Drug Discovery and Development

Drug Discovery and Development How are drugs discovered and developed?

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)

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.

Patent the drug • Continue to study drug metabolism • Continue to test for toxicity

Design a manufacturing process • Carry out clinical trials • Market the drug

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)

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)

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).

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

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).

Choosing the Bioassay • Definitions: • In vitro: In an artificial environment, as in a test tube or culture media • In vivo: In the living body, referring to tests conductedin living animals • Ex vivo: Usually refers to doing the test on a tissue taken from a living organism.

Choosing the Bioassay (cont.) In vitro testing • Has advantages in terms of speed and requires relatively small amounts of compound • Speed may be increased to the point where it is possible to analyze several hundred compounds in a single day (high throughput screening) • Results may not translate to living animals

Choosing the Bioassay (cont.) In vivo tests • More expensive • May cause suffering to animals • Results may be clouded by interference with other biological systems

Finding the Lead Screening Natural Products • Plants, microbes, the marine world, and animals, all provide a rich source of structurally complex natural products.

Finding the Lead (cont.) Screening synthetic banks • Pharmaceutical companies have prepared thousands of compounds • These are stored (in the freezer!), cataloged and screened on new targets as these new targets are identified

Computer-Assisted Drug Design • If one knows the precise molecular structure of the target (enzyme or receptor), then one can use a computer to design a perfectly-fitting ligand. • Drawbacks: Most commercially available programs do not allow conformational movement in the target (as the ligand is being designed and/or docked into the active site). Thus, most programs are somewhat inaccurate representations of reality.

Structure-Activity-Relationships (SAR’s) • Once a lead has been discovered, it is important to understand precisely which structural features are responsible for its biological activity (i.e. to identify the “pharmacophore”)

The pharmacophore is the precise section of the molecule that is responsible for biological activity

Next step: Improve Pharmacokinetic Properties Improve pharmacokinetic properties. Pharmacokinetic = The study of absorption, distribution, metabolism and excretion of a drug (ADME)

Metabolism of Drugs • The body regards drugs as foreign substances, not produced naturally. • Sometimes such substances are referred to as “xenobiotics” • Body has “goal” of removing such xenobiotics from system by excretion in the urine • The kidney is set up to allow polar substances to escape in the urine, so the body tries to chemically transform the drugs into more polar structures.

Manufacture of Drugs • Pharmaceutical companies must make a profit to continue to exist • Therefore, drugs must be sold at a profit • One must have readily available, inexpensive starting materials • One must have an efficient synthetic route to the compound • As few steps as possible • Inexpensive reagents

The route must be suitable to the “scale up” needed for the production of at least tens of kilograms of final product • This may limit the structural complexity and/or ultimate size (i.e. mw) of the final product • In some cases, it may be useful to design microbial processes which produce highly functional, advanced intermediates. This type of process usually is more efficient than trying to prepare the same intermediate using synthetic methodology.

Toxicity • Toxicity standards are continually becoming tougher • Must use in vivo (i.e. animal) testing to screen for toxicity • Each animal is slightly different, with different metabolic systems, etc. • Thus a drug may be toxic to one species and not to another

Example: Thalidomide Thalidomide was developed by German pharmaceutical company Grünenthal. It was sold from 1957 to 1961 in almost 50 countries under at least 40 names. Thalidomide was chiefly sold and prescribed during the late 1950s and early 1960s to pregnant women, as an antiemetic to combat morning sickness and as an aid to help them sleep. Before its release, inadequate tests were performed to assess the drug's safety, with catastrophic results for the children of women who had taken thalidomide during their pregnancies. Antiemetic = a medication that helps prevent and control nausea and vomiting

Birth defects caused by use of thalidomide

Clinical Trials • Phase I: Drug is tested on healthy volunteers to determine toxicity relative to dose and to screen for unexpected side effects

Clinical Trials • Phase II: Drug is tested on small group of patients to see if drug has any beneficial effect and to determine the dose level needed for this effect.

Clinical Trials • Phase III: Drug is tested on much larger group of patients and compared with existing treatments and with a placebo

Clinical Trials • Phase IV: Drug is placed on the market and patients are monitored for side effects

Drug Discovery and Development