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Medicinal Chemistry (An Introduction)

Medicinal Chemistry (An Introduction). Dr. Caroline Sheppard CHEM 3202 October 16, 2014. What is medicinal chemistry?. The science that deals with the discovery or design of new therapeutic chemicals and the development of these chemicals into useful medicine. What is “medicine”?.

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Medicinal Chemistry (An Introduction)

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  1. Medicinal Chemistry(An Introduction) Dr. Caroline Sheppard CHEM 3202 October 16, 2014

  2. What is medicinal chemistry? • The science that deals with the discovery or design of new therapeutic chemicals and the development of these chemicals into useful medicine

  3. What is “medicine”? • Drugs, pharmaceuticals • Media distinction • A compound that interacts with a biological system, and produces a biological response (ideally desired and positive) • “Good” vs. “Bad” Drugs • No medicine has only benefits or drawbacks • Heroin (diamorphine) • Withdrawn from market 1903 • Curare: deadly poison • Used in surgery today

  4. What is medicinal chemistry? • The science that deals with the discovery or design of new therapeutic chemicals and the development of these chemicals into useful medicine or • Under what conditions are drugs “good,” and what do they do to the body?

  5. Everyday drugs • Still produce a response; many are addictive • Caffeine, sugar, nicotine, alcohol, food additives, vitamins, herbs • Ex: Basil: • 50 potential carcinogens • Used for a variety of medical disorders • Fever and common cold • Coughs • Sore throat • Respiratory disorder • Kidney stones • Heart disorder • Stress • Mouth infections • Insect bites • Skin disorders • Teeth disorder • Headaches • Eye disorders

  6. Caffeine

  7. History of medicinal chemistry • Studied/practiced for thousands of years • Medicine men/witch doctors • Roots, plants, trees, berries, herbs • Often placebos, lots of trial and error • Last 150 years: understanding of molecular targets, mechanism of reaction/response, isolation of natural products and synthesis of analogs • Drug Discovery: • Successful process • More than 10 years, $300 million, 10000 tested compounds, for one drug! II. Choose a drug target III. Find a lead compound IV. Optimize lead I. Choose a disease V. Clinical Trials VI. Market

  8. Finding lead compounds • Random screening of compounds • Computer-aided design • Existing drugs • For your disease of interest • For another disease • Viagra

  9. E E P S S E + S P E E E ES EP E + P Finding lead compounds • Enzyme substrate, product, or inhibitor

  10. Examples • Increase [S] • Decreased levels of GABA cause seizures • GABA aminotransferase degrades GABA • Inhibition of enzyme raise GABA levels • Vigabatrin (Saybril) • Decrease [P] • Xanthine converts to uric acid with xanthine oxidase • Excess uric acid leads to gout • Enzyme inhibition lowers uric acid production • Allopurinol (Zyloprim)

  11. Finding lead compounds • Chance • Penicillin V • Isoniazid • Antabuse (Disulfiram) • Acetanilide

  12. Taxol Finding lead compounds • Natural Products • Complicated structures • Clues from ancient medical folklore • Examples: • Taxol (yew tree) • Quinine (chincona bark) • Cocaine (coca bush) • Aspirin (willow) • Morphine (opium, poppy)

  13. Cocaine • South American coca bush • Plant used as a stimulant, mystical/religious reasons • Isolated 1880’s • Anesthetic in dentistry • Addiction: Freud • Used for depression; other drug addiction • Drug development based on structure • Procaine (Novocain)

  14. Aspirin • 400 BC: Hippocrates • Chew bark of willow tree for pain (childbirth and eye infections) • Once thought to cure malaria; actually an antipyretic • Active component of willow bark = salicin • Mechanism of action: COX-1 and COX-2 enzymes

  15. Opium poppy • Papaversomniferum “Sleep-bringing poppy” • Latex from pod • Tincture or smoked • Mixture of alkaloids • Morphine prescribed for: • Chronic headache • Epilepsy • Asthma • Fevers • Leprosy • “troubles to which women are subject” • Also used in baking

  16. Morphine • Timeline: • 1803 isolated • 1833 purified • 1853 medicine (invention of syringe) • 1881 functional groups identified • 1925 structure proposed • 1953 synthesis • 1968 structure confirmed • 1973 receptors • Elevates pain threshold • Respiratory problems, addiction, withdrawal, constipation

  17. Pharmacophore 2.19 morphine (R = R’ = H) codeine (R = CH3, R’ = H) heroin (R = R’ = COCH3) 2.20 levorphanol (R = OH) 2.23 meperidine (Demerol) 2.24 dextropropoxyphene (Darvon) 2.25 methadone Silverman, The Organic Chemistry of Drug Design and Drug Action

  18. Factors to consider in drug design • Pharmacokinetics • Drug absorption, distribution, and elimination • Method of administration • Metabolism • Dosage • Cytochrome P450s • Toxicity of metabolites hypericin hyperforin

  19. Taxol Factors to consider in drug design • Synthesis/Manufacturing process • Steps, yield, scale, cost, safety, chirality • Natural products and semi-synthetic procedures

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