Chapter 9 Drug Discovery and Evaluation
Preclinical Process
Drug Discovery
Compound-Centered Drug Discovery
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.
Compound | Source |
---|---|
Penicillin | Penicillium mold |
Morphine | Opium poppy |
Cyclosporine | Fungus |
Penicillin
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.
Endogenous Ligands
Target-Centered Drug Discovery
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.