Biol/Chem 444 Drug Discovery in addition to Development Drugs: Natural sources Synthetic so

Biol/Chem 444 Drug Discovery in addition to Development Drugs: Natural sources Synthetic so www.phwiki.com

Biol/Chem 444 Drug Discovery in addition to Development Drugs: Natural sources Synthetic so

Jackman, Elizabeth, Local News Reporter has reference to this Academic Journal, PHwiki organized this Journal Biol/Chem 444 Drug Discovery in addition to Development Drugs: Natural sources Synthetic sources Targets: Introduction McCurdy 3/20/08 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 in addition to chemical companies start research labs in addition to discover medical applications. (Bayer) Industry devoted solely to pharmaceuticals begins 1905 – John Langley: theory of receptive substances History of Drug Discovery 1909 – First rational drug design. Goal: safer syphilis treatment than Atoxyl (below). Paul Erhlich in addition to Sacachiro Hata wanted to maximize toxicity to pathogen in addition to minimize toxicity to human (therapeutic index). Synthetic: 600 compounds; evaluated ratio of minimum curative dose in addition to maximum tolerated dose. They found Salvarsan (which was replaced by penicillin in the 1940’s) 1960 – First successful attempt to relate chemical structure to biological action quantitatively (QSAR = Quantitative structure-activity relationships). Hansch in addition to Fujita

Claremont Graduate University US www.phwiki.com

This Particular University is Related to this Particular Journal

History of Drug Discovery Mid to late 20th century – underst in addition to disease states, biological structures, processes, drug transport, distribution, metabolism. Medicinal chemists use this knowledge to modify chemical structure to ifluence a drug’s activity, stability, etc. Example: procaine = local anaesthetic; Procainamide = antirhythmic Profile of Today’s 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 in addition to 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 in addition to resistance in pathogens. Profile of Today’s Pharmaceutical Business Found in the environment! Pharmaceuticals are a small fraction of the thous in addition to s 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:

Profile of Today’s Pharmaceutical Business Interdisciplinary!!! Profile of Today’s Pharmaceutical Business Combination of large pharma in addition to small biotech (outsourcing, licensing new technologies, “alliances”) Mergers, etc:

Profile of Today’s Pharmaceutical Business Global economy China: new focus by industry Profile of Today’s Pharmaceutical Business “Filling the Pipeline” using 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 Profile of Today’s Pharmaceutical Business “Filling the Pipeline” Small molecules vs. Biologics 2006 2004

Number of small-molecule drugs, recombinant proteins in addition to monoclonal antibody therapeutics approved in the United States during 1980–2001. Total number of each product type approved during 1980–2001. mAb, monoclonal antibody; rDNA, recombinant protein; SMD, small-molecule drug. Profile of Today’s Pharmaceutical Business “Filling the Pipeline” Small molecules vs. Biologics over time Profile of Today’s 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 in addition to personalized medicine. Profile of Today’s Pharmaceutical Business “Filling the Pipeline” Top companies in addition to Approved Drugs

Figure 1 Therapeutic target classes. All current therapeutic targets can be subdivided into seven main classes, wherein enzymes in addition to receptors represent the largest part. Adapted with permission from Ref. 1 © American Association as long as the Advancement of Science (2000). Profile of Today’s Pharmaceutical Business Types of targets Rising costs of one drug: 1999 $600million. Today $897million. Clinical development costs 3/5 that amount. Profile of Today’s Pharmaceutical Business Profile of Today’s Pharmaceutical Business In 2004, industry spent twice as much on R&D as it did as long as promotion of the drug

Profile of Today’s Pharmaceutical Business Patents – Patents as long as bid competitors to use the originators’ inventions. They benefit the public by disclosing valuable inventions that might otherwise remain trade secrets They compensate pharmaceutical companies as long as risky research projects to discover new drugs. In 1980’s 5-7 years elapsed be as long as e a competing drug appeared; in 1990’s 3 years Profile of Today’s Pharmaceutical Business Patents (continued) In 2006, 6 major products lost patent protections Companies attempting to retain profits by re as long as mulating. (Ambien CR = controlled release) Profile of Today’s 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)

Figure 2 Mean clinical in addition to approval phase lengths as long as small-molecule drugs approved in the United States during 1970–2001. Profile of Today’s Pharmaceutical Business Profile of Today’s Pharmaceutical Business Overall, higher safety concerns (sparked by Vioxx recall in 2004) have made FDA more conservative in approvals, more vocal in warnings, in addition to have made companies more likely to spend more time testing, in addition to to suspend research be as long as e clinical trials. Profile of Today’s Pharmaceutical Business Economic, social, in addition to political issues – Unlike US, other nations have not raised prices on drugs. Richer nations are subsidizing poorer nations (anti-HIV drugs, as long as example). How do companies make up as long as increased costs but no price increases Focus on diseases of rich Americans Pursue “blockbuster drugs” (not antimicrobials, etc) Mergers; rely on biotech companies as long as innovations Consumer approval of the industry has declined (79% approval in 1997; 44% approval in 2004)

Jackman, Elizabeth Glendale Star, The Local News Reporter www.phwiki.com

Drug Discovery overview A drug discovery ef as long as t 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 in addition to synthesized to obtain the desired properties (Note: Molecular Conceptor software uses locks (biological targets) in addition to keys (drugs) to illustrate the concepts involved in drug discovery) Drug Discovery overview Approaches to lead discovery: Serendipity (luck) Screening Chemical Modification Rational 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

Drug Discovery overview 2. Screening Testing a r in addition to om in addition to large number of different molecules as long as biological activity reveals leads. Innovations have led to the automation of synthesis (combinatorial synthesis) in addition to testing (high-throughput screening). Example: Prontosil is derived from a dye that exhibited antibacterial properties. 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 in addition to Limitation: you end up with something very similar to what you start with. Drug Discovery overview 4. Rational Drug Design; Example – Cimetadine (Tagamet) Starts with a validated biological target in addition to ends up with a drug that optimally interacts with the target in addition to 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), in addition to SCREENED. N-guanyl-histamine showed some antagonist properties = LEAD compound.

Drug Discovery overview Rational Drug Design – a historical perspective 1970’s: no biological target structures known, so all pharmacophore-based approaches. 1990’s: recombinant DNA, cloning, etc. helped the generation of 3D structural data of biological targets. Present: plenty of structural data of biological targets, but also improved technology to increase pharmacophore-based projects. Drug Discovery overview References: Friary, R. Jobs in the Drug Industry A Career Guide as long as Chemists; Academic Press: San Diego, CA, 2000. Thomas, G. Medicinal Chemistry An Introduction; John Wiley & Sons: New York, NY, 2000. Williams, D. A.; Lemke, T.L. Foye’s Principles of Medicinal Chemistry; Lippincott Williams & Wilkins: Baltimore, MD, 2002. Science 2004, 303, 1795-1822. Chemical in addition to Engineering News 2008, 86 (8) p. 13-17 Chemical in addition to Engineering News 2007, 85 (49) p. 13-24 Chemical in addition to Engineering News 2006, 84 (49) Chemical in addition to Engineering News 2006, 84 (44) p. 14-20 Chemical in addition to Engineering News 2006, 84 (25) Special Issue on Pharma. Chemical in addition to Engineering News 2006, 84 (10), 21-27. Chemical in addition to Engineering News 2005, 83 (49), 15-32. Chemical in addition to Engineering News 2005, 83 (23), 21-29. Chemical in addition to Engineering News 2004, 82 (30), 23-32. Chemical in addition to Engineering News 2004, 82 (12), 51-56. Chemical in addition to Engineering News 2004, 82 (49), 18-29. Chemical in addition to Engineering News 2004, 82 (7), 23-36. Molecular Conceptor K3; C1

Jackman, Elizabeth Local News Reporter

Jackman, Elizabeth is from United States and they belong to Glendale Star, The and they are from  Glendale, United States got related to this Particular Journal. and Jackman, Elizabeth deal with the subjects like Local Government and Politics; Local News

Journal Ratings by Claremont Graduate University

This Particular Journal got reviewed and rated by Claremont Graduate University and short form of this particular Institution is US and gave this Journal an Excellent Rating.