Patrick An Introduction to Medicinal Chemistry 3/e Chapter 9 DRUG DISCOVERY: FINDING A LEAD

1. Patrick An Introduction to Medicinal Chemistry 3/e Chapter 9 DRUG DISCOVERY: FINDING A LEAD Part 2: Section 9.4 (Lead compounds from the natural world)

2. Contents Part 2: Section 9.4 Lead compounds from the natural world 4. The Lead Compound 4.1. Sources of Lead Compounds 4.2. Identification of Lead Compounds 4.3. Lead Compounds from the Natural World (21 slides) - Plant Extracts (4 slides) - Plants and Ancient Records (9 slides) - Herbal Remedies of Olde - Venoms and Toxins (4 slides) - Endogenous Compounds (3 Slides) [25 slides]

3. 4 The Lead Compound Introduction • A compound demonstrating a property likely to be therapeutically useful • The level of activity and target selectivity are not crucial • Used as the starting point for drug design and development • Found by design (molecular modelling or NMR) or by screening compounds (natural or synthetic) • Need to identify a suitable test in order to find a lead compound • Active Principle - a compound that is isolated from a natural extract and which is principally responsible for the extract’s pharmacological activity. Often used as a lead compound.

4. Plantlife (flowers, trees, bushes) Micro-organisms (bacteria, fungi) Animal life (frogs, snakes, scorpions) Biochemicals (Neurotransmitters, hormones) Marine chemistry (corals, bacteria, fish etc) Chemical synthesis (traditional) Combinatorial synthesis Computer aided drug design 4.1 Sources of Lead Compounds A) The Natural World B) The Synthetic World C) The Virtual World

5. 4.2 Identification of Lead Compounds A) Isolation and purification solvent-solvent extraction chromatography crystallisation distillation B) Structure determination elemental analysis molecular weight mass spectrum infra red ultra violet nmr (1H, 13C, 2D) X-ray crystallography

6. 4.3 Lead Compounds from the Natural World PLANT EXTRACTS

7. 4.3 Lead Compounds from the Natural World PLANT EXTRACTS MORPHINE POPPY CAPSULE

8. 4.3 Lead Compounds from the Natural World PLANT EXTRACTS • OPIUM- Morphine • CINCHONA BARK- Quinine • YEW TREE- Taxol

9. 4.3 Lead Compounds from the Natural World PLANT EXTRACTS WILLOW TREE - SALICYLIC ACID Aspirin COCA BUSH - COCAINE Procaine

10. 4.3 Lead Compounds from the Natural World PLANTS AND ANCIENT RECORDS

11. 4.3 Lead Compounds from the Natural World PLANTS AND ANCIENT RECORDS ARTEMISININ

12. 4.3 Lead Compounds from the Natural World PLANTS AND ANCIENT RECORDS ARTEMISININ

13. 4.3 Lead Compounds from the Natural World PLANTS AND ANCIENT RECORDS ARTEMISININ

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17. 4.3 Lead Compounds from the Natural World PLANTS AND ANCIENT RECORDS THE BEATONS OF PENNYCROSS

18. Produce one pedigree dog Add a liberal sprinkling of juicy spiders Flavour with essence of dog turd Simmer for 20 minutes then enjoy THE BEATONS OF PENNYCROSS CURE for EPILEPSY Heat a cauldron of water until warm to the touch

19. 4.3 Lead Compounds from the Natural World HERBAL REMEDIES OF OLDE Majority may have worked through a placebo effect

20. 4.3 Lead Compounds from the Natural World VENOMS AND TOXINS Teprotide Captopril (anti-hypertensive)

21. 4.3 Lead Compounds from the Natural World VENOMS AND TOXINS

22. 4.3 Lead Compounds from the Natural World VENOMS AND TOXINS Tubocurarine (from curare)

23. 4.3 Lead Compounds from the Natural World VENOMS AND TOXINS Tubocurarine (from curare) Atracurium (Neuromuscular blocker)

24. Agonist Agonist 4.3 Lead Compounds from the Natural World ENDOGENOUS COMPOUNDS NATURAL LIGANDS FOR RECEPTORS

25. Antagonist Antagonist 4.3 Lead Compounds from the Natural World ENDOGENOUS COMPOUNDS NATURAL LIGANDS FOR RECEPTORS

26. Enkephalinase inhibitors Enkephalins Protease inhibitors Peptides 4.3 Lead Compounds from the Natural World ENDOGENOUS COMPOUNDS NATURAL SUBSTRATES FOR ENZYMES