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Veröffentlicht von:Bernhardt Nanninga Geändert vor über 10 Jahren
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- From Leads to Developmental Candidates -
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, )
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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 = min-1 (50-fold) S = 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 = 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 => labile ester group is required!
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Lead Optimization - Example IV From Peptides to Peptidomimetics
Fibrinogen binds to Fibrinogen receptor => Initiation of blood clotting Binding is inhibited by Arg-Gly-Asp (RGD)-tripeptid
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Lead Optimization - Example IV From 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 Prodrug: 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 Prodrug: 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 Drug: Prodrug: orally active rapid penetration of blood-brain barrier due to amino acid carrier! Auxillary drugs: central MAO inhibitor prevents dopamine oxidation peripheral decarboxylase inhib. prevents L-Dopa decarboxylation
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The Prodrug concept - Example IV
anti-convulsive neurotransmitter orally inactive no penetration of blood-brain barrier Prodrug: 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
(Taken from Oprea et al., J. Chem. Inf. Comput. Sci. 2001, 41, ) 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 Approach:Screening Scenarios
Library Size lead like drug like HTS of company pools 1,000,000 100,000 10,000 1,000 100 10 Graffinity SAR by NMR CrystalLEAD In-Silico Screens 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
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