10.2 · Chemistry & society
From molecule to medicine
The long road from a target to an approved drug.
By the end you should be able to:
- Describe the stages of drug discovery and development
Key idea
How drugs work: shape and binding
Most drugs act by binding to a biological target, usually a protein such as an enzyme or a receptor, and blocking or triggering what it does. Binding depends on the drug's shape fitting the binding site and on the intermolecular forces between them: hydrogen bonds, ion–ion attractions and dispersion forces.
Small structural changes can therefore make large differences to how strongly a drug binds, which other proteins it also hits (side effects), how soluble it is and how well it crosses cell membranes. Designing and testing those changes is much of the work of drug development.
Method
The drug-development pipeline
- Target identification: find a molecule, such as an enzyme or receptor, whose activity drives the disease.
- Hit and lead discovery: screen large compound libraries (high-throughput screening), natural products or computer-designed molecules for anything that binds (a "hit"). The most promising hit becomes the lead.
- Lead optimization: medicinal chemists modify the lead's structure to improve potency, selectivity, stability and absorption, and to reduce toxicity.
- Preclinical testing: laboratory (cell) and animal studies of effectiveness, toxicity and dosing, followed by permission to begin human trials.
- Phase I: a small group (about 20–100, often healthy volunteers): safety, dosage and how the body handles the drug.
- Phase II: a few hundred patients: does it work (efficacy), and what side effects occur?
- Phase III: large trials (hundreds to thousands of patients), usually randomized and blinded, comparing the drug with the standard treatment or a placebo.
- Regulatory review and approval: all the data go to Health Canada (a New Drug Submission) or the U.S. FDA (a New Drug Application).
- Phase IV: post-market surveillance for rare or long-term side effects in the whole population.
Key idea
Time, cost and attrition
- The whole process typically takes 10–15 years.
- Most candidates fail. Of thousands of compounds screened, only a handful reach clinical trials, and only about 1 in 10 drugs that enter Phase I is approved. Common reasons are lack of efficacy, toxicity and poor absorption.
- Development costs are often estimated at more than US$1 billion per approved drug, a figure that includes the cost of all the failures.
- Many drugs start from natural products: aspirin (willow bark), morphine (opium poppy), penicillin (a mould) and paclitaxel, or Taxol (the Pacific yew).
Common mistake
Pipeline traps
- Wrong: Phase I tests whether the drug works. Right: Phase I tests safety and dosage in a small group; efficacy is tested in Phase II and confirmed in Phase III.
- Wrong: approval ends the testing. Right: Phase IV monitoring continues after approval and can lead to new warnings or withdrawal from the market.
- Wrong: animal testing comes after human trials. Right: preclinical (lab and animal) testing comes first.
- Wrong: Phase III compares the drug with nothing. Right: it usually compares the drug with the current standard treatment, or with a placebo when no treatment exists.
Worked example
Worked example: name the stage
| Description | Stage |
|---|---|
| Chemists add a fluorine atom to a lead compound to slow its breakdown in the liver | lead optimization |
| A compound is given to rats to find the dose that causes liver damage | preclinical testing |
| 60 healthy volunteers receive increasing doses to check safety | Phase I |
| 250 patients receive the drug to see whether it lowers their blood pressure | Phase II |
| 3000 patients are randomly assigned the new drug or the current best treatment | Phase III |
| A rare heart side effect is reported two years after the drug goes on sale | Phase IV |
Worked example
Worked example: aspirin as lead optimization
Willow bark was used against pain and fever for centuries. Its active compound is converted in the body to salicylic acid, which relieves pain but badly irritates the stomach.
In 1897 chemists at Bayer converted the –OH group of salicylic acid into an ester (acetylation), giving acetylsalicylic acid, . The small structural change kept the pain-relieving activity and reduced the irritation. That is lead optimization: a natural lead, improved by changing its structure.
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