Chemistry 2223b ▯ Winter 2013–14 ▯ Western University
Topic 7. Role of Chemistry in Pharmaceutical Drugs
▯ In this chapter, we will discuss the importance of chemists and chemistry in the
discovery and development of pharmaceutical drugs. We will also look at:
o Sulfa antibiotics, which illustrate the importance of drug pKa; and
o Photodynamic therapy, which uses chromophores to destroy tissue.
▯ Background material that is important includes:
o Reactions of amines and carboxylic acids
o Mechanism of substitution reactions
o Factors affecting the strengths of organic acids
o Singlet and triplet states
▯ After studying this section, attempt:
o All practice problems
o 2009 final exam: 45–50 2011 final exam: 50–52 Drugs ▯ 2
A. Pharmaceutical Development
1. Economics of Pharmaceutical Development
▯ The estimated average cost, to research, discover, test, and bring a new drug to
market exceeds $800 million, and this process takes 12–15 years.
2. Food and Drug Administration (FDA) Model (also used by Health Canada)
▯ The development of new drugs can be classified into three broad stages.
o Drug discovery and preclinical evaluation
▯ This is where chemists (and biochemists) have the greatest role.
▯ For example, the biological target needs to be identified, drug candidates
need to be designed and synthesized in the lab, and samples from in vitro
and animal studies need to be analyzed for various compounds.
o Clinical evaluations
o FDA approval, marketing, and post-market surveillance Drugs ▯ 3
a. Drug discovery and preclinical evaluation
▯ Scientists identify new drug candidates that have the potential to achieve a desired
biological effect; these are called new molecular entities or new chemical entities.
This may require research on the fundamentals of disease or biological processes,
and on the action of existing drugs.
▯ There are four popular methods used to find new candidates.
▯ Method 1: Extraction from natural sources.
Morphine and opiates Penicillin Taxol Drugs ▯ 4
▯ Method 2: Structure-Activity Relationship Studies (SARS) are used to make better
compounds from those identified serendipitously or by purposeful searching.
o SARS determine the effect of structural changes to the molecule on its activity.
O O O
HN H N
▯ Method 3: Structure-Guided Drug Design (SGDD)
is an in silico technique, where computers design a
drug that binds to the specified target.
o Relenza and Tamiflu, both of which inhibit the
influenza enzyme neuraminidase, were
designed by SGDD. Drugs ▯ 5
▯ Method 4: High-Throughput Screening (HTS) allows the rapid, automated screening
of huge libraries of compounds, usually prepared by combinatorial synthesis
(combichem), against a multitude of possible targets. Assays are typically performed
in microwell plates using robotic instrumentation… but chemists and biochemists are
still needed to interpret the results. Drugs ▯ 6
▯ Regardless of the method used, the best candidates (typically 1-5 out of every
10000) are patented and subjected to preclinical evaluation.
▯ Preclinical studies include in vitro testing (test-tube studies using bacteria, human
cells, enzymes, etc.), as well as ADME(T) studies in vivo (live animals, such as
mice). FDA approval is not required to perform in vitro or animal studies.
o Absorption, Distribution, Metabolism, Excretion, (Toxicity)
▯ The ADMET set of studies alone does not evaluate the efficacy of the drug.
▯ If the preclinical data are not desirable (e.g. high toxicity, poor bioavailability,
metabolized too quickly, etc.), that is the end of consideration for that compound.
▯ If the preclinical data are desirable, then an investigational new drug (IND)
application is filed with the FDA for molecule. If the FDA approves the application,
clinical evaluation in humans can commence. Drugs ▯ 7
b. Clinical evaluation
▯ Clinical evaluation in humans occurs in three phases. The evaluation is usually
aborted if data from any one of the phases is negative (undesirable). The overall
process takes many years and is expensive. Chemists have some roles in clinical
studies: they formulate the drugs, analyze the metabolites, etc.
Phase Main objectives Typical sample size
I Safety, ADMET, side effects, and < 100 healthy volunteers
safe dosage range
Effectiveness and short- < 500 volunteers with
II term side effects targeted disease or symptom
Effectiveness, longer-term side Thousands of volunteers with
III effects, optimum dosage, optimum
route of administration targeted disease or symptom
▯ Permission needs to be granted by the FDA prior to proceeding to the next phase.
The odds of passing all three phases are about 10%.
▯ While clinical trials are very long, the FDA may fast track an IND should it target a
serious or life-threatening condition for which no current treatments exist. Drugs ▯ 8
c. FDA approval and post-market surveillance
▯ If the clinical trials are positive, then the company submits a new drug application
(NDA) for the therapeutic use specified. If the FDA is satisfied that the drug has a
relatively high benefit-versus-risk ratio, then the drug is approved for marketing.
▯ Although drugs are approved for specificic uses, physicians can prescribe a drug
off-label and use it for something else besides the approved use. For example,
cancer drugs that are approved for one type of cancer often work for other cancers.
▯ After the drug is on the market, pharmacovigilance (post-market surveillance)
occurs. A drug may be withdrawn or restricted for various reasons. Examples:
Year Drug (use) Primary health risk
2011 Xigris (sepsis) None – drug was useless
2010 Meridia/Reductil (appetite suppressant) Cardiovascular events
2009 Raptiva (psoriasis) Viral infection of brain
2008 Trasylol (antibleeding for heart surgery) Death (reason unknown)
2006 Tequin (antimicrobial) Severe hypo- or hyperglycemia
2004 COX-2 inhibitors (anti-inflammatory) Cardiovascular events
2003 Serzone (antidepressant) Liver damage Drugs ▯ 9
B. Sulfanilamide: An Unexpected Antibiotic
▯ In 1932, Gerhard Domagk was working at the German conglomerate IG Farben
when he discovered that protonsil rubum, a red leather dye, protected mice when
they were injected with a lethal dosage of streptococci bacteria.
▯ Shortly thereafter, Domagk’s daughter pricked herself with a needle and developed
a streptococci infection. Her lymph nodes were lanced fourteen times to discharge
fluid. Doctors insisted on the amputation of her arm, but her father disagreed.
▯ After ingesting some of the leather dye, she fully recovered.
H 2 N O
N S NH
O Drugs ▯ 10
▯ What was puzzling was that protonsil was ineffective in test-tube experiments
against bacteria, but it worked when ingested. This mystery was later solved by the
Pasteur Institute in France, where it was found that the liver reduced the dye into
two halves. This discovery gave birth to the discipline of drug metabolism.
did not kill
NH H2N NH 2 bacteria
2 azo group
H 2 N O
N S NH
O H N S NH Sulfanilamide
2 2 drug
▯ One-half did not have any bacterial activity, but the other half, a chemical known as
sulfanilamide, was fully active. i.e. the dye was metabolized into an active form.
▯ After this discovery, Protonsil was then rapidly abandoned in favour of chemically
simpler sulfanilamide, as it was an existing chemical that was easily prepared. Drugs ▯ 11
2. Mechanism of Antibacterial Activity
▯ Tetrahydrofolate, the reduced form of folic acid (vitamin B9), is needed for DNA
synthesis. Mammals cannot make folic acid or its derivatives, so they need to
consume it in their diet. Folic acid is then biologically reduced to tetrahydrofolate.
OH H N
N N folic acid
N N NH
HOOC O H 2
N N NH2
HOOC O H H
OH N N N
N N NH2
H H Drugs ▯ 12
▯ Bacteria cannot transport folic acid or its derivatives across the cell membrane, so
they synthesize DHF from three components, one of which is p-aminobenzoic acid.
HOOC O PABA
OH H N
N N dihydrofolate
N N NH 2
▯ The biosynthesis of involves two coupling reactions to link the three units together.
After DHF is made, it is reduced in the bacterial cell to tetrahydrofolate. Drugs ▯ 13
▯ The first step involves the linking of the pteridine derivative to PABA, where the
amine from PABA replaces the OH group on the pteridine viN an S 2 reaction.
▯ To perform this reaction, the OH is turned into a good leaving group. In this case, it
is phosphorylated twice. Note that PABA is negatively charged at physiological pH.