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Medicinal 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 ) of drugs • drug-receptor interactions • development of drugs • screening techniques • (D.O.) • classical medicinal chemistry, hit-to-lead development • fragment-based • 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: , Churchill Livingstone; 6th ed. • E.J. Corey, B. Czakó, L. Kürti, and (Wiley) • D.S. Johnson, J.J. Li: The Art of Drug Synthesis (Wiley) ! Journals: • Nature Reviews • 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 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? Complexity observation accidential accidential History of of drug History focus on taken from:taken Real World Drug Discovery cell-biology focus on molecular function , R. Rydzewski, Elsevier 2008 ,Elsevier R. Rydzewski, focus on 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 () 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 (; 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 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 sales 2013

1 Humira (adalimumab) Rheumatoid AbbVie $11 billion arthritis 2 Enbrel (etanercept) Rheumatoid Amgen recombinant $8.75 billion arthritis fusion protein 3 Advair (fluticasone Asthma, chronic GSK small $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 $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 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)

http://www.ibtimes.com/11-blockbuster-drugs-watch-2015-1857100 Properties of typical drugs

• small, organic molecules (Lipinski’s Rule of Five): molecularweight < 500, not too polar, not too many functional groups that can serve as H-bond donors or acceptors • or: natural products • should be not too complicated (price!) • no reactive groups in the molecule Typical drugs

Cl O OH OH F COOH HN N N N N H O NH N O F COOH N O F O N

Atorvastatin Ciprofloxacin Gefitinib

NH2 HO H N OH H H H OH N N N N S N HO O N O O O NH COOH HN O NH S

Indinavir Imipenem Lamivudine

O O N O CH3 O N CH O O HN 3 NH N F N O N N S S H O N N N O N H H3C O O

Linezolid Rosiglitazone Sildenafil

gleevecgleevec Blockbusters are often similar....

HO OChiral Cl DDT Vol. 7, No. 10 May 2002 N O HO O N N N O N NH

H N O S N Me N Lovastatin O Losartan Omeprazole O Me

HO OChiral H O N N O N S NH N O N F F O O N H N O F HO O Lansoprazole

Simvastatin Valsartan Drug Discovery Today

Figure 8. Structural similarity in blockbusters. Examples of structural similarities between compounds within a given class: 3-hydroxy-3-methylglutaryl CoA (HMGCoA) reductase inhibitors (lovastatin and simvastatin), angiotensin II antagonists (losartan and valsartan), and proton-pump inhibitors (omeprazole and lansoprazole). Recombinant Drugs

SUPPLEMENTARY INFORMATION In format provided by Goodman (NOVEMBER 2009)

Table S2 | Top five products by consensus revenue in 2013E

Product Company 2013E consensus 2012E–2013E revenue (billions) % change

Avastin Roche $8.90 6%

Advair Diskus GlaxoSmithKline $8.58 -10%

Humira Abbott $7.98 2%

Mabthera/Rituxan Roche $7.56 3%

Lantus Sanofi-Aventis $6.84 7%

NATURE REVIEWS | DRUG DISCOVERY www.nature.com/reviews/drugdisc Portfolio share of biologics Derivates of Natural Products Gleevec: Target Identification

• Identification of an oncogene (a gene that results in increases tumorgenic activity): – chronic myelogenous Leukaemia is characterized by excessive proliferation of certain cells – CML results from gene translocation between chromosomes 9 and 22 – as a result a BCR-ABL gene is created, that encoded for the BCR-ABL kinase – The sole expression of the BCR-ABL gene is identified as the sole oncogenic event resulting in induction of Leukaemia in mice.

Capdeville, Nat.Rev.Drug.Discov. 1 (2002),493 Gleevec: Medicinal Chemistry

• Lead compound identified from screen for inhibitors of the protein kinase C (PCK). Strong binding is retained when the pyridyl unit is added.

• Presence of an amide group on the phenyl ring provided inhibitory activity against tyrosine kinases such as BCR-ABL kinase (target hopping)

• Substitution at position 6 of the diaminophenyl ring abolished PCK inhibitory activity while retaining it at tyrosine kinases (increasing selectivity)

• Improvement of ADME properties. Addition of a polar side-chain markedly increases both solubility and oral . To avoid the mutagenic potential of aniline

compounds a CH2 spacer was inserted.

Capdeville, Nat.Rev.Drug.Discov. 1 (2002),493 Gleevec binds to the inactive conformation of BCR-ABL

• the structures of active kinases are similar. Hence it is difficult to find a selective inhibitor for kinases • Gleevec binds to the inactive form, which is structurally different in the various kinases, and thereby achieves good selectivity Gleevec: Pharmacological Profiling

• In-vitro studies – The selective inhibitory activity of Gleevec was demonstrated on a cellular level on the constitutively active p210(BCR-ABL) kinase. – Inhibition of autophosphorylation of BCR-ABL by Gleevec • In-vivo studies – treatment of BCR-ABL transformed cell-lines with Gleevec results in dose-dependent reduction of tumor growth – the anti-tumor effect is specific for BCR-ABL expressing cells – Gleevec re-activates apoptosis in BCR-ABL cells by suppressing the capacity of STAT5 to activate the expression of the anti-

apototic protein BCL-XL. – Gleevec restores normal cell-cycle progression

Capdeville, Nat.Rev.Drug.Discov. 1 (2002),493 Gleevec: Clinical Development

Chronic phase Advanced phases

Accelerated phase Blastic phase (blast crisis)

Median duration up Median survival Median 4–6 years stabilization to 1 year 3–6 months

• Demonstration of dose-response relationship in patients with chronic phase CML. • mathematical modelling of data confirmed the useful therapeutic dose to be around 400mg • a large multinational study with close to 1000 patients from all three phases of the disease revealed that treatment was most efficient when started in an early phase of disease progression • approval by FDA in 2001 • efficiency of Gleevec can be improved by co-administration of inhibitors of P-glycoprotein • studies of factors leading to Gleevec resistance

Capdeville, Nat.Rev.Drug.Discov. 1 (2002),493 Time-Frame for Development

Glivec development timeline May 2001 – Approved by the FDA for CML.

June 1998 – June 2000 – November 2001 – 1990 – Lead compound 1996 – In vivo activity shown First patient with Phase III trials Approved in identified in a screen for in BCR–ABL-transformed CML treated. initiated. Europe and Japan inhibitors of PKC. cells in syngeneic mice. for CML.

Discovery Clinical development

H H

N N N

N O

N

1992 – First batch June 1999 – February 2001 – February 2002 – of Glivec synthesized. Phase II trials NDA submitted Approved by the initiated. to FDA for CML. FDA for GIST.

Typical development timeline

Clinical Discovery development Typically ~8 years Typically ~7 years

Capdeville, Nat.Rev.Drug.Discov. 1 (2002),493 Fighting resistances arising from Gleevec

• resistances occur upon selective pressure for forming mutations that do not bind any more to Gleevec • a non-competitive inhibitor may suppress formation of drug- resistant BCR-ABL mutants because resistant strains need to develop mutations in two unrelated regions of the protein simultaneously • a allosteric inhibitor was developed that binds to the myristate binding site of the BCR-ABL kinase (GNF-2/GNF-5) • combination therapy with Gleevec and GNF-2 seems to completely suppress formation of resistant forms of BCR-ABL kinase

Zhang et al., Nature 2010 (463), 501. Development of allosteric inhibitors of BCR-ABL

122.0 122.0

123.0 123.0

124.0 124.0

125.0 125.0 8.0 7.0 p.p.m. 8.0 7.0 p.p.m.

ATP binding! site

myristyl binding! site

Zhang et al., Nature 2010 (463), 501. combinations are more resistant towards resistance

Mutations indicated by red spheres on Abl with size proportional to the degree of resistance

Kinase domain 91 91 96 SH3 domain 84 S229P 96 81 P112S T315l 75 72 Catalytic site 96 100 H N Resistant colonies 2 2 66 0 7 10 0 59 Day 21 52 Y128D 4 Y139C 50 0 2 0 4 Day 12 SH2 domain 2 0 0 2 C464Y 0 Day 9 V506L P465S 0 F497L 25 10 5 4 2 1 25 10 5 Myristoyl E505K pocket GNF-2 Imatinib GNF-2 + 1 µM imatinib COOH Concentration (µM)

Effect of various concentrations of GNF-2, imatinib, or combinations of both on the number of emerging Ba/F3.Bcr–Abl-resistant clones

Zhang et al., Nature 2010 (463), 501.