1. Drug Discovery and Development How are drugs discovered and developed?

2. Basic Steps Choose a disease Choose a drug target Identify a “bioassay” bioassay = A test used to determine biological activity. Find a “lead compound” “lead compound” = structure that has some activity against the chosen target, but not yet good enough to be the drug itself. If not known, determine the structure of the “lead compound” Synthesize analogs of the lead Identify Structure-Activity-Relationships (SAR’s)

3. Structure-Activity-Relationship (SAR) = How does the activity change as structure is systematically altered? Identify the “pharmacophore” pharmacophore = the structural features directly responsible for activity Optimize structure to improve interactions with target Determine toxicity and efficacy in animal models. Determine pharmacodynamics and pharmacokinetics of the drug. Pharmacodynamics explores what a drug does to the body, whereas pharmacokinetics explores what the body does to the drug.

4. Basic steps (cont.) Patent the drug Study drug metabolism Test for toxicity Design a manufacturing process Carry out clinical trials Market the drug

5. Choosing a Disease Pharmaceutical companies are commercial enterprises Pharmaceutical companies will, therefore, tend to avoid products with a small market (i.e. a disease which only affects a small subset of the population)

6. Choosing a Disease Pharmaceutical companies will also avoid products that would be consumed by individuals of lower economic status (i.e. a disease which only affects third world countries)

7. Choosing a Disease (cont.) Most research is carried out on diseases which afflict “first world” countries: (e.g. cancer, cardiovascular diseases, depression, diabetes, flu, migraine, obesity).

8. The Orphan Drug Act The Orphan Drug Act of 1983 was passed to encourage pharmaceutical companies to develop drugs to treat diseases which affect fewer than 200,000 people in the US Under this law, companies who develop such a drug are entitled to market it without competition for seven years. This is considered a significant benefit, since the standards for patent protection are much more stringent.

9. Identifying a Drug Target Drug Target = specific macromolecule, or biological system, which the drug will interact with Sometimes this can happen through incidental observation…

10. Identifying a Drug Target (cont.) Example: In addition to their being able to inhibit the uptake of noradrenaline, the older tricyclic antidepressants were observed to “ incidentally ” inhibit serotonin uptake. Thus, it was decided to prepare molecules which could specifically inhibit serotonin uptake. It wasn ’ t clear that this would work, but it eventually resulted in the production of fluoxetine (Prozac).