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Biol/Chem 444 Drug Discovery and Development Drugs: Natural sources Synthetic sources Targets: Introduction McCurdy 3/20/08

Dec 23, 2015



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  • Biol/Chem 444 Drug Discovery and Development Drugs: Natural sources Synthetic sources Targets: Introduction McCurdy 3/20/08
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  • History of Drug Discovery Folk medicine - natural product remedies Early 19th century - extraction of compounds from plants (morphine, cocaine). Apothecaries (Hoffman-La Roche) Late 19th century - fewer natural products used, more synthetic substances. Dye and chemical companies start research labs and discover medical applications. (Bayer) Industry devoted solely to pharmaceuticals begins 1905 - John Langley: theory of receptive substances
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  • History of Drug Discovery 1909 - First rational drug design. Goal: safer syphilis treatment than Atoxyl (below). Paul Erhlich and Sacachiro Hata wanted to maximize toxicity to pathogen and minimize toxicity to human (therapeutic index). Synthetic: 600 compounds; evaluated ratio of minimum curative dose and maximum tolerated dose. They found Salvarsan (which was replaced by penicillin in the 1940s) 1960 - First successful attempt to relate chemical structure to biological action quantitatively (QSAR = Quantitative structure- activity relationships). Hansch and Fujita
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  • History of Drug Discovery Mid to late 20th century - understand disease states, biological structures, processes, drug transport, distribution, metabolism. Medicinal chemists use this knowledge to modify chemical structure to ifluence a drugs activity, stability, etc. Example: procaine = local anaesthetic; Procainamide = antirhythmic
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  • Profile of Todays Pharmaceutical Business Drug: Chemical substance that is used to prevent or cure diseases in humans, animals, or plants Activity: Pharmacological effect on the subject Potency: quantitative measure of the effect of the drug Classification schemes - several: chemical structure, pharmacological action, physiological classification Benefits: Improve quality of life and life expectancy (47 years in 1850; 78 years today). Result = shift of population demographics to a more healthy elderly population Problems: Cost, overdose, side effects (COX-2 inhibitors - Vioxx). Overuse can result in tolerance in humans and resistance in pathogens.
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  • Profile of Todays Pharmaceutical Business Found in the environment! Pharmaceuticals are a small fraction of the thousands of man-made chemicals in the environment. Feminized male fish Found in earthworms Very few found in drinking water (ibuprofen) or sources of drinking water. Way below levels that would affect humans. Problems, continued:
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  • Profile of Todays Pharmaceutical Business Interdisciplinary!!!
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  • Profile of Todays Pharmaceutical Business Combination of large pharma and small biotech (outsourcing, licensing new technologies, alliances) Mergers, etc:
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  • Profile of Todays Pharmaceutical Business Global economy China: new focus by industry
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  • Profile of Todays Pharmaceutical Business Filling the Pipelineusing new technologies: Combinatorial synthesis, genomics, personalized medicine are promising but expensive. Making more compounds does not necessarily mean finding more drugs; genomic-proteomic output has not had much commercial success - target validation takes a long time. Failure rate: 1 in 5000 drugs reach clinical trials; 1 in 10,000 reaches marketing
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  • Profile of Todays Pharmaceutical Business Filling the Pipeline Small molecules vs. Biologics 20062004
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  • Number of small-molecule drugs, recombinant proteins and monoclonal antibody therapeutics approved in the United States during 19802001. *Total number of each product type approved during 19802001. mAb, monoclonal antibody; rDNA, recombinant protein; SMD, small-molecule drug. Profile of Todays Pharmaceutical Business Filling the Pipeline Small molecules vs. Biologics over time
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  • Profile of Todays Pharmaceutical Business Filling the Pipeline Top products Industry has been primarily based on the blockbuster model (>$1 billion in sales; high numbers of patients). May not be able to keep coming up with these blockbusters, so they are also focusing on specialty markets and personalized medicine.
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  • Profile of Todays Pharmaceutical Business Filling the Pipeline Top companies and Approved Drugs
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  • Figure 1 | Therapeutic target classes. All current therapeutic targets can be subdivided into seven main classes, wherein enzymes and receptors represent the largest part. Adapted with permission from Ref. 1 American Association for the Advancement of Science (2000). Profile of Todays Pharmaceutical Business Types of targets
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  • Rising costs of one drug: 1999 $600million. Today $897million. Clinical development costs 3/5 that amount. Profile of Todays Pharmaceutical Business
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  • In 2004, industry spent twice as much on R&D as it did for promotion of the drug
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  • Profile of Todays Pharmaceutical Business Patents - Patents forbid competitors to use the originators inventions. They benefit the public by disclosing valuable inventions that might otherwise remain trade secrets They compensate pharmaceutical companies for risky research projects to discover new drugs. In 1980s 5-7 years elapsed before a competing drug appeared; in 1990s 3 years
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  • Profile of Todays Pharmaceutical Business Patents (continued) In 2006, 6 major products lost patent protections Companies attempting to retain profits by reformulating. (Ambien CR = controlled release)
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  • Profile of Todays Pharmaceutical Business Time to market: 10-12 years. By contrast, a chemist develops a new adhesive in 3 months! Why? (Biochemical, animal, human trials; scaleup; approvals from FDA, EPA, OSHA)
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  • Figure 2 | Mean clinical and approval phase lengths for small- molecule drugs approved in the United States during 19702001. Profile of Todays Pharmaceutical Business
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  • Overall, higher safety concerns (sparked by Vioxx recall in 2004) have made FDA more conservative in approvals, more vocal in warnings, and have made companies more likely to spend more time testing, and to suspend research before clinical trials.
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  • Profile of Todays Pharmaceutical Business Economic, social, and political issues - Unlike US, other nations have not raised prices on drugs. Richer nations are subsidizing poorer nations (anti-HIV drugs, for example). How do companies make up for increased costs but no price increases? Focus on diseases of rich Americans Pursue "blockbuster drugs" (not antimicrobials, etc) Mergers; rely on biotech companies for innovations Consumer approval of the industry has declined (79% approval in 1997; 44% approval in 2004)
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  • Drug Discovery overview A drug discovery effort addresses a biological target that has been shown to play a role in the development of the disease or starts from a molecule with interesting biological activities. Lead discovery. Identification of a compound that triggers specific biological actions. Lead optimization. Properties of the lead are tested with biological assays; new molecules are designed and synthesized to obtain the desired properties (Note: Molecular Conceptor software uses locks (biological targets) and keys (drugs) to illustrate the concepts involved in drug discovery)
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  • Drug Discovery overview Approaches to lead discovery: Serendipity (luck) Screening Chemical Modification Rational
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  • Drug Discovery overview 1. Serendipity Chance favors the prepared mind 1928 Fleming studied Staph, but contamination of plates with airborne mold. Noticed bacteria were lysed in the area of mold. A mold product inhibited the growth of bacteria: the antibiotic penicillin
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  • Drug Discovery overview 2. Screening Testing a random and large number of different molecules for biological activity reveals leads. Innovations have led to the automation of synthesis (combinatorial synthesis) and testing (high-throughput screening). Example: Prontosil is derived from a dye that exhibited antibacterial properties.
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  • Drug Discovery overview 3. Chemical Modification Traditional method. An analog of a known, active compound is synthesized with a minor modification, that will lead to improved biological activity. Advantage and Limitation: you end up with something very similar to what you start with.
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  • Drug Discovery overview 4. Rational Drug Design; Example - Cimetadine (Tagamet) Starts with a validated biological target and ends up with a drug that optimally interacts with the target and triggers the desired biological action. Problem: histamine triggers release of stomach acid. Want a histamine antagonist to prevent stomach acid release by histamine = VALIDATED BIOLOGICAL TARGET. Histamine analogs were synthesized with systematically varied structures (chemical modification), and SCREENED. N-guanyl-histamine showed some antagonist properties = LEAD compound.
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  • Drug Discovery overview 4. Rational Drug Design - Cimetadine (Tagamet) - continued b. More po
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