor indinavir and cyclooxygenase 2 inhibitors such as celecoxib.

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36.3 Analyses of Genomes Hold Great Promise for Drug Discovery

The human genome encodes approximately 21,000 proteins, and many more if derivatives due to alternative mRNA splicing and posttranslational modification are included. The genome sequences can be examined for potential drug targets. Large families of proteins known to participate in key physiological processes such as the protein kinases and 7TM receptors have each yielded several targets for which drugs have been developed. The genomes of model organisms also are useful for drug-development studies. Strains of mice with particular genes disrupted have been useful in validating certain drug targets. The genomes of bacteria, viruses, and parasites encode many potential drug targets that can be exploited owing to their important functions and their differences from human proteins, minimizing the potential for side effects. Genetic differences between individuals can be examined and correlated with differences in responses to drugs, potentially aiding both clinical treatments and drug development.

36.4 The Clinical Development of Drugs Proceeds Through Several Phases

Before compounds can be given to human beings as drugs, they must be extensively tested for safety and efficacy. Clinical trials are performed in stages: first testing safety, then safety and efficacy in a small population, and finally safety and efficacy in a larger population to detect rarer adverse effects. Largely due to the expenses associated with clinical trials, the cost of developing a new drug has been estimated to be more than $800 million. Even when a drug has been approved for use, complications can arise. With regard to infectious diseases and cancer, patients often develop resistance to a drug after it has been administered for a period of time because variants of the disease agent that are less susceptible to the drug arise and replicate, even when the drug is present.