Drug Discovery, Development, and Design

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Drug Discovery, Development, and Design

• Chapters 9, 10, and 12

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Drug Discovery

• History
• General plan
• Successful process
• More than 10 years
• More than 300 million
• More than 10000 tested compounds
• For one drug!

IV. Optimize lead
III. Find a lead compound
II. Choose a drug target
I. Choose a disease
VI. Market
V. Clinical Trials
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I. Choosing a Disease

• What factors?
• Medical
• Economic
• Geographical

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II. Choosing a Drug Target

• What are they?
• How are they discovered?
• From drugs
• From chemical messengers
• Molecular genetics
• Multiple targets
• Bioassay
• In Vitro
• High throughput screening
• NMR
• In Vivo

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III. Find a Lead Compound

• Where?
• Random screening
• Synthetic chemicals
• Natural products

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III. Find a Lead Compound

• Existing drugs
• Previously marketed for same disease
• Used for other diseases

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III. Find a Lead Compound

• Existing drugs
• Natural substrate or product
• Alter structure (cimetidine)
• Product of enzyme catalysis
• Enzyme inhibitor
• Allosteric substrate

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III. Find a Lead Compound

• Existing drugs
• Natural substrate or product
• Combinatorial synthesis

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III. Find a Lead Compound

• Existing drugs
• Natural substrate or product
• Combinatorial synthesis
• Computer-aided design
• X-ray crystallography of binding sites
• Molecular modeling to design drug

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III. Find a Lead Compound

• Existing drugs
• Natural substrate or product
• Combinatorial synthesis
• Computer-aided design
• Chance

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III. Find a Lead Compound

• Existing drugs
• Natural substrate or product
• Combinatorial synthesis
• Computer-aided design
• Chance
• NMR

Binding Site
Protein
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Protein
NO OBSERVABLE BIOLOGICAL EFFECT
13
13C NMR
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CH3
CH
CH
CH3
CH2
CH2
CH
C
C
13C NMR
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Protein
Optimize epitope
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Protein
Optimize epitope
Optimize epitope
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Link
Protein
Optimize epitope
Optimize epitope
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LEAD COMPOUND
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Me
Epitope B
Epitope A
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Lead compound
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III. Find a Lead Compound

• After lead compound is found, but before
  optimizing
• Isolate
• Purify
• Structural confirmation

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IV. Optimize Lead Compound

• Structure-activity relationships (SARs)

Alcohol
Amine
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Alkene
Aromatic
No fit
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IV. Optimize Lead Compound
Ketone
Ester
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Esters as prodrugs
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Amide
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Carboxylic acids
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Isosteres and Bioisosteres
Propranolol
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Other functional groups

• Acid chlorides
• Anhydrides
• Alkyl halides
• Aryl halides
• Nitro groups
• Alkynes
• Thiols
• Nitriles

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Example
Slightly reduced activity
Activity eliminated
Activity eliminated
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IV. Optimize Lead Compound

• Analogs of pharmacophore (remember morphine)
• Goals?
• 1. Variation of alkyl substituents
• 2. Variation of chain length

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3. Extension of structure
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Example
Adrenaline
Salbutamol (Ventolin) (Anti-asthmatic)
Propranolol (b-Blocker)
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b-Adrenoceptor
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b-Adrenoceptor
SALBUTAMOL
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a-Adrenoceptor
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a-Adrenoceptor
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Variation of Ring Size and Structure
4. Change in substitution pattern
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Variation of Ring Size and Structure
5. Variation in ring size
6. Variation in ring structure
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7. Simplification
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Procaine from Cocaine
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8. Rigidification
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Example
Less active
More active
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Problems to Consider

• Pharmacokinetics
• Metabolism
• Prodrugs
• Synthesis/Manufacturing process

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V. Toxicity Testing and Clinical Trials

• Testing
• Trials
• Phase 1
• Phase 2
• Phase 3
• Phase 4
• Orphan drugs

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VI. Market

• Patents
• Pharmaceutical reps
• AMSA PharmFree project

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Oxamniquine

• Case study
• Read pp.219-223 and summarize (5 point
  assignment)
• Due Wednesday, 3/12

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Pharmacophore
2.19 morphine (R R H) codeine (R CH3, R
H) heroin (R R COCH3)
2.20 levorphanol (R OH) 2.23 meperidine
(Demerol) 2.24 dextropropoxyphene
(Darvon) 2.25 methadone
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