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This medical PowerPoint presentation is about drug discovery and development, a complex and multi-stage process of creating new medications to treat diseases or improve health outcomes. The process involves various steps, including target identification, lead identification, lead optimization, preclinical testing, clinical trials, and regulatory approval.

The first stage of drug discovery is target identification, where researchers identify a specific molecular target that can be manipulated to treat a disease. This can involve a range of approaches, such as screening large libraries of compounds or studying disease mechanisms at the molecular level.

Once a potential target has been identified, researchers move on to lead identification, where they identify compounds that can interact with the target and potentially have a therapeutic effect. This involves screening large numbers of compounds to find those that have the desired activity.

The next step is lead optimization, where researchers refine the structure of the lead compounds to improve their potency, selectivity, and safety. This involves iterative cycles of chemical synthesis, testing, and optimization.

After lead optimization, the lead compounds undergo preclinical testing to assess their safety and efficacy in animal models. This involves rigorous testing to evaluate pharmacokinetics, toxicity, and other important parameters.

If a compound successfully passes preclinical testing, it can move on to clinical trials, which involve testing in humans. Clinical trials are conducted in three phases, each of which involves testing the drug in larger groups of people to evaluate safety and efficacy.

Finally, if the drug successfully passes clinical trials, it can be submitted for regulatory approval. Regulatory agencies such as the FDA or EMA evaluate the safety and efficacy data to determine if the drug can be approved for use in the general population.

Overall, drug discovery and development is a highly complex and challenging process that requires a range of scientific expertise and resources. Despite the challenges, the development of new drugs is essential for improving human health and treating a wide range of diseases.

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Published on : Jun 23, 2023 | Views : 1400 | Downloads : 2

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Slide 1-

Drug Discovery and Development How are drugs discovered and developed?
Slide 2-

Choose a disease Choose a drug target Identify a “bioassay” bioassay = A test used to determine biological activity.
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Find a “lead compound” “lead compound” = structure that has some activity against the chosen target, but not yet good enough to be the drug itself. If not known, determine the structure of the “lead compound”
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Synthesize analogs of the lead Identify Structure-Activity-Relationships (SAR’s) Synthesize analogs of the lead Identify Structure-Activity-Relationships (SAR’s)
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Identify the “pharmacophore” pharmacophore = the structural features directly responsible for activity Optimize structure to improve interactions with target
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Determine toxicity and efficacy in animal models.
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Determine pharmacodynamics and pharmacokinetics of the drug. Pharmacodynamics explores what a drug does to the body, whereas pharmacokinetics explores what the body does to the drug.
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Patent the drug Continue to study drug metabolism Continue to test for toxicity
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Design a manufacturing process Carry out clinical trials Market the drug
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Choosing a Disease Pharmaceutical companies are commercial enterprises Pharmaceutical companies will, therefore, tend to avoid products with a small market (i.e. a disease which only affects a small subset of the population)
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Choosing a Disease Pharmaceutical companies will also avoid products that would be consumed by individuals of lower economic status (i.e. a disease which only affects third world countries)
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Choosing a Disease (cont.) Most research is carried out on diseases which afflict “first world” countries: (e.g. cancer, cardiovascular diseases, depression, diabetes, flu, migraine, obesity).
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The Orphan Drug Act The Orphan Drug Act of 1983 was passed to encourage pharmaceutical companies to develop drugs to treat diseases which affect fewer than 200,000 people in the US
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Under this law, companies who develop such a drug are entitled to market it without competition for seven years. This is considered a significant benefit, since the standards for patent protection are much more stringent.
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Identifying a Drug Target Drug Target = specific macromolecule, or biological system, which the drug will interact with Sometimes this can happen through incidental observation…
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Identifying a Drug Target (cont.) Example: In addition to their being able to inhibit the uptake of noradrenaline, the older tricyclic antidepressants were observed to “incidentally” inhibit serotonin uptake. Thus, it was decided to prepare molecules which could specifically inhibit serotonin uptake. It wasn’t clear that this would work, but it eventually resulted in the production of fluoxetine (Prozac).
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The mapping of the human genome should help! In the past, many medicines (and lead compounds) were isolated from plant sources. Since plants did not evolve with human beings in mind, the fact that they posses chemicals which results in effects on humans is incidental.
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Having the genetic code for the production of an enzyme or a receptor may enable us to over-express that protein and determine its structure and biological function. If it is deemed important to the disease process, inhibitors (of enzymes), or antagonists or agonists of the receptors can be prepared through a process called rational drug design.
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Simultaneously, Chemistry is Improving! This is necessary, since, ultimately, plants and natural sources are not likely to provide the cures to all diseases. In a process called “combinatorial chemistry” large numbers of compounds can be prepared at one time. The efficiency of synthetic chemical transformations is improving.
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Selectivity is Important! e.g. targeting a bacterial enzyme, which is not present in mammals, or which has significant structural differences from the corresponding enzyme in mammals
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The Standards are Being Raised More is known about the biological chemistry of living systems For example: Targeting one subtype of receptor may enable the pharmaceutical chemist to avoid potentially troublesome side effects.
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Problems can arise Example: The chosen target, may over time, lose its sensitivity to the drug Example: The penicillin-binding-protein (PBP) known to the the primary target of penicillin in the bacterial species Staphylococcus aureus has evolved a mutant form that no longer recognizes penicillin.
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Choosing the Bioassay Definitions: In vitro: In an artificial environment, as in a test tube or culture media In vivo: In the living body, referring to tests conductedin living animals Ex vivo: Usually refers to doing the test on a tissue taken from a living organism.
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Choosing the Bioassay (cont.) In vitro testing Has advantages in terms of speed and requires relatively small amounts of compound Speed may be increased to the point where it is possible to analyze several hundred compounds in a single day (high throughput screening) Results may not translate to living animals
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Choosing the Bioassay (cont.) In vivo tests More expensive May cause suffering to animals Results may be clouded by interference with other biological systems
Slide 26-

Finding the Lead Screening Natural Products Plants, microbes, the marine world, and animals, all provide a rich source of structurally complex natural products.
Slide 27-

It is necessary to have a quick assay for the desired biological activity and to be able to separate the bioactive compound from the other inactive substances Lastly, a structural determination will need to be made
Slide 28-

Finding the Lead (cont.) Screening synthetic banks Pharmaceutical companies have prepared thousands of compounds These are stored (in the freezer!), cataloged and screened on new targets as these new targets are identified
Slide 29-

Finding the Lead (cont.) Using Someone Else’s Lead Design structure which is similar to existing lead, but different enough to avoid patent restrictions. Sometimes this can lead to dramatic improvements in biological activity and pharmacokinetic profile. (e.g. modern penicillins are much better drugs than original discovery).
Slide 30-

Finding the Lead (cont.) Enhance a side effect
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Use structural similarity to a natural ligand
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Computer-Assisted Drug Design If one knows the precise molecular structure of the target (enzyme or receptor), then one can use a computer to design a perfectly-fitting ligand. Drawbacks: Most commercially available programs do not allow conformational movement in the target (as the ligand is being designed and/or docked into the active site). Thus, most programs are somewhat inaccurate representations of reality.
Slide 33-

Serendipity: a chance occurrence Must be accompanied by an experimentalist who understands the “big picture” (and is not solely focused on his/her immediate research goal), who has an open mind toward unexpected results, and who has the ability to use deductive logic in the explanation of such results. Example: Penicillin discovery Example: development of Viagra to treat erectile dysfunction
Slide 34-

Finding a Lead (cont.) Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizer's Sandwich, Kent research facility in England. It was initially studied for use in hypertension (high blood pressure) and angina pectoris (a form of ischaemic cardiovascular disease). Phase I clinical trials under the direction of Ian Osterloh suggested that the drug had little effect on angina, but that it could induce marked penile erections.
Slide 35-

Pfizer therefore decided to market it for erectile dysfunction, rather than for angina. The drug was patented in 1996, approved for use in erectile dysfunction by the Food and Drug Administration on March 27, 1998, becoming the first pill approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year. It soon became a great success: annual sales of Viagra in the period 1999–2001 exceeded $1 billion.
Slide 36-

Finding a Lead (cont.)
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Structure-Activity-Relationships (SAR’s) Once a lead has been discovered, it is important to understand precisely which structural features are responsible for its biological activity (i.e. to identify the “pharmacophore”)
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The pharmacophore is the precise section of the molecule that is responsible for biological activity
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This may enable one to prepare a more active molecule This may allow the elimination of “excessive” functionality, thus reducing the toxicity and cost of production of the active material This can be done through synthetic modifications Example: R-OH can be converted to R-OCH3 to see if O-H is involved in an important interaction Example: R-NH2 can be converted to R-NH-COR’ to see if interaction with positive charge on protonated amine is an important interaction
Slide 42-

Link
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Next step: Improve Pharmacokinetic Properties Improve pharmacokinetic properties.pharmacokinetic = The study of absorption, distribution, metabolism and excretion of a drug (ADME). Video exercise=MedicationDistribution&title=Medication%20Absorption,%20Distribution,%20Metabolism%20and%20Excretion%20Animation&publication_ID=2450
Slide 44-

Metabolism of Drugs The body regards drugs as foreign substances, not produced naturally. Sometimes such substances are referred to as “xenobiotics” Body has “goal” of removing such xenobiotics from system by excretion in the urine The kidney is set up to allow polar substances to escape in the urine, so the body tries to chemically transform the drugs into more polar structures.
Slide 45-

Metabolism of Drugs (cont.) Phase 1 Metabolism involves the conversion of nonpolar bonds (eg C-H bonds) to more polar bonds (eg C-OH bonds). A key enzyme is the cytochrome P450 system, which catalyzes this reaction: RH + O2 + 2H+ + 2e– → ROH + H2O
Slide 46-

Mechanism of Cytochrome P450
Slide 47-

Phase I metabolism may either detoxify or toxify. Phase I reactions produce a more polar molecule that is easier to eliminate. Phase I reactions can sometimes result in a substance more toxic than the originally ingested substance. An example is the Phase I metabolism of acetonitrile
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Slide 50-

The Liver Oral administration frequently brings the drugs (via the portal system) to the liver
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Metabolism of Drugs (cont.) Phase II metabolism links the drug to still more polar molecules to render them even more easy to excrete
Slide 52-

Metabolism of Drugs (cont.) Another Phase II reaction is sulfation (shown below)
Slide 53-

Phase II Metabolism Phase II reactions most commonly detoxify Phase II reactions usually occur at polar sites, like COOH, OH, etc.
Slide 54-

Manufacture of Drugs Pharmaceutical companies must make a profit to continue to exist Therefore, drugs must be sold at a profit One must have readily available, inexpensive starting materials One must have an efficient synthetic route to the compound As few steps as possible Inexpensive reagents
Slide 55-

The route must be suitable to the “scale up” needed for the production of at least tens of kilograms of final product This may limit the structural complexity and/or ultimate size (i.e. mw) of the final product In some cases, it may be useful to design microbial processes which produce highly functional, advanced intermediates. This type of process usually is more efficient than trying to prepare the same intermediate using synthetic methodology.
Slide 56-

Toxicity Toxicity standards are continually becoming tougher Must use in vivo (i.e. animal) testing to screen for toxicity Each animal is slightly different, with different metabolic systems, etc. Thus a drug may be toxic to one species and not to another
Slide 57-

Example: Thalidomide Thalidomide was developed by German pharmaceutical company Grünenthal. It was sold from 1957 to 1961 in almost 50 countries under at least 40 names. Thalidomide was chiefly sold and prescribed during the late 1950s and early 1960s to pregnant women, as an antiemetic to combat morning sickness and as an aid to help them sleep. Before its release, inadequate tests were performed to assess the drug's safety, with catastrophic results for the children of women who had taken thalidomide during their pregnancies. Antiemetic = a medication that helps prevent and control nausea and vomiting
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Birth defects caused by use of thalidomide
Slide 60-

Example: Thalidomide From 1956 to 1962, approximately 10,000 children were born with severe malformities, including phocomelia, because their mothers had taken thalidomide during pregnancy. In 1962, in reaction to the tragedy, the United States Congress enacted laws requiring tests for safety during pregnancy before a drug can receive approval for sale in the U.S. Phocomelia presents at birth very short or absent long bones and flipper-like appearance of hands and sometimes feet.
Slide 61-

Example: Thalidomide Researchers, however, continued to work with the drug. Soon after its banishment, an Israeli doctor discovered anti-inflammatory effects of thalidomide and began to look for uses of the medication despite its teratogenic effects. He found that patients with erythema nodosum leprosum, a painful skin condition associated with leprosy, experienced relief of their pain by taking thalidomide. Teratogenic = Causing malformations in a fetus
Slide 62-

Thalidomide Further work conducted in 1991 by Dr. Gilla Kaplan at Rockefeller University in New York City showed that thalidomide worked in leprosy by inhibiting tumor necrosis factor alpha. Kaplan partnered with Celgene Corporation to further develop the potential for thalidomide. Subsequent research has shown that it is effective in multiple myeloma, and it is now approved by the FDA for use in this malignancy. There are studies underway to determine the drug's effects on arachnoiditis, Crohn's disease, and several types of cancers.
Slide 63-

Clinical Trials Phase I: Drug is tested on healthy volunteers to determine toxicity relative to dose and to screen for unexpected side effects
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Clinical Trials Phase II: Drug is tested on small group of patients to see if drug has any beneficial effect and to determine the dose level needed for this effect.
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Clinical Trials Phase III: Drug is tested on much larger group of patients and compared with existing treatments and with a placebo
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Clinical Trials Phase IV: Drug is placed on the market and patients are monitored for side effects
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Assigned Reading Haffner Marlene E; Whitley Janet; Moses Marie Two decades of orphan product development. Nature reviews. Drug discovery (2002), 1(10), 821-5. Link Franks Michael E; Macpherson Gordon R; Figg William D Thalidomide. Lancet (2004), 363(9423), 1802-11. Link Abou-Gharbia, Magid. Discovery of innovative small molecule therapeutics. Journal of Medicinal Chemistry (2009), 52(1), 2-9. Link Paul, S. M. et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nature Reviews Drug Discovery (2010), 9: 203-214. Jorgensen, W. L. The many roles of computation in drug discovery. Science (2004) 303: 1813-1818. Butcher, E. C. et al. Systems biology in drug discovery. Nature biotechnology (2004) 22(10): 1253-1259.
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Optional Additional Reading Bartlett J Blake; Dredge Keith; Dalgleish Angus G The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nature reviews. Cancer (2004), 4(4), 314-22. Link Cragg, G. M.; Newman, D. J. Nature: a vital source of leads for anticancer drug development. Phytochemistry Reviews (2009), 8(2), 313-331. Link Betz, U. A. K. et al. Genomics: success or failure to deliver drug targets? Current Opinion in Chemical Biology (2005), 9: 387-391 Sams-Dodd, F. Target-based drug discovery: is something wrong? Drug Discovery Today (2005) 10: 139-147.
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Homework Questions What is an ‘orphan drug’. Why has the Orphan Drug Act been successful? Thalidomide is actually a mixture of two compounds. Draw their structures and list the physiological effects of each. What does ADMET stand for? List several possible reasons for poor efficacy of drug candidates in in vivo models. Explain how structure-based design was used to develop an inhibitor with improved selectivity for TACE over MMP-1 and MMP-9. How can the pharmaceutical industry increase the probability of technical success (p(TS))? What are the major causes of Phase II and III attrition?