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

Penicillin

Penicillin was discovered in 1928 by Alexander Fleming while he was studying Staphylococcus variants. A mold growing on his culture was causing his bacteria to lyse. The broth in which this fungus was grown proved to be inhibitory for a number of bacteria. The mold belonged to the genus Penicillium, leading Fleming to name it penicillin.

It was not until 1941 that the therapeutic potential of penicillin was realized in a small clinical trial. Production methods improved during the 1940s until penicillin could be manufactured in mass quantities by 1950.

Once the chemical structure of penicillin was established, chemists began work on synthesizing new versions, each with its own distinct properties (Figure 9-1). Penicillin-resistant bacteria produce β-lactamase enzymes that attack the penicillin structure. A simple modification of the structure of penicillin created a bulky chemical chain that blocks β-lactamases from the β-lactam site, resulting in the β-lactamase–resistant drug cloxacillin.

Figure 9-1 A, Penicillin. B, Cloxacillin. C, Amoxicillin.

Endogenous Ligands

Endogenous agonists such as epinephrine, acetylcholine, and dopamine have a variety of pharmacologic effects. Once the chemical structures of these agonists became known, pharmaceutical chemists began designing drugs that closely resembled these structures, with key modifications to improve their potency and bioavailability or minimize their toxicity. Examples include succinylcholine.

Succinylcholine

Recall from the chapter on autonomic pharmacology the mechanism of action of succinylcholine. Succinylcholine is two acetylcholine molecules joined together. This simple modification accounts for the prolonged action of succinylcholine when compared with acetylcholine (Figure 9-2).

Figure 9-2 A, Succinylcholine. B, Acetylcholine.

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).

Antisense oligonucleotides are directed at specific nucleotide sequences in messenger RNA (mRNA).

The sequences in mRNA are known as the “sense” strand, and when these sequences are known, a complementary “antisense” strand is designed to bind this sense strand in a sequence-specific manner. Once bound, the antisense strand prevents the mRNA from being translated into a protein.

• One antisense agent, fomivirsen, has already been approved for use in treatment of cytomegalovirus (CMV) retinitis.

Second-generation antisense agents are designed to signal for destruction of the sense strand, once they have bound to it. The sense strand is destroyed by enzymes (RNAses), allowing the antisense strand to be used again.

• Cancer is an example of a series of diseases that are perfectly suited for antisense therapy. An example is targeting of the bcl-2 protein, an antiapoptotic protein that is overexpressed in many cancers.

• Apoptosis, or programmed cell death, is an orderly process by which damaged cells quietly facilitate their own death. Prevention of apoptosis through proteins such as bcl-2 is one of the key reasons that cancer cells are so difficult to kill.

• By targeting its mRNA and selectively inhibiting the expression of the bcl-2 protein, antisense agents can remove this survival instinct from a cancer cell, making it much easier to kill with cytotoxic therapies.

The newest generation of antisense is small interfering RNA (siRNA). These substances behave similarly to second-generation antisense, although they occur naturally in the body. Several siRNA agents are in clinical trials.

Figure 9-3 Antisense oligonucleotides.

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

Tools Used in Drug Discovery

The first step in the creation of a new drug is to find a match between a chemical compound and a promising new molecular target (receptor). This previously daunting process, much like finding a needle in a haystack, has become increasingly automated over the years. Two of the key tools used in this automated process are high throughput screening and combinatorial chemistry.

High throughput screening

This is an automated system that allows for the rapid screening of thousands of compounds.

It allows one to assay for receptor binding and to identify biochemical and cellular targets.

Combinatorial chemistry

This is an automated method allows for the generation of a large number of compounds from a small number of precursors. This technology allows pharmaceutical companies to create very large libraries of compounds that systematically cover most or all of the possible variations in structure that may occur around a common precursor.

Once a match, also commonly referred to as a hit, has been found, this becomes a lead compound. This lead compound is typically assigned to a research group, which will then try to make minor adjustments to the compound to maximize its affinity for its receptor, as well as attempt to improve its pharmacokinetic characteristics. This stage, in which scientists try to improve this lead compound, is referred to as lead optimization.

Preclinical Testing

After a compound has been synthesized, and appears to have efficacy, fine tuning is then done, focusing on the following issues.

Pharmacodynamics

Tests are performed in vitro to determine receptor binding affinity. Investigators at this point are interested in how specific the drug is for its receptor target, as this will provide an indication of the potential for the drug to cause side effects. Generally speaking, the less specific a drug is for its receptor, the greater the incidence of side effects.

Pharmacokinetics

A key step in the development process is to determine the route of metabolism for the drug. If metabolized by CYP450 enzymes, the isoenzymes involved will be identified. Tests will also be performed to determine whether the drug is an inducer or inhibitor (or neither) of metabolizing enzymes, again with a focus on CYP450.

Being an inhibitor or inducer of metabolizing enzymes is generally considered to be a weakness for a new drug, owing to the potential for drug interactions. Early tests can be performed on isolated enzymes in vitro, but in vivo testing will inevitably be performed to determine the effects of a drug in a whole animal.

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