Chem 195 Drug Discovery

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Chem 195 - Drug Discovery

• Fridays 9-11 am - Hildebrand B36/Latimer 435/TBD
• One midterm, a final project - due 5/17 - outline
  due 4/19
• No lecture on February 22
• Course Web Page www.cchem.berkeley.edu/chem195/f
  ilename
• Number of guest lectures
• Office Hours - Latimer 549 time TBD

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Course Outline

• What is Drug Discovery?
• History of Drug Discovery
• Key Advances in Drug Discovery 1950 until today
• Drug Discovery Today
• Case Studies

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What is a drug?

• Defined composition with a pharmacological effect
• Regulated by the Food and Drug Administration
  (FDA)
• What is the process of Drug Discovery and
  Development?

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Drugs and the Discovery Process

• Small Molecules
• Natural products
• fermentation broths
• plant extracts
• animal fluids (e.g., snake venoms)
• Synthetic Medicinal Chemicals
• Project medicinal chemistry derived
• Combinatorial chemistry derived
• Biologicals
• Natural products (isolation)
• Recombinant products
• Chimeric or novel recombinant products

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Some recent blockbuster drugs
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Some not so typical drugs
Integrilin
Insulin
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Discovery vs. Development

• Discovery includes Concept, mechanism, assay,
  screening, hit identification, lead
  demonstration, lead optimization
• Discovery also includes In Vivo proof of concept
  in animals and concomitant demonstration of a
  therapeutic index
• Development begins when the decision is made to
  put a molecule into phase I clinical trials

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Discovery and Development

• The time from conception to approval of a new
  drug is typically 10-15 years
• The vast majority of molecules fail along the way
• The estimated cost to bring to market a
  successful drug is now 800 million!! (Dimasi,
  2000)

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Drug Discovery 100 years ago
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Drug Discovery Processes Today
Physiological Hypothesis
Primary Assays Biochemical Cellular
Pharmacological Physiological
Molecular Biological Hypothesis (Genomics)
Initial Hit Compounds
Screening

Sources of Molecules Natural Products
Synthetic Chemicals Combichem Biologicals
Chemical Hypothesis
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Drug Discovery Processes - II
Hit to Lead Chemistry - physical properties -in
vitro metabolism
Secondary Evaluation - Mechanism Of Action -
Dose Response
Initial Hit Compounds
Initial Synthetic Evaluation - analytics -
first analogs
First In Vivo Tests - PK, efficacy, toxicity
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Drug Discovery Processes - III
Lead Optimization Potency Selectivity Physical
Properties PK Metabolism Oral Bioavailability Synt
hetic Ease Scalability
Pharmacology Multiple In Vivo Models Chronic
Dosing Preliminary Tox
Development Candidate (and Backups)
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Drug Discovery Disciplines

• Medicine
• Physiology/pathology
• Pharmacology
• Molecular/cellular biology
• Automation/robotics
• Medicinal, analytical,and combinatorial chemistry
• Structural and computational chemistries

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Drug Discovery Program Rationales

• Unmet Medical Need
• Me Too! - Market - (s)
• Drugs in search of indications
• Side-effects often lead to new indications
• Indications in search of drugs
• Mechanism based, hypothesis driven, reductionism

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Serendipity and Drug Discovery

• Often molecules are discovered/synthesized for
  one indication and then turn out to be useful for
  others
• Tamoxifen (birth control and cancer)
• Viagra (hypertension and erectile dysfunction)
• Salvarsan (Sleeping sickness and syphilis)
• Interferon-a (hairy cell leukemia and Hepatitis
  C)

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Issues in Drug Discovery

• Hits and Leads - Is it a Druggable target?
• Resistance
• Pharmacodynamics
• Delivery - oral and otherwise
• Metabolism
• Solubility, toxicity
• Patentability

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Drug Discovery Early Approaches

• First pharmacological agents were natural
  products - often not always complex mixtures
• Foxglove -gt digitalis (1664)
• Willow Bark extracts -gt Salicylates -gt aspirin
• -gt Cox2 inhibitors
• As early as 1500 BC!
• Screening of agents which stained cells or
  micro-organisms differentially

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History of Modern Drug Discovery

• Paul Ehrlich (1854-1915) and Chemotherapy
• Confluence of microbiology - theory of infection
  (Koch, Pasteur) and the German chemical dye
  industry
• Saw immunity as a sub-set of chemotherapy
• Development of diagnostic tests with specific
  dyes for microorganisms
• Testing of diagnostic agents for antibiotic
  activity (Trypanosomes)

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Ehrlich conceived and recognized many of the key
elements in present drug discovery

• Recognition of chemicals for therapy
• Synthetic chemistry as a means to make many
  derivatives
• Metabolism - active metabolite concept
• Resistance - organismal, heritable basis

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Ehrlichs Analysis (1908) Leads to a Set of New
Molecules
Bechamp
Arsanilic Acid Active against Trypanosomes
In Vivo Metabolism
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Ehrlich and Parasitology

• A series of more than 300 compounds were made -
  at a new institute where there was a chemist and
  a bacteriologist.
• Compounds were tested for toxicity in the mouse
  and showed a range of gt 1500 fold but were
  relatively non-toxic.
• Then tested for anti-trypanosomal activity in a
  mouse model

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Ehrlich, Resistance, and Metabolism

• Arsanilic acid showed variable toxicity and
  efficacy in mouse model. The two correlated.
• The reduced forms showed greater toxicity and
  much greater anti-trypanosomal activity.
• Toxicity gt by 50 fold activity greater by more
  than 5,000 fold !
• Obtained mouse strains which were completely
  resistant!
• Some initial testing in resistant strain(s).

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Ehrlichs Most Successful Compounds
606 aka Salvarsan First useful
anti-Spirochete Treatment of Syphilis
418 Anti-trypanosomal compound In mice not man
Many compounds tested against trypanosomes first,
but the strain used was resistant to many! Then a
new post-doc came with expertise in a syphilis
spirochete model in the mouse. The same
compounds were tested and 606 shown to be
remarkably active. Salvarsan was then actually
used clinically as one of the first effective
treatments for Syphilis
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Summary

• Drug Discovery is interdisciplinary
• Serendipity can play a major role
• Chance rewards the prepared mind
• Early work started with in vivo models and no
  knowledge of mechanism
• Drug Discovery today is driven by an
  understanding of the molecular basis of disease

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Reading for Chem 195

• Chapter 7 - General Approaches to Discovering New
  Drugs An Historical Perspective by C.R.
  Ganellin in Medicinal Chemistry, the role of
  Organic Chemistry in Drug Research 2nd Edition
• Dimasi review - New Drug Development in the US
  1963 to 1999 - posted as pdf at
  cchem.berkeley.edu/chem195/Dimasi.pdfEhrlich
  review - Erhlich.pdf
• http//pubs.acs.org/journals/pharmcent/index.html
  - The Pharmaceutical Century
• Lecture notes will be posted at /lecture1.ppt

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Next Week

• History of Drug Discovery
• The sulfonamides
• Aspirin and Insulin, if time allows