Week 1 DavidsonX D001x Medicinal Chemistry Weekly Summary

7/27/2019 Week 1 DavidsonX D001x Medicinal Chemistry Weekly Summary

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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 summarypage.



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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. Opiatesare 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.


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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 Medicineconcerning 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.

Arecent articlein 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.
http://www.biomedcentral.com/1741-7015/11/222http://www.biomedcentral.com/1741-7015/11/222http://www.biomedcentral.com/1741-7015/11/222http://www.biomedcentral.com/1741-7015/11/222


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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

butstill availablefrom various places online.

Why is a vasoconstrictor a decongestant?

Vasoconstrictors cause blood vessels to shrink and reduce inflammation and drainage in nasaltissues.

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, adverseevent, 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 thatlists examples of serious adverse effects.

A side effect is anyunintended 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. TheWikipedia entry on alkaloidsshows a number of examples, many of which

violate the guidelines listed here.
http://www.amazon.com/Prototypes-Their-Exploitation-Walter-Sneader/dp/0471948470http://www.amazon.com/Prototypes-Their-Exploitation-Walter-Sneader/dp/0471948470http://www.amazon.com/Prototypes-Their-Exploitation-Walter-Sneader/dp/0471948470http://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htmhttp://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htmhttp://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htmhttp://en.wikipedia.org/wiki/Alkaloidhttp://en.wikipedia.org/wiki/Alkaloidhttp://en.wikipedia.org/wiki/Alkaloidhttp://en.wikipedia.org/wiki/Alkaloidhttp://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htmhttp://www.amazon.com/Prototypes-Their-Exploitation-Walter-Sneader/dp/0471948470


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Another drug with a tragic story is thalidomide.

The story of thalidomide is well documented. Theaccount on Wikipediais 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 isNapoleon's Buttons: How 17 Molecules Changed Historyby 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 keyfunctional 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
http://en.wikipedia.org/wiki/Thalidomidehttp://en.wikipedia.org/wiki/Thalidomidehttp://en.wikipedia.org/wiki/Thalidomidehttp://en.wikipedia.org/wiki/Dexfenfluraminehttp://en.wikipedia.org/wiki/Dexfenfluraminehttp://en.wikipedia.org/wiki/Dexfenfluraminehttp://www.amazon.com/Napoleons-Buttons-Molecules-Changed-History/dp/1585423319http://www.amazon.com/Napoleons-Buttons-Molecules-Changed-History/dp/1585423319http://www.amazon.com/Napoleons-Buttons-Molecules-Changed-History/dp/1585423319http://www.amazon.com/Napoleons-Buttons-Molecules-Changed-History/dp/1585423319http://www.amazon.com/Napoleons-Buttons-Molecules-Changed-History/dp/1585423319http://www.amazon.com/Napoleons-Buttons-Molecules-Changed-History/dp/1585423319http://www.amazon.com/Napoleons-Buttons-Molecules-Changed-History/dp/1585423319http://en.wikipedia.org/wiki/Dexfenfluraminehttp://en.wikipedia.org/wiki/Thalidomide


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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 anabstract- full text is not freely available). Some methods are even based onbrain 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 notselling 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.
http://www.ncbi.nlm.nih.gov/pubmed/11465562http://www.ncbi.nlm.nih.gov/pubmed/11465562http://www.ncbi.nlm.nih.gov/pubmed/11465562http://www.ncbi.nlm.nih.gov/pubmed/11465562http://www.plosone.org/article/info%3adoi/10.1371/journal.pone.0024124http://www.plosone.org/article/info%3adoi/10.1371/journal.pone.0024124http://www.plosone.org/article/info%3adoi/10.1371/journal.pone.0024124http://www.plosone.org/article/info%3adoi/10.1371/journal.pone.0024124http://www.ncbi.nlm.nih.gov/pubmed/11465562http://www.ncbi.nlm.nih.gov/pubmed/11465562


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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 canconfidently 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


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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.




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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 tipsSulfa drugs video

Are sulfa drugs antibiotics?

The term antibioticoriginally 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 antiparasiticactivity. 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.


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TheHeads of Medicines Agency,a European medical organization, haspublished 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 thechlorine 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 thatwomen 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).

http://www.hma.eu/http://www.hma.eu/http://www.hma.eu/http://www.hma.eu/fileadmin/dateien/Veterinary_medicines/00-HMA_Vet/02-HMA_Task_Force/03_HMA_vet_TF_AMR/2012_11_HMA_agreed_AB_AM_definitions.pdfhttp://www.hma.eu/fileadmin/dateien/Veterinary_medicines/00-HMA_Vet/02-HMA_Task_Force/03_HMA_vet_TF_AMR/2012_11_HMA_agreed_AB_AM_definitions.pdfhttp://www.hma.eu/fileadmin/dateien/Veterinary_medicines/00-HMA_Vet/02-HMA_Task_Force/03_HMA_vet_TF_AMR/2012_11_HMA_agreed_AB_AM_definitions.pdfhttp://www.nih.gov/news/health/feb2014/nci-06.htmhttp://www.nih.gov/news/health/feb2014/nci-06.htmhttp://www.nih.gov/news/health/feb2014/nci-06.htmhttp://www.nih.gov/news/health/feb2014/nci-06.htmhttp://www.nih.gov/news/health/feb2014/nci-06.htmhttp://www.nih.gov/news/health/feb2014/nci-06.htmhttp://www.hma.eu/fileadmin/dateien/Veterinary_medicines/00-HMA_Vet/02-HMA_Task_Force/03_HMA_vet_TF_AMR/2012_11_HMA_agreed_AB_AM_definitions.pdfhttp://www.hma.eu/


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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 Organizationand 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 thelinked bulletinfrom 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.
http://www.who.int/bulletin/volumes/86/10/07-049965/en/http://www.who.int/bulletin/volumes/86/10/07-049965/en/http://www.who.int/bulletin/volumes/86/10/07-049965/en/http://www.who.int/bulletin/volumes/86/10/07-049965/en/


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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 Googledoes have acached 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.

http://webcache.googleusercontent.com/search?q=cache:yqAcZSHiPUMJ:www.fda.gov/downloads/aboutfda/centersoffices/oc/globalproductpathway/ucm259845.pdf+&cd=1&hl=en&ct=clnk&gl=us&client=firefox-ahttp://webcache.googleusercontent.com/search?q=cache:yqAcZSHiPUMJ:www.fda.gov/downloads/aboutfda/centersoffices/oc/globalproductpathway/ucm259845.pdf+&cd=1&hl=en&ct=clnk&gl=us&client=firefox-ahttp://webcache.googleusercontent.com/search?q=cache:yqAcZSHiPUMJ:www.fda.gov/downloads/aboutfda/centersoffices/oc/globalproductpathway/ucm259845.pdf+&cd=1&hl=en&ct=clnk&gl=us&client=firefox-ahttp://webcache.googleusercontent.com/search?q=cache:yqAcZSHiPUMJ:www.fda.gov/downloads/aboutfda/centersoffices/oc/globalproductpathway/ucm259845.pdf+&cd=1&hl=en&ct=clnk&gl=us&client=firefox-a


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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 stimulantproperties. In a phenotype-based approach to a drug

that treats insomnia, one would look for substances with hypnoticproperties (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.


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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 thebody. 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 eXchangeand 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.

Arecent articlein Science Business eXchangediscusses developments in phenotype-based drug

discovery. While the title of the article "Phenotypic screening, take two" implies that the article is
http://www.nature.com/scibx/journal/v5/n15/full/scibx.2012.380.htmlhttp://www.nature.com/scibx/journal/v5/n15/full/scibx.2012.380.htmlhttp://www.nature.com/scibx/journal/v5/n15/full/scibx.2012.380.htmlhttp://www.nature.com/scibx/journal/v5/n15/full/scibx.2012.380.html


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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 notableapproaches. 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.


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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 hasan 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.




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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 Lillyanalyzed recent financial datafrom 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.
http://www.nature.com/nrd/journal/v9/n3/full/nrd3078.htmlhttp://www.nature.com/nrd/journal/v9/n3/full/nrd3078.htmlhttp://www.nature.com/nrd/journal/v9/n3/full/nrd3078.htmlhttp://www.nature.com/nrd/journal/v9/n3/full/nrd3078.html


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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 avery expensive and risky endeavor.



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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.1Drugs

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,2one 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


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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 NewDrugs. 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 nicewebpage that gives a simple, concise overviewof 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

normallyonly 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
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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 behaviorcan 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 costof 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.


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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 putapproximately 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'sOrphan 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 genericmanufactures tend to be slow gaining approval. This delay extends the profitability of biologics.


2.3 Intellectual Property

Patents and branding video



http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/significantamendmentstothefdcact/orphandrugact/default.htmhttp://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/significantamendmentstothefdcact/orphandrugact/default.htmhttp://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/significantamendmentstothefdcact/orphandrugact/default.htmhttp://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/significantamendmentstothefdcact/orphandrugact/default.htm


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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 Ranitidine1

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 acomposition 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.


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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.



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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 inventionof 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) correspondsto celecoxib. Additional comments have been added within brackets.

A class of compounds useful in treating inflammation-related disorders is defined by Formula I:

wherein R1is selected from sulfamyl[SO2NH2], halo, alkyl, alkoxy, hydroxyl and haloalkyl;

wherein R2is 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 R3is 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,


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N-arylsulfamyl, arylsulfonyl, N,N-dialkylsulfamyl, N-alkyl-N-arylsulfamyl, heterocyclic,

heterocycloalkyl and aralkyl;

wherein R4is selected from aryl[phenyl - a benzene ring], cycloalkyl, cycloalkenyl and heterocyclic;

wherein R4is 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 thispatent 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 R1is selected from fluoro, chloro, bromo, fluoromethyl, difluoromethyl, trifluoromethyl,

chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,

difluorochloromethyl, dichloropropyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl,


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dichloroethyl, methyl, ethyl, propyl, hydroxyl, methoxy, ethoxy, propoxy and n-butoxy;

wherein R2is selected from fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,

dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,

difluoroethyl, dichlorofluoromethyl, difluoropropyl, dichloroethyl and dichloropropyl;

wherein R3is hydrido; and

wherein R4is phenyl substituted at a substitutable position with sulfamyl; or a pharmaceutically-

acceptable salt thereof.



FAQ, help and tips

Patents and branding videoWhat 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 maintainsa list

of non-member nations.

If generic drugs are profitable, then drug companies should make generics.

The term drug companyincludes 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?
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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?

Thestory of ritonavir and its polymorphscan be found on Wikipedia. Scroll down to the

"Polymorphism and temporary market withdrawal" heading.

http://en.wikipedia.org/wiki/Supplementary_protection_certificatehttp://en.wikipedia.org/wiki/Supplementary_protection_certificatehttp://en.wikipedia.org/wiki/Ritonavirhttp://en.wikipedia.org/wiki/Ritonavirhttp://en.wikipedia.org/wiki/Ritonavirhttp://en.wikipedia.org/wiki/Ritonavirhttp://en.wikipedia.org/wiki/Supplementary_protection_certificate

Documents

Week 1 DavidsonX D001x Medicinal Chemistry Weekly Summary