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 OPTIONAL-Please participate in the online discussion forum.

Chapter 1 - Pre-Regulatory Medicine Introduction to Chapter 1 Chapter 1 contains three subsections. 

Natural Products

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Synthetic Drugs

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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. OPTIONAL-Please OPTIONAL-Please participate in the online discussion forum.

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.  page. OPTIONAL-Please OPTIONAL-Please participate in the online discussion forum.

Pharmacophores in drugs Background : The phenethylamine compounds mentioned in the video are relatively small structures

with an easily identified pharmacophore. 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. 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 o nly 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. OPTIONAL-Please participate in the online discussion forum.

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.

Please complete the online exercise. OPTIONAL-Please participate in the online discussion forum.

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. OPTIONAL-Please participate in the online discussion forum.

1.2 Synthetic Drugs Sulfa drugs video Please watch the online video (6 minutes, 23 seconds). Clarifications and corrections

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. A condensed summary of this video can be found in the Video summary  page. OPTIONAL-Please participate in the online discussion forum.

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.

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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.

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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.

OPTIONAL-Please participate in the online discussion forum.

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.

Please complete the online exercise. OPTIONAL-Please participate in the online discussion forum.

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.

Please complete the online exercise. OPTIONAL-Please participate in the online discussion forum.

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).

OPTIONAL-Please participate in the online discussion forum.

1.3 Need for Regulation Elixir Sulfanilamide tragedy video Please watch the online video (7 minutes, 33 seconds). A condensed summary of this video can be found in the Video summary  page. OPTIONAL-Please participate in the online discussion forum.

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. Please complete the online exercise. OPTIONAL-Please participate in the online discussion forum.

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. OPTIONAL-Please participate in the online discussion forum.

Chapter 2 - Drug Discovery: From Concept to Market Introduction to Chapter 2 Chapter 2 contains three subsections. 

Phenotype- vs. Target-Based Drug Discovery

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Drug Development Outline

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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. OPTIONAL-Please participate in the online discussion forum.

2.1 Phenotype- and Target-Based Drug Discovery Phenotype vs. target video Please watch the online video (6 minutes, 20 seconds). Clarifications and corrections

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). A condensed summary of this video can be found in the Video summary  page. OPTIONAL-Please participate in the online discussion forum.

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. OPTIONAL-Please participate in the online discussion forum.

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. Please complete the online exercise. OPTIONAL-Please participate in the online discussion forum.

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 phenotypebased 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. OPTIONAL-Please participate in the online discussion forum.

2.2 Drug Discovery Outline Drug discovery outline video Please watch the online video (8 minutes 22 seconds). Clarifications and corrections

Phase I trials initially involve healthy volunteers, not patients. For more commentary on this topic see the 2.2 FAQ, help, and tips unit. A condensed summary of this video can be found in the Video summary  page. OPTIONAL-Please participate in the online discussion forum.

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%

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phase II = 34%

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phase III = 70%

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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. OPTIONAL-Please participate in the online discussion forum.

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. OPTIONAL-Please participate in the online discussion forum.

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 (doubleblinded) 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. OPTIONAL-Please participate in the online discussion forum.

2.3 Intellectual Property Patents and branding video Please watch the online video (7 minutes 17 seconds). A condensed summary of this video can be found in the Video summary  page. OPTIONAL-Please participate in the online discussion forum.

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 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. OPTIONAL-Please participate in the online discussion forum.

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 R1 is selected from sulfamyl  [SO2NH2], halo, alkyl, alkoxy, hydroxyl and haloalkyl; wherein R2 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 R3 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 R4 is selected from aryl [phenyl - a benzene ring], cycloalkyl, cycloalkenyl and heterocyclic; wherein R4 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,Ndialkylamino, 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. OPTIONAL-Please participate in the online discussion forum.

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 R1 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 R2 is selected from fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, difluoroethyl, dichlorofluoromethyl, difluoropropyl, dichloroethyl and dichloropropyl; wherein R3 is hydrido; and wherein R4 is phenyl substituted at a substitutable position with sulfamyl; or a pharmaceuticallyacceptable salt thereof. Please complete the online exercise. OPTIONAL-Please participate in the online discussion forum.

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 sixmonth 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. OPTIONAL-Please participate in the online discussion forum.