Medicinal Chemistry

all material is available online as pdf files under the following URL:
http://www.oci.uzh.ch/group.pages/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 computational chemistry in drug development (K.B.) patent issues

Books and other information sources

Monographs: G. Patrick: Introduction to Medicinal Chemistry, Oxford University Press, 2005 (very good introduction) H.-J. Bhm, 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. Czak, L. Krti, 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
of the mother

2 infection of appendix 3 accidents

3 quality of life 1 2

age

Medicine ca. 1950

1 childbed fever of the mother asepsis 3 2 infection of the appendix 3 accident tetanus vaccination anesthesia, antibiotics

quality of life
1

age

Medicine after ~ 1950

quality of life

age

most common cause of death for 22-44 year old people

65 years and older...

Male Arteriosclerosis Cardiac Infarction Lung Cancer 7,7% 6,9% 4,7% 3,8% 3,7% 2,9% 2,8% 2,4% 1,7% 9,7% 9,8% 8,3% 6,1% 4,3% 3,5% 3,0% 2,7% 2,3% 2,1% 2,1% Female Arteriosclerosis Cardiac insu ciency Cardiac Infarction Stroke hypertension-related heart condition Breast cancer Pneumonia Cardiac arrhythmia Lung Cancer obstructive lung disease (smokers lung)

Cardiac insu ciency obstructive lung disease (smokers lung) Prostate Cancer

Stroke Pneumonia Colon Cancer Pancreatic Cancer

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 recipies 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 recipies Era of horrible epidemics (e.g. Pest, Lepra, Pox, Tuberculosis) Arabic medicine: Development of medical procedures for drug preparation (destillation)

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 inocculated a boy with blister fluid from a woman with cowpox. He later inocculated 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 froim 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

nosa

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

History of drug development

Complexity

focus on molecular function accidential observation focus on cell-biology

focus on biochemistry

Blockbuster
Best-selling pharmaceutical products 20022004
Product Trade (Generic) name Lipitor (Atorvastatin) Zocor (Simvastatin) Plavix (Clopidrogrel) Advair (Fluticasone; Salmetrol) Norvasc (Amlodipine) Zyprexa (Olanzapine) Paxil (Paroxetine) Nexium (Esomaprazole) Zoloft (Sertraline) Celebrex (Celecoxib) Effexor (Venlafaxine) Prevacid (Lansoprazole) Diovan (Valsartan) Fosamax (Alendronate) Risperdal (Risperidone) Pfizer Merck Company Sales figures for 2002 (US$ billion) Company IMS Sales figures for 2003 (US$ billion) Company IMS 10.3 Sales figures for 2004 (US$ billion) Company 10.86 5.20 5.20 4.50 4.46 4.42 3.90 3.88 3.36 3.30 3.30 3.10 3.10 3.10 3.00 IMS 12.00 5.90 5.00 4.70 4.80 4.80 3.90 4.80 NA NA 3.70 3.80 NA NA NA

cholesterol-lowering 7.90 8.60 medication 9.23

5.60 5.01 6.10 lipid-lowering6.20 agent anti-platelet medication BMS and Sanofi-Aventis 3.10 NA 4.20 3.70 anti-asthma medication GSK 2.00 NA 3.60 NA blood pressure-lowering agent Pfizer 3.80 4.00 4.33 4.50 Eli-Lilly 3.60 4.00 4.27 4.80 anti-depressant anti-depressant GSK 1.90 NA 3.00 3.90 amount of acid produced in the stomach AstraZeneca 1.97 NA 3.30 3.80 decreases the anti-depressant Pfizer 2.74 NA 3.10 3.40 Pfizer Wyeth Takeda and Abbott Novartis Merck J&J 3.00 NA drug anti-inammatory 2.00 NA anti-depressant 1.90 2.70 2.50 NA

3.70 3.60 3.30 4.00 decreases the amount of acid produced in the stomach prevents vasoconstriction 1.66 NA 2.50 NA 2.20 NA agent 2.50 NA anti-osteoporosis antipsychoticNA medication 2.50 2.10 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.

Properties of typical drugs

small, organic molecules (Lipinskis 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 chemical synthesis should be not too complicated (price!) no reactive groups in the molecule

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

Atorvastatin

Ciprofloxacin

Gefitinib

HO H N N O N NH O OH H N OH

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

Indinavir
O N F N H

Imipenem

Lamivudine

O O O H N O N CH3 N O S NH O H3C N O O S N HN

O N

CH3 N

N O

Linezolid

Rosiglitazone

Sildenafil

Blockbusters are often similar....

HO O O O N N N NH H N S Me OChiral HO N Cl N

DDT Vol. 7, No. 10 May 2002

O N

Lovastatin

Losartan Omeprazole
O Me

HO O O H O

OChiral N H N NH N S O O N F F F

N O N HO O N

Lansoprazole Valsartan
Drug Discovery Today

Simvastatin

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
Interferon GM-CSF EPO Antibodies Insulin Factor VIII 3 Mrd. $ 2,5 Mrd. $ 3,5 Mrd. $ 2,2 Mrd. $ 2,9 Mrd. $ 0,5 Mrd. $

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 bioavailability. To avoid the mutagenic potential of aniline compounds a CH2 spacer was inserted.

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 antiapototic protein BCL-XL. Gleevec restores normal cell-cycle progression

Gleevec: Clinical Development

Chronic phase Accelerated phase Advanced phases Blastic phase (blast crisis) Median 46 years stabilization Median duration up to 1 year Median survival 36 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

Time-Frame for Development

Capdeville, Nat.Rev.Drug.Discov. 1 (2002),493