Drug Development and Sources of Drugs

1. How were medicines used before the 20th century ?: Most medicines were mainly herbs and potions 2. discovery, design and development of one new drug ?: - can take 15 yrs - involves the synthesis of 10,000 compounds - cost in the region of $2 billion 3. What happened in the mid 1800's that allowed natural products to be more effective ?: serious efforts were made to isolate and purify the chemicals responsible for these medicinal properties. they were also studied e.g., morphine from opium cocaine from coca leaves quine from bark of cinchona trees 4. Tricyclic antidepressants - Desipramine: e.g., desipramine: - inhibit the uptake of the neurotransmitter noradrenaline from nerve synapses - also inhibit a neurotransmitter called serotonin = lead to fluoxetine (selective serotonin uptake inhibitor ) best selling antidepressant drug. 5. Olanzapine: - A compound which interacts with a variety of biological targets - used in the treatment of schizophrenia - bind to receptors: serotonin, dopamine, muscarine, noradrenaline and histamine. 6. Techniques used to identify a chemic starting point - Hit molecule: - High throughput screening - Natural products - Medical Folklore - Natural ligands - Existing drugs - Enhancing a side effect - Computer- aided design - Serendipity 7. Hit molecule identification - High throughput screening: - Thousands (even millions) of compounds are assayed against the target of interest to see if any molecules interact with this protein. 8. Hit molecule identification - Natural products: - purified organic compounds isolated from natural sources produced by pathways of primary / secondary metabolism: - plant kingdom - Microorganisms - Marines sources 1/5 - Animal sources - venoms and toxins 9. Natural products sources examples - Plant kingdom: - Morphine - Cocaine - Digitalis - Quinine - Tubocurarine - Nicotine - Muscarine 10. Natural products sources examples - Microorganisms: - Penicillin - Cephalosporins - Tetracyclines - Rifamycin - Chloramphenicol - Vancomycin (antibacterials) 11. Natural products sources examples - Marine sources: - eleutherobin - byostatins - cephalostatins - halichondrin B (often used as antitumour agents) 12. Natural products sources examples - Animal sources: - epibatidine (potent analgesic) 13. Hit molecule identification - Medical Folklore: E.g., Rhubarb root: - used as a purgative for many centuries - It was discovered that the anthraquinones present in the root were responsible for this effect = lead to discovery of the laxative dantron. 14. Hit molecule identification - Natural ligands: - Biological molecules which naturally interact with the protein can be modified to target new hits. E.g., adrenaline & nor-adrenaline = starting points for the development of adrenergic Beta agonist: - salbutamol - dobutamine - xamoterol 15. Hit molecule identification - Existing drugs: - drugs that may already be on the market but require some modifications to be more effective - a company can't market the same compound as another compound unless the patent protection has expired / but can market a compound which acts at the same biological target. 16. Hit molecule identification - Serendipity: In WW2, US ship carrying mustard gas exploded & many survivors that inhaled gas lost their white blood cells 2/5 - the mustard gases were further optimised to give treatments for leukaemia (condition resulting in excess proliferation of white blood cells) 17. Topiramate: - anticonvulsant used in treatment of epilepsy - it has subsequently emerged as a possible treatment for inflammatory bowel disease. 18. Cheminformatics: During the investigation and synthesis of compounds in the research phase, huge volumes of data are generated. A continuous feedback loop is facilitated and aided by computational methods. 19. How can Computer Technologies Support Drug Development ?: 1. Storing chemical information 2. Computational Libraries and Computer-Aided Drug Design 3. Virtual Screening to Select Possible lead compounds 4. Molecular Modelling to Predict Drug Properties, Activities and Toxicities 5. Finding new uses for Existing Drugs 20. Advantages of Cheminformatics ?: - Low cost - Can be performed from knowledge of structure alone (pre-synthesis) - Reduces the number of laboratory animals used in testing - Rapid identification/ranking of possible lead candidates - Unsuitable candidates can be rapidly eliminated (Fail fast, fail cheap) - Ability to handle huge amounts of data 21. Disadvantages of Cheminformatics ?: - Predictions can sometimes be inaccurate - Need to develop/buy a suite of predictive models - Complex software can restrict users - Cheminformatics is not a standalone approach but is a complimentary technology 22. What is needed for a drug to be good ?: - Acceptable physicochemical properties 3/5 - Have a good balance of potency - Survive metabolism (for a sufficient amount of time) - Gets to the target and doesn't access compartments you don't want (e.g. brain) - Effective in an animal model - Acceptable toxicity profile etc. 23. Pharmacognosy: The branch of knowledge concerned with medicinal drugs obtained from plants or other natural sources 24. St. John's Wort: Hypericum perforatum - is commonly used as a herbal extract and it contains multiple active ingredients - it is effective for some mental health conditions, it does interact with many medicines 25. What is a natural product ?: A secondary metabolite, produced by an organism, which may lead to enhanced survival traits, but is not strictly necessary for the survival of the organism. 26. Primary metabolites: - directly involved in normal growth, development, and reproduction. - performs a physiological function in the organism. - typically present in many organisms - do not show pharmacological actions 27. Examples of Primary metabolites ?: - Amino Acids - Proteins - Sugars - Organic acids 28. What are Secondary metabolites ?: - not required for normal growth, development, and reproduction - usually has an important ecological function 4/5 - present is restricted to a limited number of organisms - can show pharmacological actions 29. Types of secondary metabolites ?: Alkaloids (nitrogenous, acid soluble) Terpenes (composed of isoprene units) Glycosides (molecules with sugars attached) Steroids (biosynthesis involves squalene) Phenolics (contain at least one phenolic moiety) 30. Essential medicines: Those drugs that satisfy the health care needs of the majority of the population. 31. Drugs on the WHO list of essential medicines include ?: Morphine Quinine Colchicine Atropine 32. Paclitaxel: An anticancer drug from the Pacific yew tree Taxus brevifolia 33. Pergonal: - contains a mixture of human LH and FSH to treat infertility - obtained from the urine of nuns post-menopausal in Italy 34. Premarin (conjugated estrogens): - licenced in the UK for hormone replacement therapy for oestrogen deficiency symptoms in post-menopausal women and prevention of osteoporosis - sourced from Pregnant mares unrine 35. Hyaluronic acid: - used clinically as an injection to treat osteoarthritis of the knee - it is extracted from the combs of chickens 36. Exenatide (Byetta): - used to treat type 2 diabetes - sourced from saliva of Gila monster - venomous lizard 5/5