Week 1 DavidsonX D001x Medicinal Chemistry Weekly Summary

Welcome to Week 1
Starting week one video

Please watch the online video (1 minutes 7 seconds).
OPTIONAL-Please participate in the online discussion forum.
Chapter 1 - Pre-Regulatory Medicine
Introduction to Chapter 1
Chapter 1 contains three subsections.
Natural Products
Synthetic Drugs
Need for Regulation
At the conclusion of this chapter, you should have an appreciation for the types of drugs that have
been used throughout history and up to the late 1930s. You should also understand the challenges
faced by drug regulatory agencies as they try to enforce the creation of a safe and effective drug
supply.
1.1 Natural Products
Ephedrine video
Please watch the online video (7 minutes, 6 seconds).
Clarifications and corrections
The description on side effects and adverse events is not correct. Please review the comments in
the last unit of Chapter 1.1 (FAQ, help, and tips).
A condensed summary of this video can be found in the Video summary page.

Pharmacophores in drugs
Background: The phenethylamine compounds mentioned in the video are relatively small structures
with an easily identified pharmacophore. Pharmacophores in drugs can be considerably more
complex.
Instructions: Read the passage concerning compounds that contain the same pharmacophore
elements as morphine. Use the information to answer the questions that follow the text.
Learning Goal: To examine a molecule's structure and determine whether a molecule contains a
specified pharmacophore.
Opiates, Opioids, and Their Pharmacophores
A notable natural product that can be traced to the early history of humankind is morphine (1).
Morphine is found in opium, the residue that seeps from damaged poppy seed pods. Morphine is a
complex alkaloid with very potent analgesic (pain relieving) properties. Beyond offering pain relief,
morphine is also highly addictive.

Morphine is not the only compound found in opium. Opium contains approximately two dozen
other compounds including codeine (2). Morphine and codeine are both known as opiates. Opiates
are naturally occurring compounds that share the same activity as morphine.

A number of compounds similar to morphine and codeine can be synthesized in a lab. Some are
prepared by modifying morphine itself. Examples of synthetic and semi-synthetic morphine
analogues include heroin (3) and methadone (4). These unnatural compounds with morphine-like
activity are called opioids. Methadone looks very little like morphine, but it is still considered an
opioid because of its biological activity.

Almost all opiates and opioids share common structural features known as the morphine rule. The
morphine rule stipulates the structural requirements for a compound to have morphine-like activity.
Specifically, the morphine requires a compound to have (1) a benzene ring (2) attached to a
quaternary carbon connected by (3) a two-carbon spacer to (4) a tertiary amine. These structural
elements describe the pharmacophore of morphine.

The pharmacophore cores of heroin and methadone are shown below traced in blue.

Collectively the opiates and opioids play a key role in pain management. Because of their addictive
properties, opiates and opioids are not suitable for long-term use. For certain situations, such as
post-operative surgery pain, they are very effective and safe.
Please complete the online exercise.
Regulation of herbal dietary supplements?
Background: Many herbal medicines have been used for thousands of years and continue to be
used today. The herbal medicine, or herbal supplement, industry is very loosely regulated in the
United States as well as most nations.
Instructions: Read the linked article below from BMC Medicine concerning the quality of herbal
supplements in the marketplace. Use the information in the article to answer the questions that
follow.
Learning Goal: To understand purity issues within the herbal supplement industry.
A recent article in BMC Medicine reported that possibly a high percentage of herbal supplements
contain little or none of the supposed active plant material.
Please return to the online course and read the article to which the above paragraph refers.

FAQ, help and tips
Ephedrine Video
What is the original reference for Ma Huang and Shen Nung?
The reference is Walter Sneader's Drug Prototypes and Their Exploitation. The text is out of print
but still available from various places online.
Why is a vasoconstrictor a decongestant?
Vasoconstrictors cause blood vessels to shrink and reduce inflammation and drainage in nasal
tissues.
Are the anti-cough properties of ephedrine directly linked to vasoconstriction?
Ephendrine's effects in the body are not limited to vasoconstriction. The effects of ephedrine
collectively influence a number of patient symptoms, including cough, observed appetite, and heart
rate.
Please clarify the difference between a "side effect" and "adverse event".
The terminology in the video is not correct. An adverse effect, adverse event, or adverse drug
reaction is any undesired effect that is caused by a medication. Some adverse effects are more
serious than others. The FDA has a page that lists examples of serious adverse effects.
A side effect is any unintended effect of a drug. Side effects can be undesirable (adverse effect) or
desirable. Some drugs have been found to have beneficial side effects that have later been used for
treatment of a different disease. An example is raloxifene. Raloxifene was initially approved for
treating osteoporosis in postmenopausal women. The drug was later found to also be effective for
reducing the risk of breast cancer in certain women.
How complex must a molecule be to be called an alkaloid?
There are no firm rules on defining an alkaloid, although many people have attempted to define the
term. Alkaloids are natural products, typically contain a basic nitrogen, and often including a ring in
their structure. The Wikipedia entry on alkaloids shows a number of examples, many of which
violate the guidelines listed here.

Another drug with a tragic story is thalidomide.
The story of thalidomide is well documented. The account on Wikipedia is fairly exhaustive.
Most of the molecules in the video explicitly show the configuration of stereocenters, but
fenfluramine does not. Why?
Fenfluramine was sold in its racemic form, so its stereochemistry is not defined in the video. Note
that a single enantiomer form of fenfluramine, dexfenfluramine, was also available in the late
1990s. Like fenfluramine, dexfenfluramine was withdrawn from the marketplace.
Is methylphenidate, an ADHD drug, also a member of the phenethylamine class?
Yes it is. The structure is shown below with the phenethylamine scaffold in bold.

Is there any additional recommended reading for this part of the course?
One recommended text is Napoleon's Buttons: How 17 Molecules Changed History by Penny Le
Couteur and Jay Burreson. It covers many molecules from the early, pre-regulatory days of
medicine.
Pharmacophores in drugs
If fentanyl does not follow the morphine rule, then how can it have the same effect as morphine?
The morphine rule follows an old way of envisioning a pharmacophore. Specifically, the morphine
rule describes a pharmacophore based upon strictly defined structural elements and functional
groups. The newer approach (which is not very new) emphasizes the exact distance between key
parts of a molecule. How that separation distance is achieved -- whether by a two carbon linker or
something else -- is not important. The important idea is that the key groups are held in the correct
position relative to one another.
So, while fentanyl does not fit the morphine rule, fentanyl is still a molecule that preserves the key
functional groups in the correct orientation for opioid receptor binding.
How is the analgesic effect of a drug measured?
Pain relief is difficult to measure in a quantitative manner. The rat tail flick test is a classic
method. In this test, a rat's tail is placed in hot water or on a hot surface. The time it takes the rat

to remove is tail is then recorded. A more effective pain reliever would allow the rat to tolerate the
discomfort for a longer period of time.
Studies on the evaluation of pain relief are commonly encountered in the literature (link to an
abstract - full text is not freely available). Some methods are even based on brain wave analysis.
Are there any opioids that are more potent than fentanyl?
Several opioids with greater analgesic activity are known. They include a number of fentanyl
derivatives - 3-methylfentanyl (10-15x the potency of fentanyl), carfentanyl (100x), and
ohmefentanyl (28x).

Regulation of herbal dietary supplements
Are herbal manufacturers regulated?
In the United States, as long as the manufacturer does not make medical claims on the benefits of
the product, the herbal products are considered to be a dietary supplement, not a drug or medical
device. Companies are therefore not required to register with the FDA. In other words, an herbal
medicine may have zero effect and still be legally sold.
If the manufacturer is not selling the product on the label, then the manufacturer is engaging in
fraud. Government authorities can take action against fraud.
What brands of dietary supplements were tested in the study?
The brands are not disclosed in the study.

What do the terms "rbcL" and "ITS2" mean?
These are specific genetic sequences that differ significantly between one type of plant and
another. By studying these sequences that have been isolated from the herbal supplement, one can
confidently identify the plant material in the sample.
1.2 Synthetic Drugs
Sulfa drugs video
Although the term antibiotic is often used with synthetic molecules like the sulfa drugs, the term
antibiotics only applies to natural products with antibacterial properties. Please review the
comments in the last unit of Chapter 1.2 (FAQ, help, and tips).
Domagk's first name is Gerhard, not Georg. The video is incorrect, but the transcription is
correct.
Late in the video (6:04) the transcription incorrectly reads regiment instead of regimen.
Early synthetic drugs
Background: Around the middle to late 1800s, organic chemistry had advanced sufficiently to allow
the preparation of organic molecules as drugs.
Instructions: Read the passage of text below on three very early synthetic drugs.
Learning Goal: To gain exposure to the early important synthetic pharmaceuticals.
Below are three very early synthetic drugs.
chloral hydrate
Chloral hydrate (1) is a solid formed by the reaction of trichloroacetaldehyde and water. The
compound is a potent sedative. Once its properties were discovered around 1870, chloral
hydrate was used widely in medicine. Chloral hydrate was prone to abuse, and solutions of
chloral hydrate became called "knock-out drops" or a "Mickey Finn". The phrase "slip him a

Mickey" became synonymous with using chloral hydrate to incapacitate a person for ignoble
ends.

aspirin
Aspirin (2) was first prepared around 1900 by a scientist at Bayer. It is an effective analgesic,
antipyretic (reduces fever), anti-inflammatory, and anticoagulant (reduces blood clotting). The
name Aspirin is still under trademark protection in some parts of the world. In those
jurisdictions the generic form of the compound is referred to as acetylsalicylic acid, or ASA.

phenobarbitol
Phenobarbitol (3) is an anticonvulsant. Phenobarbitol was discovered around 1900 during a
flurry of early research in the area of barbiturates as anticonvulsants and
sedatives. Phenobarbitol continues to be used widely today, especially in less developed
nations.

Drawing molecules
Background: An important aspect of this course is being able to draw and submit chemical
structures for evaluation by the edX grader. The tool that allows drawing and submission is called
JSME, which edX has available as an embedded tool for use by courses.
Instructions: Use the JSME tool to build and submit chemical structures for grading.
Learning Goal: To use the JSME tool in edX and practice drawing chemical structures.

Pharmacophore of sulfonamide antibiotics
Background: Sulfanilamide is the parent molecule of the sulfa drug class. The simple structure of
sulfanilamide very nearly describes the pharmacophore of the sulfa drugs.
Instructions: Read the text below and use the information to answer the questions on the
pharmacophore of sulfa drugs.
Learning Goal: To identify sulfonamide antibiotics based upon their structural features.
As an early class of drugs, sulfonamide antibiotics have been extensively explored. Literally
thousands of different sulfonamides were prepared and tested in the 1930s and 1940s. Through
these studies, the pattern of activity and pharmacophore for sulfonamide antibiotics became clear.
The pharmacophore for sulfonamides (1) consists of a 4-aminosulfonamide core with tolerance for
aryl and acyl groups on the sulfonamide nitrogen. Almost all sulfonamide antibiotics follow this
simple model.

FAQ, help and tips
Sulfa drugs video
Are sulfa drugs antibiotics?
The term antibiotic originally applied to molecules like penicillin, a compound isolated from a
natural source with activity against bacteria. Over time, some people have associated the term
antibiotic with any molecule (natural or synthetic) that is used to treat a bacterial infection.
Technically, this use of the term antibiotic to describe synthetic compounds is incorrect. Synthetic
molecules like the sulfa drugs are antimicrobials. Antimicrobials can have antibacterial, antifungal,
or antiparasitic activity. The sulfa drugs are antimicrobials with antibacterial activity.
Whether it is appropriate or not, terminology usage around antibiotics seems to be less and less
formal. Some people care greatly about the proper usage of the terms, and others are not as
careful. Regardless of how the terms should or should not be used, one should be aware when
liberties are being taken with definitions.

The Heads of Medicines Agency, a European medical organization, has published a statement (pdf)
about the use of the term antibiotic.
Are there other common uses for sulfa drugs?
Sulfamethoxazole is mentioned in the video as a treatment for middle ear
infections. Sulfamethoxazole (with trimethoprim) is also a first-line treatment for certain types of
urinary tract infections.
Early synthetic drugs
Is chloral hydrate stable? Shouldn't it lose water and form an aldehyde?
All aldehydes can react with water and form the corresponding hydrate. This equilibrium between
the aldehyde and its hydrate normally favors the aldehyde. In the case of chloral, because of the
chlorine atoms, the equilibrium strongly favors the hydrate.

I work in a botany lab, and we use chloral hydrate regularly.
Yes, chloral hydrate can be used as a "clearing agent" to prepare certain plant and animal specimens
for observation under a microscope. It must be handled carefully because it is potentially toxic.
Why do some adults take children's aspirin?
A regimen of daily, low-dose (81 mg) aspirin has been linked to reduced risk of heart attacks in
adults. Recently, the US National Institutes of Health reported that women who take aspirin show a
reduced risk for certain ovarian cancers. Chronic use of aspirin carries some health risks, but it can
apparently also bring some benefits.
What makes a compound a barbiturate?
Barbiturates, including phenobarbital, have a core structure that is derived from barbituric acid
(shown below).


1.3 Need for Regulation
Elixir Sulfanilamide tragedy video
Continued issues with diethylene glycol
Background: Since 1938 the US Food and Drug Administration has held increased powers of
oversight over the safety and effectiveness of pharmaceuticals in the United States. The drug
regulatory agencies of other nations hold very similar roles and powers.
Instructions: Read the text below and the accompanying report from the World Health Organization
and answer the subsequent questions.
Learning Goal: To understand the complexities and risks that international trade creates for drug
regulatory agencies trying to maintain a safe drug supply.
Diethylene glycol played a deadly role in the Elixir Sulfanilamide tragedy. Unfortunately diethylene
glycol continues to be found in medicines despite the efforts of drug regulatory agencies. In 2006
many people, likely several hundred, died in Panama after taking cold medicine containing
diethylene glycol.
Read the linked bulletin from the World Health Organization and answer the questions below
Please return to the online course and read the bulletin to which the above paragraph refers.
FAQ, help and tips
Continued issues with diethylene glycol
Why isn't diethylene glycol banned?
Diethylene glycol, while it is highly toxic if ingested, can be used safely in creams and lotions for
topical use.

What can be done to ensure the safety of health products in a global economy?
This is clearly a difficult challenge. The FDA recently assembled a report entitled Pathway to Global
Product Safety and Quality. The report is no longer accessible through the FDA website, but Google
does have a cached version of the original page. (Some of the graphics are incomplete.) While a
global supply chain can be regulated, a more practical question might be whether such a supply
chain can be monitored or whether regulations can be enforced.
Was the use of diethylene glycol in Panama intentional or an accident?
The last line of the WHO report implies that the incident in Panama arose because of disregard for
safety regulations. Indeed, other media outlets have covered the story, and the cause can allegedly
be attributed to intentional mislabeling of chemicals.
Why would an unsafe chemical be used to formulate cough syrup?
The standard thickener in oral syrups is glycerol (or glycerin), which is safe for ingestion. Glycerol is
much more expensive than diethylene glycol. An unscrupulous supplier might be tempted to charge
a buyer (pharmaceutical manufacturer) for the more expensive glycerol and instead provide the less
expensive diethylene glycol. Both are thick, clear, colorless liquids. If the manufacturer does not
perform a chemical analysis of the material, the manufacturer will formulate drugs with a toxic
substance.

Chapter 2 - Drug Discovery: From Concept to Market
Introduction to Chapter 2
Chapter 2 contains three subsections.
Phenotype- vs. Target-Based Drug Discovery
Drug Development Outline
Intellectual Property
At the conclusion of this chapter, you should understand the different stages of development for a
drug. You should also know the difference between generic and branded drugs as well as the role of
patents in drug discovery.
2.1 Phenotype- and Target-Based Drug Discovery
Phenotype vs. target video
The video describes the hypothetical development of a drug for insomnia. At 2:30 the graphics
in the video refer to leaves with stimulant properties. In a phenotype-based approach to a drug
that treats insomnia, one would look for substances with hypnotic properties (not a stimulant).
Mixing target and phenotype
Background: In their traditional forms, target-based drug discovery tends to rely upon in vitro
testing for lead optimization, and phenotype-based drug discovery leans upon in vivo testing.
Instructions: Read the passage below on how phenotype-based drug discovery programs often
blend with target-based techniques.
Learning Goal: To understand that different approaches to drug discovery can frequently blur
together.

A strength for phenotype-based drug discovery is that the compounds of interest are known to be
active because their activity has already been observed in a living organism. The reliance on in vivo
testing, however, is a significant hindrance for phenotype-based drug discovery. The in vivo tests
are more involved and longer than in vitro tests, and the lead optimization process is slower as a
result.
A more ideal situation would be to start with a compound with known in vivo activity and the ability
to optimize its potency with quick in vitro screens. This ideal situation is a cross between
phenotype- and target-based drug discovery and most often begins with the phenotype model and
switches over to the target method.
The phenotype model begins with an observed effect in vivo. The compound that causes the effect
is the lead molecule. Instead of continuing the program with improving the lead with more in vivo
testing, the drug discovery group works to discover the protein to which the molecule binds in the
body. In other words, the discovery group seeks out the target responsible for the biological
activity. Once the target is known, a molecular biology group will attempt to develop a biochemical
binding assay to test the ability of a molecule to bind the target. Newly prepared compounds are
then tested with the rapid in vitro binding assay.
In this blended model, the discovery group can be more confident that the final molecule will have
activity in animals. Additionally, the improvement of the activity of the lead will be accelerated
because it is being accomplished with in vitro methods. When performed properly (not easy!), the
blended approach can combine the best of both drug development methods. Drug programs that
discover their leads through phenotype-based observations, regardless of how they later optimize
the lead, are typically categorized as phenotype-based discovery programs.
Support for phenotype-based drug discovery
Background: The topics of phenotype- and target-based drug discovery can be very divisive. Both
methods of drug development have very vocal supporters and detractors. There has recently been
a push for a renewed emphasis on phenotype-based methods.
Instructions: Read linked article from Science Business eXchange and answer the subsequent
questions.
Learning Goal: To gain an appreciation and understanding for phenotype-based drug discovery in a
medicinal chemistry course that will emphasize target-based drug discovery.
A recent article in Science Business eXchange discusses developments in phenotype-based drug
discovery. While the title of the article "Phenotypic screening, take two" implies that the article is

strongly in favor of phenotype-based drug discovery, the article actual advocates for a blend
between phenotype- and target-based methods.
Please return to the online course and read the article to which the above paragraph refers.
FAQ, help and tips
Phenotype vs. target video
What are the other approaches to drug discovery?
Target-based drug discovery and phenotype-based drug discovery are the two notable
approaches. There may be others, but they are rarely encountered.
Animal testing involves rats. What other animals are often used?
Mice, rats, rabbits, dogs, and monkeys are the most frequently encountered species in animal
studies.
If optimization in the phenotype approach is slow and time is money, then isn't the phenotype-
based approach actually more expensive than the target-based approach?
An advocate for phenotype-based discovery might counter that molecules discovered through a
phenotype approach have a better chance of becoming a drug because they have established
efficacy. Both methods have their proponents, and each method has its strengths.
Mixing target and phenotype
For the phenotype approach, having a starting molecule with activity seems like a major
limitation.
Finding a molecule with activity is a challenge, but researchers are getting better at it. The science
of developing phenotypic assays using cell and tissue cultures is improving. With such testing
methods, phenotypic screening is not exclusively limited to testing in animals.
How can you know that molecules discovered in a phenotypic screen does not have metabolism
problems or cause unwanted side effects?
Those are potential problems, but those problems are also found with compounds that are
discovered through a target-based approach.

How might herbal medicine research fit into the blended approach?
Research in herbal medicines fit nicely into a blended program. Many herbs have been used for
centuries for some therapeutic use. This is the observed activity. Some compound in the herb has
an effect. If the effect is known to be associated with a known target, then extracts from the herb
might be separated into individual molecules (or mixtures of molecules) and tested in an in vitro
assay for target activity. This route moves the program quickly into a target-based approach.
If no target is known, then the components in the herb may be tested on animals - mice or rats - in
order to determine which molecule in the herb causes the observed effect. Once identified, that
molecule might be tested against a range of known targets (in vitro) to see if it binds strongly to any
of them. This pathway blends more slowly into a target-based approach.
Have any drugs been discovered through the phenotypic approach, blended or otherwise?
Absolutely. Early drugs were all developed without target-based methods (in vitro
screening). Examples include penicillin and the benzodiazepines, including diazepam. Because the
renaissance of phenotype discovery is a fairly recent phenomenon, fewer new drugs have reached
the market in this manner. Arguably, one example is sildenafil (Viagra), which will be covered more
in a later chapter of the course.
2.2 Drug Discovery Outline
Drug discovery outline video
Phase I trials initially involve healthy volunteers, not patients. For more commentary on this
topic see the 2.2 FAQ, help, and tips unit.

The cost of doing business
Background: The total cost of bringing a drug to market is highly debated, but the most reliable
estimates seem to place the figure at around US$1 billion or higher.
Instructions: Read the following text concerning the costs of drug development as well as both the
risks and reasons for failure of a drug discovery program.
Learning Goal: To appreciate the costs and challenges that drug program faces at each stage of
development.
In 2010 a group from Eli Lilly analyzed recent financial data from 13 large pharmaceutical
companies. From this data set the researchers were able to determine the out-of-pocket costs for
each stage of drug development. The percentage breakdown is shown in the pie chart below.

Notice that the pre-clinical stages of drug discovery are considerably less than half of the overall cost
of drug development. Expenses grow quickly as a compound enters clinical trials. The high costs of
clinical trials reflect the high cost of healthcare. Subjects in a clinical trial must be closely monitored,
and the medical diagnostic tests can be very costly. Medical tests for subjects may range from
routine metabolic blood tests to more involved procedures such as CAT scans. The nature of the
required tests depends upon the therapeutic area of the drug candidate.
In general, the costs per subject tend to be highest in phase I, when patients are monitored
extremely closely for adverse events. Costs per subject tend to drop somewhat in phase II and even
further in phase III. The total cost of each phase follows the opposite trend. Phase III is highest, then
phase II, and finally phase I. The total costs reflect the fact that the number of subjects increases as
the drug candidate advances through the various trials.

The group from Lilly also analyzed the rate of failure of different stages of drug development. Their
findings are summarized in the bar graph below. The graph shows the percentage of compounds
that enter a stage of development and fail to advance past that stage.

Within the pharmaceutical industry, people frequently state that only 1 in 5 molecules tested in the
clinic will ever become a drug. The Lilly findings actually paint a much more grim picture. Ignoring
the preclinical phase, one can convert the data in the bar graph into a percent chance that a clinical
candidate (IND) will successfully become a new drug (successful NDA). For this calculation, one
must convert the failure percentages into success percentages (% success = 100% -% failure). The
success percentages for the different stages are...
phase I = 54%
phase II = 34%
phase III = 70%
NDA = 91%
If these success percentages are all multiplied together as fractions (0.54 0.34 0.70 0.91), the
result is 0.117, or an 11.7% overall success rate for an IND for becoming an approved drug. That is
corresponds to just 1 in 8.5 clinical candidates becoming a drug. The business of drug discovery is a
very expensive and risky endeavor.

Fail fast, fail cheap
Background: Most attempts to develop a drug end in failure and greatly reduce the financial viability
of the drug industry as a whole.
Instructions: Read the following text about the changes some in the pharmaceutical industry are
considering in order to increase the productivity of the industry as a whole. Keep in mind the
information on development costs and failure rates from the previous unit as you read through the
passage below.
Learning Goal: To gain exposure to emerging business trends within the drug industry.
A somewhat new phrase in the drug industry is "fail fast, fail cheap". This phrase is a response to
the realization that many molecules are advanced through the drug development process and falter
toward the end. Molecules that fail close to the end require large expenditures of resources and
never provide any return on the investment.
Reasons for failure of a clinical candidate can include efficacy, safety, and economic factors.
1
Drugs
that fail for efficacy reasons are either not effective at all or lack sufficient efficacy. Safety problems
could be related to toxicity in either animals or humans. Economic factors include a limited market
for a drug or low anticipated return on investment. For example, company A might pull the plug on
a drug candidate if company B successfully develops a highly effective competing drug. The
challenge for the fail fast, fail cheap philosophy is to understand if and/or how critical efficacy,
safety, and economic problems can be identified earlier in the development process so that
unsuccessful compounds can be identified quickly (fail fast) without draining resources (fail cheap).
According to the Lilly study noted in the previous unit,
2
one stage of clinical trials that stands out as
particularly troublesome for drug candidates is phase II. The failure rate for compounds advanced
into phase II is a staggering 66%. Phase II is the stage in which an IND's efficacy in humans is first
confirmed. Failure in phase II is therefore most closely aligned with efficacy problems, although
safety and economic problems can also appear during phase II.
The link between efficacy and the high failure rate of compounds is phase II is partially responsible
for the growing interest in phenotype-based approaches to drug discovery. Remember that
phenotypic assays place an emphasis on the effect of a drug over the ability of the drug to bind a

specific target. Presumably, by emphasizing the effect of a drug early in the discovery process will
lead to a higher success rate for INDs in phase II trials.
1. DiMasi, J. A. Risks in New Drug Development: Approval Success Rates for Investigational New
Drugs. Clin. Pharmacol. Ther. 2001, 69, 297-307.
2. Paul, S. M.; Mytelka, D. S.; Dunwiddie, C. T.; Persinger, C. C.; Munos, B. H.; Lindborg, S. R.;
Schacht, A. L. How to improve R&D productivity: the pharmaceutical industry's grand challenge.
Nat. Rev. Drug Discov. 2010, 9, 203-214.
FAQ, help and tips
Drug discovery outline video
Is there another place where one can learn more about the FDA's approval process?
Yes. The FDA maintains a very nice webpage that gives a simple, concise overview of the drug
review process.
Do phase I trials only include healthy volunteers as subjects?
No. Phase I trials are divided into two parts - phase Ia and Ib. Phase Ia studies are very small and
normally only involve healthy volunteers. During a phase Ia study, the sponsoring company learns
short-term toxicity information and can begin to understand the half-life and metabolism of the
drug in humans. In phase Ib, patients (not healthy) are used as subjects so researchers can
understand how the disease state affects short-term toxicity, half-life, and metabolism of the clinical
candidate.
In some instances, especially in the case of the development of highly toxic anticancer drugs,
patients are the subjects in phase Ia trials. Giving a healthy volunteer a highly toxic drug is generally
considered unethical, regardless of whether the volunteer is compensated for his time.
Are placebos used in clinical trials?
Yes. Clinical trials are generally (always?) controlled and double-blinded. In a controlled study,
some patients receive a placebo (sugar pill) instead of the clinical candidate. In this manner the
effect in a patient receiving the medication can be compared to the effect in a patient who did not
receive the medication.
So what is a blinded trial?
In a blinded trial, either the patient (single-blinded) or both the patient and healthcare staff (double-
blinded) do not know which patients receive the medication or which patients receive a

placebo. Blinding of the trials protects the integrity of the results. Of course, somebody must know
which patient receives which pill. All the dosing and medical information is encoded, and clinical
support staff work through the results outside the clinical to determine the effect of the medication.
Please clarify what an assay is.
An assay is a test that allows one to see the behavior of a molecule. The term behavior can be
anything - binding a target protein, killing bacteria in a petri dish, or reducing the size of a tumor in
mice. The behavior of the molecule should be linked somehow to the desired activity of the
molecule in humans.
The bacteria in a petri dish is a simple example. Compounds can be added to separate regions of a
petri dish that has been inoculated with bacteria. The bacteria are then given time to grow. If any
of the dishes show regions with no bacteria growth, then the compounds added to those regions
can be identified as having antibacterial activity.
Cellular assays like the bacterial example tend to be slower to perform than biochemical assays that
test for target binding. In the early 2000s a chemist at a major pharmaceutical company stated that
a good biochemical assay could be used to screen a million compounds within a week at a cost of
US$100,000.
How much can the size of different phase trials vary?
Lots and lots. The video says that a phase I trial might have 10 to 20 volunteers. That may be true,
but the number could be higher, perhaps up to 100. Furthermore, a given drug candidate will have
more than one phase I study. Thinking about the numbers of subjects as increasing by a factor of 10
across the trials (e.g., phase 1 = 10-20, phase 2 = 100-200, phase 3 = 1,000-2,000) is simply way to
sense the scale of each phase, but there is no firm rule on how many subjects are required. The
sponsoring company needs to include enough subjects to be confident that beneficial outcomes can
be measured in a statistically significant way.
The cost of doing business
How can the cost of clinical trials be reduced?
Clinical trials are expensive for two reasons. One is the number of patients involved. Two is the cost
of healthcare and monitoring of the patients. For the statistics of the data analysis to confirm the
safety and effectiveness of a drug candidate, the number of patients can be reduced only so
much. Therefore, meaningful cost cutting requires cutting the cost of patient monitoring.
In recent years, some pharmaceutical companies have explored conducting clinical trials in nations
with lower costs for healthcare. The results have reportedly been mixed because the data collected
in the study are sometimes unreliable.

How many drugs might a large pharmaceutical company launch each year?
The Lilly article projects that a large company might aim to launch 4 or 5 new drugs a year. At
current approval rates of 1 drug per 8.5 clinical candidates, a drug company would need to put
approximately 40 drugs into the clinic each year. Drug companies currently cannot sustain that pace
of generating new clinical candidates, and there is great concern across the industry that the stated
goal of producing new drugs cannot be met without some change in the drug discovery process.
If economics is such an important factor in drug discovery, how do drugs for rare diseases get
developed?
Drugs for rare diseases are sometimes developed under special circumstances. In the US, such
drugs fall under the FDA's Orphan Drug Act. By developing an orphan drug, the sponsoring company
is allowed to include fewer subjects in clinical trials (reducing costs) and to gain patent extensions
(improving potential profitability). Currently, insurance companies are agreeable to reimbursing
orphan drugs, especially those with life saving or life extending benefits, at a high rate. Therefore,
the drug company can set higher prices for the drug. Collectively, these factors can make orphan
drugs financially viable.
Do costs differ for traditional drugs (small molecules, orally delivered drugs) and biologics
(proteins)?
Small molecule drugs are the focal point of this course. The costs of developing small molecule
drugs does tend to be lower than biologics because the technology of small molecule drugs is more
simple. The technology of biologics also makes biologic drugs more difficult to replicate, so generic
manufactures tend to be slow gaining approval. This delay extends the profitability of biologics.
2.3 Intellectual Property
Patents and branding video

Composition of matter in action
Background: Patents are a type of intellectual property. While they are invaluable to the drug
industry for the exclusive rights they afford, patents are legally very complex.
Instructions: Read the passage below for one example of how the composition of matter patent is
used in the drug industry.
Learning Goal: To learn about composition of matter patents and crystal polymorphs.
Crystalline Polymorphs of Ranitidine
1

Drugs are normally protected with a composition of matter patent. Surprisingly, some drugs require
multiple different composition of matter patents. Multiple patents are needed when a drug exists in
multiple, different crystalline forms. These different forms are called polymorphs.
In polymorphs the same molecule can pack together in different orientations and patterns. Each
pattern is a different polymorph. A simple example of polymorphs can be found with bricks, which
can be stacked in various patterns as pavers. A few patterns are shown below. Molecules can stack
in different patterns in much the same fashion.

Because polymorphs can have different physical properties (e.g., solubility and melting point), a
drug company must be able to control which polymorph of a drug is being synthesized.
Ranitidine (1) is a drug that treats acid reflux. In 1978 Glaxo, the discoverer of ranitidine, obtained a
composition of matter patent on the compound. At the time, the term of patents was 17 years from
the date of issue. Therefore, Glaxo's patent on ranitidine was set to expire in 1995, or 17 years after
1978.

As Glaxo continued to research ranitidine, a second polymorph was discovered. Glaxo obtained a
composition of matter patent on the second polymorph, called Form 2, in 1985. The Form 2 patent
would expire in 2002.
Glaxo ultimately marketed ranitidine as Form 2 under the name of Zantac. During the 1980s Zantac
was a blockbuster drug, and its success continued into the 1990s.
Around 1990 a company called Novopharm, a generic drug manufacturer, started to develop a
generic form of ranitidine. Novopharm hoped to capitalize on Form 1 of ranitidine because the
patent on Form 1 would expire in 1995. During their research, chemists at Novopharm tried to
make the original, Form 1 polymorph of ranitidine based on the Glaxo procedures. To their surprise,
the Novopharm chemists could only prepare Form 2. Novopharm reasoned that if Form 2 was
known all the way back in 1978 in the first work on ranitidine, then the 1985 Form 2 patent was not
valid. Novopharm pushed ahead and applied to the FDA to market generic ranitidine in 1995,
corresponding to the expiration of the Form 1 (perhaps Form 2) patent.
Glaxo then sued Novopharm for planning to market ranitidine's Form 2, on which Glaxo held a
patent until 2002. A third-party lab was called in to prepare Form 1 of ranitidine from Glaxo's 1978
Form 1 patent. The lab successfully reproduced the procedure to make Form 1, and Glaxo won the
case.
Novopharm went back to work and managed to reproduce the Form 1 procedure. Novopharm then
filed paperwork with the FDA to market generic ranitidine (Form 1) starting in 1995, the year of
expiration of Glaxo's Form 1 patent.
Glaxo again sued Novopharm. This time, Glaxo claimed that Novopharm's Form 1 of ranitidine likely
contained impurities of Form 2. If so, then marketing this mixture would violate Glaxo's exclusive
rights to Form 2. Novopharm provided evidence that their ranitidine was free of Form 2, and
Novopharm won the case.
1. Bernstein, J. Polymorphism and Patents from a Chemist's Point of View. In Hilfiker, R. (Ed.)
Polymorphism: In the Pharmaceutical Industry. Weinheim, Germany: Wiley-VCH, 2006, Chapter
14.

Patent legalese
Background: Patents are a vital means that pharmaceutical companies use to protect their
inventions.
Instructions: Read the passage concerning one of the early patents for celecoxib.
Learning Goals: To appreciate the extreme degree to which the legal language of patents both
discloses and obscures an invention.
Celecoxib, sold under the brand name Celebrex, is an analgesic and anti-inflammatory. Celecoxib is
the first example of a COX-2 inhibitor, a class of drug that was hoped to provide patients with a safe
option for long-term pain management. While COX-2 inhibitors have been found to carry long-term
risks and some have been withdrawn from the market, celecoxib continues to be a widely
prescribed drug for pain relief.

The first composition of matter patent from the development of celecoxib appeared in the middle
1990s. A portion of the description of the invention of the patent is shown below. This passage
broadly lists the types of compounds covered in the patent. The patent covers very many potential
R-groups on a core scaffold (I). Only one combination of R-groups (bolded in the text) corresponds
to celecoxib. Additional comments have been added within brackets.

A class of compounds useful in treating inflammation-related disorders is defined by Formula I:
wherein R
1
is selected from sulfamyl [SO2NH2], halo, alkyl, alkoxy, hydroxyl and haloalkyl;
wherein R
2
is selected from hydrido, halo, haloalkyl [CF3 - trifluoromethyl], cyano, nitro, formyl,
carboxyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino, cyanoamidino, amido, alkoxy,
amidoalkyl, N-monoalkylamido, N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido,
alkylcarbonyl, alkylcarbonylalkyl, hydroxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, N-alkylsulfamyl,
N-arylsulfamyl, arylsulfonyl, N,N-dialkylsulfamyl, N-alkyl-N-arylsulfamyl and heterocyclic;
wherein R
3
is selected from hydrido [H], halo, haloalkyl, cyano, nitro, formyl, carboxyl,
alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino, cyanoamidino, amido, alkoxy,
amidoalkyl, N-monoalkylamido, N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido,
alkylcarbonyl, alkylcarbonylalkyl, hydroxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, N-alkylsulfamyl,

N-arylsulfamyl, arylsulfonyl, N,N-dialkylsulfamyl, N-alkyl-N-arylsulfamyl, heterocyclic,
heterocycloalkyl and aralkyl;
wherein R
4
is selected from aryl [phenyl - a benzene ring], cycloalkyl, cycloalkenyl and heterocyclic;
wherein R
4
is optionally substituted at a substitutable position with one or more radicals selected
from halo, alkylthio, alkylsulfinyl, alkyl [CH3 - methyl], alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl,
amido, N-monoalkylamido, N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, haloalkyl,
hydroxyl, alkoxy hydroxyalkyl haloalkoxy, sulfamyl, N-alkylsulfamyl, amino, N-alkylamino, N,N-
dialkylamino, heterocyclic, nitro and acylamino;
The excerpt from the celecoxib patent is just one short passage from approximately ten pages of
similar text. Each page covers potentially thousands of different molecules.
Why do patents of this type list so many different compounds? Listing a large number of R-groups
allows two things to happen. First, the patent can cover many compounds. Keep in mind that this
patent was around the time that celecoxib was a lead compound. Whether celecoxib would become
a drug was unknown. Other promising leads that did not become drugs are possibly part of this
patent. Second, by including a variety of R-groups in the patent, the company can prevent another
company from launching a very similar compound as a competing drug.
Patent practice
Background: Composition of matter patents typically cover a large number of molecular structures
in a very characteristic language.
Instructions: Read the excerpt from a 1995 patent for celecoxib and answer the questions that
follow.
Learning Goals: To gain practice working through the chemical structures as they are disclosed in
patents.
From a 1995 patent that covers the structure of celecoxib. The text has been modified slightly for
the purposes of this exercise.

A fourth preferred class of compounds consists of those compounds of Formula I
wherein R
1
is selected from fluoro, chloro, bromo, fluoromethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichloropropyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl,

dichloroethyl, methyl, ethyl, propyl, hydroxyl, methoxy, ethoxy, propoxy and n-butoxy;
wherein R
2
is selected from fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
difluoroethyl, dichlorofluoromethyl, difluoropropyl, dichloroethyl and dichloropropyl;
wherein R
3
is hydrido; and
wherein R
4
is phenyl substituted at a substitutable position with sulfamyl; or a pharmaceutically-
acceptable salt thereof.
FAQ, help and tips
Patents and branding video
What is a world patent?
A world or global patent does not exist. Patents are issued by individual nations. Companies can
simultaneously apply for patents in multiple nations through the Patent Cooperation Treaty
(PCT). Because most pharmaceuticals are intended to be marketed in many parts of the world, most
drug companies take advantage of the PCT application process. Virtually all nations with significant
drug markets are members of the PCT. The World Intellectual Property Organization maintains a list
of non-member nations.
If generic drugs are profitable, then drug companies should make generics.
The term drug company includes manufactures of both branded and generic drugs. Larger
pharmaceutical companies are most closely associated with branded drugs, but they do work in
generic drugs too. Under current law in the United States, the first generic manufacturer with an
approved generic formulation receives a six-month window of market exclusivity. During that six-
month window, only the branded manufacturer and approved generic manufacturer may sell the
drug. Because competition is limited, the price of the generic drug is often not much lower than the
branded drug. Profitability for both the branded and generic drugs are high during this
period. After the exclusivity window has expired, other generic drugs enter the market, and prices
drop quickly.
As the profits of branded drug manufacturers have been decreased in recent years, larger drug
companies are seeking additional sources of revenue. Capitalizing on generic profits is one potential
source.
Why don't drug companies wait later to file patents on drug candidates?

Drug companies normally apply for patents around the preclinical stage so that another drug
company cannot stumble across the same idea and file for its own patents. Drug companies often
work in the same therapeutic areas, and competition can be fierce.
I have heard of the Hatch-Waxman Act. What is it?
The Hatch-Waxman Act, or more properly the Drug Price Competition and Patent Term Restoration
Act of 1983, was a piece of legislation in the United States that created new procedures for the
approval and handling of generic drugs. As the law was perceived as a benefit to generic
manufacturers, branded manufacturers opposed the legislation and fought for concessions. The law
therefore has clauses that allow branded manufactures to extend their patent terms to offset lost
time for clinical trials and the NDA.
As a law of the United States, the patent effects of the Hatch-Waxman Act only pertain to United
States patents. The European Union nations have similar patent considerations in the form of the
supplementary protection certificate (SPC).
Composition of matter in action
Ritonavir is another drug with a surprising polymorph story?
The story of ritonavir and its polymorphs can be found on Wikipedia. Scroll down to the
"Polymorphism and temporary market withdrawal" heading.

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