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Medicinal Chemistry Medicinal Chemistry all material is available online as pdf files under the following URL: ! http://www.chem.uzh.ch/zerbe/MedChem/Course_MedChem.html The Medicinal Chemistry Course • ADME (adsorption, distribution, metabolism and excretion) of drugs • drug-receptor interactions • development of drugs • screening techniques • combinatorial chemistry (D.O.) • classical medicinal chemistry, hit-to-lead development • fragment-based drug design • rational drug design / de-novo drug design • natural products • case studies of drug synthesis (D.O.) • the common targets for drugs (receptors) • biophysical methods for determination of structure and binding interactions • antibacterial drugs • antiviral drugs • anti-cancer drugs • anti-inflammatory drugs • patent issues (P.F.) Books and other information sources Monographs: • G. Patrick: Introduction to Medicinal Chemistry, Oxford University Press, 2005 (very good introduction) • H.-J. Böhm, G. Klebe, H. Kubinyi: Wirkstoffdesign. Der Weg zum Arzneimittel (Spektrum Lehrbuch) (very interesting, easy to read) • G. Thomas: Medicinal Chemistry: An Introduction (Wiley), (inexpensive introduction) • H. P. Rang, M. M. Dale, J. M. Ritter: Pharmacology, Churchill Livingstone; 6th ed. • E.J. Corey, B. Czakó, L. Kürti, Molecules and Medicine (Wiley) • D.S. Johnson, J.J. Li: The Art of Drug Synthesis (Wiley) ! Journals: • Nature Reviews Drug Discovery • Drug Discovery Today • ACS Journal of Medicinal Chemistry • Trends in Pharmacological Sciences Society before 1800 1 childbed fever 2 infection of appendix of the mother 3 accidents 3 quality of 2 life 1 age Medicine ca. 1950 anesthesia, 1 childbed fever 2 infection of the appendix antibiotics of the mother asepsis 3 accident → tetanus vaccination 3 quality of 2 life 1 age Medicine after ~ 1950 quality of life age most common cause of death for 22-44 year old people 8 65 years and older... Male Female Arteriosclerosis 9,7% 9,8% Arteriosclerosis Cardiac Infarction 7,7% 8,3% Cardiac insufciency Lung Cancer 6,9% 6,1% Cardiac Infarction Cardiac insufciency 4,7% 4,3% Stroke obstructive lung disease 3,8% 3,5% hypertension-related (smokers lung) heart condition Prostate Cancer 3,7% 3,0% Breast cancer Stroke 2,9% 2,7% Pneumonia Pneumonia 2,8% 2,3% Cardiac arrhythmia Colon Cancer 2,4% 2,1% Lung Cancer Pancreatic Cancer obstructive lung disease 1,7% 2,1% (smokers lung) 2008 Medicine in the antiquity • Chinese medicine: (3500 BC) – chinese herbs, some of the ingredients are still in use today, e.g. Reserpin (blood high pressure; emotional and mental control), Ephedrine (Asthma) • Egyptian medicine (3000 BC) – Papyrus Ebers, 877 descriptions and recipes • Greek medicine (from 700 BC) – illness is no punishment from God, medicine is considered a science – diseases are due to natural causes – Hippocratic oath • Roman medicine (from approx. 200 BC): – invention of hospitals – large influence of greek medicine – Materia Medica: pharmaceutical descriptions Medicine in the Middle Ages (400 to 1500 AC) • The church preserves greek traditional recipes • Era of horrible epidemics (e.g. Pest, Lepra, Pox, Tuberculosis) • Arabic medicine: Development of medical procedures for drug preparation (distillation) afterwards.... • Development of scientific approaches: • Pox: Edward Jenner discovered that people who worked with cattle and had caught the cowpox disease (a mild disease related to smallpox) were immune and never caught smallpox. He inoculated a boy with blister fluid from a woman with cowpox. He later inoculated the same boy with fluid from smallpox, and discovered that the boy was immune against the disease. • Bill Withering introduces extracts of Digitalis for treatment of heart problems • Louis Pasteur discovers that microorganisms are responsible for diseases and develops vaccinations against rabies. He introduces attenuated viruses for treatment of rabies. until 1900 • Digitalis (isolated from the plant digitalis, stimulation of the heart muscle) • Chinin (alkaloid from peruvian bark, treatment of malaria, fever lowering) • Ipecacuanha (from the bark of ipecac, treatment of diarrhea) • Aspirin (from the meadow bark, against fever and pain) • Mercury (-> syphilis) 12 Discovery of Penicillin • Alexander Flemming discovers in 1928 that a fungus grew on a bacterial plate containing staphylococci. Close to the fungus all bacteria were killed. • Biotechnological production of penicillins was established during the second world war and helped saving the life of many soldiers 13 Robert Koch ! Nobel laureate 1905 "for his discovery and treatment of tuberculosis" Bacteria under the electron microscope Escherichia Coli Stapphylococcus Aureus Pseudomonas Aeruginosa Cholera Pseudomonas Aeruginosa Since then.... • Early 1900: synthetic drugs, foundation of pharmaceutical industry • since 1930: screening of natural products, isolation of their bioactive ingredients • late 70 ies: Development of recombinant drugs (proteins, e.g. interferons). Development of biotechnology • 2000: Deciphering of the human genom, gene therapy (?), Investigation of the molecular basis of disease • future: Personalized medicine? History of drug development focus on molecular function accidential observation focus on Complexity cell-biology focus on biochemistry taken from: Real World Drug Discovery, R. Rydzewski, Elsevier 2008 Blockbuster (2004) Best-selling pharmaceutical products 2002–2004 Product Company Sales figures for 2002 Sales figures for 2003 Sales figures for 2004 Trade (Generic) name (US$ billion) (US$ billion) (US$ billion) Company IMS Company IMS Company IMS Lipitor (Atorvastatin) Pfizer •7.9 cholesterol-lowering0 8.60 medication9.23 10.3 10.86 12.00 Zocor (Simvastatin) Merck 5.6• lipid-lowering0 6.2 agent0 5.01 6.10 5.20 5.90 Plavix (Clopidrogrel) BMS and Sanofi-Aventis •3.1 anti-platelet0 medicationNA 4.20 3.70 5.20 5.00 Advair (Fluticasone; Salmetrol) GSK 2.0• anti-asthma0 medicationNA 3.60 NA 4.50 4.70 Norvasc (Amlodipine) Pfizer 3.8• blood0 pressure-lowering4.00 agent4.33 4.50 4.46 4.80 Zyprexa (Olanzapine) Eli-Lilly 3.6• anti-depressant0 4.00 4.27 4.80 4.42 4.80 Paxil (Paroxetine) GSK 1.9• anti-depressant0 NA 3.00 3.90 3.90 3.90 Nexium (Esomaprazole) AstraZeneca 1.9• decreases7 theN Aamount of acid3.30 produced in the3.8 0stomach 3.88 4.80 Zoloft (Sertraline) Pfizer 2.7• anti-depressant4 NA 3.10 3.40 3.36 NA Celebrex (Celecoxib) Pfizer 3.0• anti-inflammatory0 NA drug 1.90 2.50 3.30 NA Effexor (Venlafaxine) Wyeth 2.0• anti-depressant0 NA 2.70 NA 3.30 3.70 Prevacid (Lansoprazole) Takeda and Abbott •3.7 decreases0 the3.6 amount0 of acid3.3 0produced in the4.0 0stomach 3.10 3.80 Diovan (Valsartan) Novartis 1.6• prevents6 vasoconstrictionNA 2.50 NA 3.10 NA Fosamax (Alendronate) Merck •2.2 anti-osteoporosis0 NA agent 2.50 NA 3.10 NA Risperdal (Risperidone) J&J 2.1• antipsychotic0 N medicationA 2.50 NA 3.00 NA Global pharma market IMS US$550 billion; global biotechnology market valued at US$55 billion; global generic market US$62 billion. Table lists top 15 Medicines in 2004 with sales of over US$3 billion. Abbreviations: BMS, Bristol-Myers Squibb; GSK, GlaxoSmithKline; J&J, Johnson and Johnson; NA, not available. Blockbusters 2013 (C&N news, supl. 09/14) name disease area company drug class sales 2013 1 Humira (adalimumab) Rheumatoid AbbVie antibody $11 billion arthritis 2 Enbrel (etanercept) Rheumatoid Amgen recombinant $8.75 billion arthritis fusion protein 3 Advair (fluticasone Asthma, chronic GSK small molecule $8.3 billion propionate and salmeterol) obstructive pulmonary disease 4 Remicade (infliximab) Rheumatoid Johnson & antibody $8.3 billion arthritis Johnson/Janssen 5 Rituxan (rituximab) Lymphoma, Roche/Genentech antibody $8 billion leukemia and rheumatoid 6 Lantus (insulin glargine) Diabetes Sanofi insulin analogue $7.5 billion 7 Avastin (bevacizumab) Cancer Roche antibody $6.5 billion 8 Herceptin (trastuzumab) Cancer Roche/Genentech antibody $6.5 billion 9 Crestor (rosuvastatin) high cholesterol AstraZeneca small molecule $6 billion 10 Januvia (sitagliptin) diabetes Merck small molecule $6 billion Top small molecule drugs OH O O N H C S H O 3 CH O HO (CH ) (CH ) N 3 H 2 6 2 4 H O O O N N H HO O H C H CH H C 3 3 Salmeterol 3 H N O CH 3 (CH ) H H HO 2 4 F N O O HO 2C OH Cl N Budesonide Cl Rosuvastatin Aripiprazole O CH 3 OH N N H3C C F H N N N N H H F NH O N 2 CH CH O 3 OH CH N 3 2 N N NH N OHC Imatinib mesylate F N CF 3 Formoterol Sitagliptin CH 3NH S O O S NH NH 2 CH 2 3 N HO C O 2 CH N Duloxetine N 2 N O F C N N 3 N PO H N N 3 2 CH N 3 CH CH 3 3 Tenofovir Celecoxib Telmisartan H O CH N O 3 NH 2 N N O H N S N N OCH 3 N NH N 2 N CH H CH 3 S 3 O CO H HO O 2 CH O H3C S O 3 N Lenalidomide + CH N 3 Esomeprazole O CH Br - CH HO C 3 Pregabalin 3 O 2 CH 3 Tiotropium bromide Valsartan predicted blockbusters (sales started/start soon) Drug Company Revenue (Billion $) 1 Opdivo Bristol-Myers $ 5.684 melanoma (antibody) Squibb 2 2 Praluent Regeneron/ $ 4.414 cholesterol lowerer (antibody) Sanofi Sanofi 3 LCZ-696 Novartis $ 3.731 angiotensin receptor-neprilysin inhibitor (small molecule) 4 Ibrance Pfizer $ 2.756 breast cancer (small molecule) 5 Iumacaftor Vertex $ 2.737 cystis fibrosis (small molecule) 6 Viekira Pak AbbieVie $ 2.500 antiviral cocktail (small molecule) 7 Evolocumab Amgen/ $ 1.862 cholesterol lowerer (antibody) Astellas 8 Gardasil 9 Merck & Co. $ 1.637 cancer vaccine for young women 9 Brexpiprazole Ostuka/ $ 1.353 schizonphrenia/depression (small Lundbeck molecule) 10 Toujeo Sanofi $ 1.265 long-lasting insulin (protein) 11 Cosentyx Novartis $ 1.082 anti-inflammatory (antibody)
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