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Lead Optimization - From Leads to Developmental
Candidates -
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Why do drugs fail in clinical development?
(Taken from Kennedy, Drug Discovery Today, 2
(10), 1997, 436-444)
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Water Solubility as a parameter for lead
optimization
Is there a relationship between bioavailability
and water solubility?
Yes, there is. It's called MAD!
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Water Solubility as a parameter for lead
optimization
The concept of the maximum absorbable dose
(MAD) MAD S x Ka x SIWV x SITT S water
solubility at pH 6.5 (mg/ml) Ka transintestinal
absorption rate constant (1/min) SIWV small
intestinal water volume ( 250 ml) SITT small
intestinal transit time ( 270 min)
Typical dose for a drug is 1 mg/kg ? for a 70 kg
patient, 70 mg drug substance must be
available in the blood
Ranges typical for drug candidates Ka 0.001 -
0.05 min-1 (50-fold) S 0.0001 - 100 mg/ml
(106-fold)
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Water Solubility as a parameter for lead
optimization
The concept of the maximum absorbable dose (MAD)
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Water Solubility as a parameter for lead
optimization
How soluble does a drug candidate have to be???
S MAD / (Ka x SIWV x SITT)
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Water Solubility as a parameter for lead
optimization
Azithromycin
Very poor absorption (Ka 0.001 min-1) Very high
water solubility (S 50 mg/ml) ?MAD 3375 mg ?
Good oral bioavailability!
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• Goals and Concepts in Lead Optimization

• Increasing in-vitro potency/efficacy by
• bioisosteric replacement of functional groups
• gradual modification of 3D shape and/or
  physicochemical properties
• Improving PC/ADME/Tox behaviour by
• replacement of toxophores
• modification of physicochemical properties (e.g.
  lipophilicity, charge, flexibility etc.)
• replacement of metabolically labile groups
• pro-drug concept

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Lead Optimization
What can be modified?
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Lead Optimization
?Modifications of aromatic substituents
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Lead Optimization
? Modifications of amide group
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Lead Optimization
? Modifications of cyclohexyl group
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Lead Optimization
? Modifications of carboxyl group
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Lead Optimization
? Modifications of chain length
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Lead Optimization
? Modifications of aromatic substituents
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The Topliss Tree A systematic lead optimization
approach
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Lead Optimization - Example I

• hormone of the thyroidal gland
• agonist of thyroxine receptor

• bioisosterical replacements of iodo groups
• potent agonist of thyroxine receptor

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Lead Optimization - Example II

• hydrophilic neurotransmitters
• orally inactive
• no penetration of blood-brain barrier

• lipophilic adrenaline mimics
• orally active
• good penetration of blood-brain barrier
• centrally stimulating effect

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Lead Optimization - Example III

• analgesic drug
• activity due to COX inhibition

• no analgesic effect
• bioisosteric replacement of ester by amide
  failed!

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Acetyl salicylic acid Mechanism of Action

• acetyl group is transferred to serine in
  active site of COX
• gt labile ester group is required!

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Lead Optimization - Example IVFrom Peptides to
Peptidomimetics
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Lead Optimization - Example IVFrom Peptides to
Peptidomimetics
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• The Prodrug concept

• Prodrugs are weak or inactive precursers of drugs
• Active drug is only generated after
  biotransformation of prodrug
• by metabolic transformation
• by spontaneous chemical degradation
• Goal improved ADME/Tox- or physicochemical
  properties

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The Prodrug concept - Example I

• central analgesic
• orally inactive
• slow penetration of blood-brain barrier

• orally inactive
• rapid penetration of blood-brain barrier
• degradation to morphine in brain
• accumulation of morphine in brain

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The Prodrug concept - Example II

• anti-hypertensive drug
• orally inactive

• orally active due to amino acid carrier
• degradation to Enalaprilat by esterases

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The Prodrug concept - Example III

• Morbus Parkinson drug
• orally inactive
• slow penetration of blood-brain barrier

• orally active
• rapid penetration of blood-brain barrier due
  to amino acid carrier!

Auxillary drugs
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The Prodrug concept - Example IV

• anti-convulsive neurotransmitter
• orally inactive
• no penetration of blood-brain barrier

• orally active
• rapid penetration of blood-brain barrier

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Drug Discovery What's next?
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Differences between leads and drugs

• Drugs compared to leads
• are heavier
• are more lipophilic
• have more ring systems, rotatable bonds,
  H-acceptors

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The Graffinity Approach
Technology

• Small molecules are immobilized on gold surface
• Protein-Ligand Affinity is measured via
  Surface-Plasmon Resonance

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The Graffinity ApproachScreening Scenarios
drug like
lead like
Library Size
1,000,000 100,000 10,000 1,000 100 10
100 200 300
400 500 600
Molweight
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The Graffinity Approach Library Synthesis
Technology

• Diversity in Microtiterplates

• LC/MS Quality control

• Daughter Microarrays

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The Graffinity Approach Library Synthesis
Technology
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The Graffinity Approach Detection
Technology

• Minimal Amounts of Protein
• Protein-Ligand Affinity Maps
• Surface-Plasmon Resonance
• No Assay Development
• Function-Blind

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Principle of Surface Plasmon Resonance - a
means to detect Protein-Ligand binding
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The Graffinity Approach Detection
Technology

• Immediate Rank-Order of Affinities

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The Graffinity Approach SAR Analysis
Technology