IB CHEMISTRY
OPTION D  MEDICINAL CHEMISTRY
D.1: PHARMACEUTICAL PRODUCTS AND DRUG ACTION
UNDERSTANDINGS
- In animal studies, the therapeutic index is the lethal dose of a drug for 50% of the population (LD 50) divided by the minimum
effective dose for 50% of the population (ED50).
- In humans, the therapeutic index is the toxic dose of a drug for 50% of the population (TD 50) divided by the minimum effective dose
for 50% of the population (ED 50).
- The therapeutic window is the range of dosages between the minimum amounts of the drug that produce the desired effect and a
medically unacceptable adverse effect.
- Dosage, tolerance, and addiction are considerations of drug administration.
- Bioavailability is the fraction of the administered dosage that reaches the target part of the body.
- The main steps in the development of synthetic drugs include identifying the need and structure, synthesis, yield and extraction.
- Drug-receptor interactions are based on the structure of the drug and the site of activity.
APPLICATION AND SKILLS
- Discussion of experimental foundations for therapeutic index and therapeutic window through both animal and human studies.
- Discussion of drug administration methods.
- Comparison of how functional groups, polarity, and medicinal administration can affect bioavailability.
NATURE OF SCIENCE
- Risks and benefits – medicines and drugs go through a variety of tests to determine their effectiveness and safety before they are
made commercially available. Pharmaceutical products are classified for their use and abuse potential.
MEDICINAL CHEMISTRY: INTRODUCTION
*Cross-disciplinary science that links  Organic chemistry, pharmacology, biochemistry, biology, medicine, mathematics, and
computer science
*Primary objective  to ________________, ___________ and _____________ new bioactive compounds (i.e. pharmaceutical
drugs) suitable for therapeutic use while taking into consideration the benefits and risks of new drugs on _______________,
____________ and the ______________________
 The production of ________________ molecules (e.g. drugs, vaccines) used specifically for the treatment of _____________ = one
of the most significant achievements of the last 100 years (e.g. eradication of ______________ & ___________, millions of
_____________ and _______________ survivors)
DEFINITIONS (Drug vs Medicine):
- DRUG: a chemical that affects how the body works – for ____________or for ________; term often associated with ____________
substances
- MEDICINE: a _____________ or synthetic substance that _______________ health (a beneficial drug)
*Drug action depends on interaction with receptors:
- The activity of most drugs is determined by their ability to ______ (based on a “good chemical fit” between drug and receptor) to a
specific _____________ in the body. The binding ____________ development of disease.
- Receptors = ______________ (e.g. enzymes), chemical structures on ________ membranes, or _________
NEW CHALLENGES FOR PHARMACEUTICAL INDUSTRY:
- ______________ resistance
- ______________ and ________________ hazards associated with cancer treatment and nuclear medicine
- appearance of new _______________ (e.g. avian flu, zika-virus)
- improving the __________________ of drugs to all parts of the world [esp. diseases for which effective treatments exist (e.g. AIDS,
malaria – over a _____________ people die of malaria every year)]
1. THE EFFECTS OF DRUGS AND MEDICINES
A PHARMACEUTICAL DRUG or MEDICINE is any chemical (natural or human-made) that does one or more or the
following:
- Prevent or cure a disease
- Alleviate the symptoms of a health condition
- Assist in medical diagnosis (e.g. inert barium sulfate used for gastrointestinal X-ray)
- alter the ___________________ state, including ______________________, _________________ level or
_____________________
- alter incoming ___________________ sensations;
- alter _______________or _________________.
2. METHODS OF ADMINISTERING DRUGS
*In order to reach the site where the drugs are needed, the majority of
drugs have to be absorbed into the ____________________.
THE DIFFERENT METHODS OF ADMINISTERING
DRUGS:
METHOD
Orally
Rectally
Parenterally: by
_____________
Inhalation
Transdermally
Eye or ear drops
DESCRIPTION / NOTES
- taken by ___________
- generally, ___________-soluble drugs - ones with many
__________ functional groups
- in the form of _______________ or ___________
- some drugs unstable in highly __________ gastric juices
found in the ____________
- subcutaneous (under the _________) injection
- intramuscular  injection into ____________ tissue
- intravenous  injection directly into ____________
(_____________ therapeutic effect)
- breathed in through the ___________ or ________
- _______________, highly dispersed drugs
- applied to _________ in the form of patches, ointments,
or therapeutic baths
- absorbed directly from the skin into the blood
- ______________ compounds
- liquids delivered directly to the opening
EXAMPLES
- tablets, capsules, pills, liquids
- treatment of digestive illnesses and
hemorrhoids
- __________ injections
- many ___________
- local ________________
- _________________ conditions (e.g. asthma)
- some ____________ treatments (e.g. estrogen)
- ______________ patches
- ________________ patch (to alleviate
symptoms of angina/cardiovascular disease)
- eye and ear infections
3. BIOAVAILABILITY OF A DRUG
*Drug bioavailability:
 The fraction of the administered dose that is absorbed into the _________________; OR, the fraction of the dose that reaches the
___________ part of the human body.
 By definition, when a drug is administered intravenously, its bioavailability is ______%.
FACTORS AFFECTING BIOAVAILABILITY:
FACTOR
EXPLANATION
- ↑ polar = ↑ _____________ in water / bloodstream
SOLUBILITY of the drug
*Drugs containing ______________, ____________ and ____________ groups are usually
*Depends ON:
soluble = quickly absorbed from GI tract into bloodstream. However, such molecules do not
- ______________ of the drug
readily pass through _______________ cell membranes.
-________________ groups present
e.g. Aspirin and morphine, for example, are administered as ionic ___________, to make
them more soluble.
METHOD OF ADMINISTRATION e.g. Early penicillins could not be taken orally because they were destroyed by
____________ acid – therefore, _____________ instead.
4. RESEARCH, DEVELOPMENT AND TESTING OF NEW PRODUCTS
TERM
Lethal Dose (LD50)
Toxic Dose (TD50)
Effective Dose (ED50)
DEFINITION
- the dose that causes __________ in ____% of the laboratory ______________
- the dose that causes ______________ (an unacceptable adverse effect) in 50% of the _______ patients
- the minimum dose of the drug that produces the ___________ therapeutic effect in 50% of the
laboratory animals or human patients
THERAPEUTIC INDEX (TI)
 The _______________ and _____________ of a drug can be expressed using its TI.
 The TI is a _________ that relates the ____________ effects of a drug to its ________
effects.
THERAPEUTIC INDEX (TI)
ANIMALS
HUMANS
LD50
ED50
TD50
ED50
EXAMPLE:
TI
INTERPRETATION
5
100
- the drug becomes dangerous if the recommended, therapeutic dose is
exceeded by _____
- the drug becomes dangerous if the recommended, therapeutic dose is
exceeded by _____
RISK OF
OVERDOSE
HIGH
THERAPEUTIC
WINDOW
LARGE
LOW
SMALL
SUMMARY:
-The smaller the TI, the easier it is to _______________ on the drug. In other words, drugs with high TI values are ___________.
Over-the-counter drugs usually have ______________ TI values.
-Therefore, administering drugs with _________________ TI values must be carefully controlled and monitored, and will depend on
factors such as __________, ___________, body ____________ and general health.
-THERAPEUTIC WINDOW - the __________ of dosages between the minimum amounts of the drug that produce the desired
effect and a medically unacceptable adverse effect (the concentration at which it starts to be become toxic).
*CONSIDERATIONS OF DRUG ADMINISTRATION
CONSIDERATION
DESCRIPTION
- When a person develops ________________ for a drug, larger and larger doses must be administered in
TOLERANCE
order to get the _______________ effect. *What are the problems associated with tolerance?
-defined as a chronic, relapsing ____________ disease that is characterized by ____________ drug seeking
ADDICTION
and use, despite harmful consequences. It is considered a brain disease because drugs change the brain; they
change its structure and how it works.
– The __________________effects associated with drug intake. *Risk-to-benefit ratio must be considered
SIDE EFFECTS
before administering.
*Ex: aspirin  can cause gastrointestinal ________________
opiates  extremely __________________
PLACEBO EFFECT
- Also called the placebo response. A remarkable phenomenon in which a placebo - a __________
treatment, an _____________ substance like sugar, distilled water, or saline solution -- can sometimes
improve a patient's condition simply because the person has the expectation that it will be helpful.
- In general, one-third of a control group taking a placebo pill (“sugar” pill) show some improvement.
5. DEVELOPMENT OF NEW SYNTHETIC DRUGS
- Pharmaceutical companies and research groups are constantly developing new drugs. (e.g. improving pre-existing drugs; and, or,
developing a completely new drug to fight a new viral strain)
- average time for development of new drug =
years
- For every drug that reaches market, ____________ fail.
- major investment/cost  ______________ of dollars *To support cost there is a focus on developing drugs that treat conditions
prevalent in the developed world. (e.g. obesity, depression, cancer, cardiovascular disease, ulcers)
*STAGES IN THE DISCOVERY AND DEVELOPMENT OF A NEW MEDICINE
STAGE 1: DISCOVERY RESEARCH (1-3 YEARS)
- identification of __________ target compounds (based oftentimes on knowledge of drug-___________
interactions/_______________ of action) *↓ ‘trial and error’ over the years
- lead compounds often derived from __________ (e.g. Taxol and yew trees) or ___________________
- synthesis of _______________ (i.e. many chemically related compounds) using a process called
______________________ chemistry
- ________________ testing (mostly ______________testing…under strict legislative control)
- determine clinical _________________ index
STAGE 2: DEVELOPMENT RESEARCH (5 – 6 YEARS)
HUMAN TESTING/TRIALS:
PHASE 1: 50 – 100 healthy ________________
PHASE 2: 200 – 400 ________________
PHASE 3: 3000+ patients (_________________-blind studies – half given _________, other half given
_____________; neither _______________nor ____________knows what they have been given.)
*application for marketing at this point
STAGE 3: REGULATORY REVIEW (1 – 2 YEARS)
- launch of product at end of review
STAGE 4: POST-MARKETING MONITORING
- post marketing ______________ surveillance
- collection of _______________ drug reaction data (may result in withdrawal of drug from market after
numerous years of usage – e.g. Thalidamide)
*YOUTUBE – GENERAL INTEREST VIDS:
1. Combinatorial Chemistry video
2. ‘Combatting the Counterfeit Drug Trade’ (Ashifi Gogo – Ted Talk)
3. ‘Undercover Agents Go on Hunt for Counterfeit Drugs’ (ABC News)
PRE-2014 PROGRAM - D9: DRUG DESIGN
D.9.1  Discuss the use of a compound library in drug design.
[Traditionally, a large collection of related compounds are synthesized individually and evaluated for biological
properties. This approach is time-consuming and expensive.]
D.9.2  Explain the use of combinatorial and parallel chemistry to synthesize new drugs.
[Combinatorial chemistry is used to synthesize a large number of different compounds and screen them for biological
activity, resulting in a “combinatorial library”. Alternatively, parallel synthesis can produce smaller, more focused
libraries. Students should be aware of the importance of solid-phase chemistry.]
Parallel Synthesis  involves the use of _______________ to carry out identical chemical processes between chemicals
such as adding fixed volumes of substances using syringes
Combinatorial Chemistry (‘Combi-Chem’)
- automated ‘trial and error’ technique used to rapidly synthesize thousands of related compounds
(e.g. penicillins - main molecular structure maintained / alter side-chain]
- synthesized compounds are then screened (in vitro or in vivo) and evaluated for desirable biological/pharmacological
properties [e.g. activity against a target enzyme]
- benefits = ↓time and $
*Hypothetical Case: Potential time and cost savings of combinatorial chemistry
One-At-A-Time Approach
Combinatorial Approach
Number of employees
4
4
Annual Budget
$2 million
$2 million
Catalysts evaluated/year
200
20,000  50,000
Average preparation and
$10,000
$40  $100
evaluation cost/catalyst
Development Time
2  10 years
0.5  2 years
The Mix and Split Variation of Combi-Chem (e.g. of Solid-Phase Parallel Synthesis):
- basically involves reacting a set of starting materials in all possible combinations
- Solid Phase/State chemistry - use of polystyrene-based resin-beads, for example
Example: Consider 3 amino acids (Use a square, circle and triangle to represent each of the three acids.)
Stage 1: Attach Amino Acid to Polystyrene-Based Resin Bead
-
Attach each amino acid to a very small (0.1 mm diameter) _________ bead. Now, there would be 3 containers,
each containing a different amino acid.
Stage 2: Mix and Split…and React
a) Mix  Mix the 3 containers from stage 1. Now, there is one beaker containing all 3 amino acids.
b) Split  Split the amino acid mixture into 3(or more) separate beakers. Now, there are three beakers, each
containing all 3 amino acids.
c) React  React each of the amino acid mixtures with a different amino acid.
(i.e. Mixture 1 + a square ; Mixture 2 + a triangle ; Mixture 3 + a circle)
*Each beaker now holds 3 different _____________. Therefore a total of 9 (32) dipeptides now exist at the end of stage 2.
Stage 3: Mix, Split, React….(same as Stage 2)
a) Mix  Mix the final three mixtures attained from part c) of Stage 2. Now, there is one beaker containing all 9
dipeptides.
b) Split  Split the mixtures into 3 separate beakers. Now, there are three beakers, each containing all 9
dipeptides.
c) React  React each mixture with a different amino acid.
*Each container now holds 9 different ________________. Therefore a total of 27 (33) tripeptides now exist at the end of
stage 3.
Stage 4: Repeat process. How many total products exist after another mix and split?
34 =
…and another , 35 =
and so on.
Sample Question: Consider three amino acids A, B and C. Calculate the number of dipeptides that could be created from
a two-stage combi-chem process. (see p. 431 of text for answer)
D.9.3  Describe how computers are used in drug design.
[Three-dimensional models of drugs can be created in silico and molecular modeling software can be used for the virtual
development and evaluation of new drugs.]
*Main Use = Molecular Modelling
 computer power doubles every _____ months ; also, cost of technology ↓ with time
 main benefits:
- ↑ safety; ↓ time and $ associated with drug design
- coverting ____ diagrams of molecules to _____ equivalents
- enables “in silica” (i.e. performed on a ____________or via computer ____________) creations
* in silica creations ideally possess the ability to mimic molecular behavior to determine medicinal/pharmacological
properties
in silica creations may be designed to:
- mimic the interaction of test molecules with target enzyme (This may involve the manipulation of a ________________
group and/or molecular _______________, for example.)
- test the effectiveness of a ligand _______________(i.e. ligands that inhibit target enzymes)