Drug Discovery and Evaluation

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Chapter 9 Drug Discovery and Evaluation

The drug discovery and evaluation process can be divided into preclinical and clinical processes. Preclinical studies are performed before studies in humans. Preclinical studies are typically carried out on animals, although there is increasing interest in using computer modeling to carry out these experiments. Once the safety profile of a drug has been established in the preclinical stage, the developers of the drug can apply to move into the human stages of testing.

Preclinical Process

The preclinical process begins with the discovery of a promising chemical compound. Fundamentally, drug discovery occurs in two ways: through either a compound-centered approach or a target-centered approach.

Drug Discovery

Compound-Centered Drug Discovery

Compound-centered discovery was the predominant source of new drugs until the late twentieth century. This approach relied very heavily on serendipity and chemistry. Receptors were not being characterized until the 1970s, so before the late twentieth century, drug discovery centered on synthesizing compounds that were then tested on biologic targets, typically receptors. The investigators were essentially blind to their biologic targets, and their inspiration for testing a compound in the first place often came from existing substances that either were found in nature or were endogenous to the body.

Natural Products

Naturally derived products were the first blockbuster drugs and paved the way for further drug discovery through compound-centered research. Once the efficacy and safety (and potential profitability) of compounds such as penicillin had been established, pharmaceutical chemists set about refining the structures of these agents to achieve specific pharmacologic effects. Table 9-1 lists some common drugs derived from natural sources.

TABLE 9-1 Common Drugs Derived from Natural Sources

Compound Source
Penicillin Penicillium mold
Morphine Opium poppy
Cyclosporine Fungus

Target-Centered Drug Discovery

Modern analytical techniques such as protein crystallography allow researchers to map the structure of a receptor, so now instead of being blind to their biologic targets, investigators can identify a target first and then design a drug to hit that target. This allows for a significant improvement in receptor specificity and accordingly a reduction in side effects. This target-centered approach has been particularly useful in indications such as cancer, allowing researchers to minimize toxicity of targeted therapies.

An understanding of the genetic basis for disease also provides new targets and will lead to gene-based therapies. The ultimate goal will be to selectively target genes that cause or contribute to disease, and prevent their expression. One of the most promising examples of this target-centered approach is antisense (Figure 9-3).

The concept of gene-based therapeutics is covered in Chapter 6.