IV' Optimize Lead Compound

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IV. Optimize Lead Compound

• Structure-activity relationships (SARs)

Alcohol
Amine
2
Alkene
Aromatic
No fit
3
IV. Optimize Lead Compound
Ketone
Ester
4
Esters as prodrugs
5
Amide
6
Carboxylic acids
7
Isosteres and Bioisosteres
Propranolol
8
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
• 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
14
b-Adrenoceptor
15
b-Adrenoceptor
SALBUTAMOL
16
a-Adrenoceptor
17
a-Adrenoceptor
18
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

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VI. Market
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Oxamniquine

• Case study

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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