dr. hans briem einführung in die arzneimittelforschung - vorlesung ws 2001/2002 lead optimization -...
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
Lead Optimization
- From Leads to Developmental Candidates -
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
Why do drugs fail in clinical development?
(Taken from Kennedy, Drug Discovery Today, 2 (10), 1997, 436-444)
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
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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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
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)
Water Solubility as a parameter for lead optimization
Ranges typical for drug candidates:
Ka = 0.001 - 0.05 min-1 (50-fold)S = 0.0001 - 100 mg/ml (106-fold)
Typical dose for a drug is 1 mg/kg
for a 70 kg patient, 70 mg drug substance must be available in the blood
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
Ka
(1/min)Solubility(mg/ml)
MAD(mg)
0.003 0.001 0.2
0.003 0.01 2.03
0.003 0.1 20.3
0.003 1.0 203
0.03 0.001 2.03
0.03 0.01 20.3
0.03 0.1 203
0.03 1 2030
Water Solubility as a parameter for lead optimization
The concept of the maximum absorbable dose (MAD):
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
How soluble does a drug candidate have to be???
Dose(mg/kg)
Dose(mg)
MAD(mg)
Ka
(1/min)Solubility(mg/ml)
0.1 7 7 0.003 0.035
0.030 0.004
1.0 70 70 0.003 0.346
0.030 0.035
10 700 700 0.003 3.460
0.030 0.350
Water Solubility as a parameter for lead optimization
S = MAD / (Ka x SIWV x SITT)
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
Azithromycin
Water Solubility as a parameter for lead optimization
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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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
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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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
N
OH
OH
O
HOOC
Lead Optimization
What can be modified?
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
N
OH
OH
O
HOOC
Hal
N
OH
OH
O
HOOC
CH3
N
OH
OH
O
HOOC
NH2
N
OH
OH
OBr
Br
HOOC
Modifications of aromatic substituents
Lead Optimization
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
N
OH
OH
O
HOOC
NH
OH
OH
O
HOOC
NH
OH
OH
O
HOOC
N
OH
OHHOOC
Lead Optimization
Modifications of amide group
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
N
OH
OH
O
HOOC
N
OH
OH
O
HOOC
NN
OH
OH
O
HOOC
N
ON
OH
OHHOOC
N
OH
OH
O
HOOC
Lead Optimization
Modifications of cyclohexyl group
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
N
OH
OH
O
HOOC
N
OH
OH
O
NH2
N
OH
OH
O
N
N
NHN
N
OH
OH
O
O
O
Lead Optimization
Modifications of carboxyl group
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
N
OH
OH
O
HOOC
N
O
HOOC
OH
OH
N
O
HOOC
OH
OH
Lead Optimization
Modifications of chain length
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
N
OH
OH
O
HOOC
N
O
O
O
HOOC
N
Hal
O
HOOC
N
O
HOOC
NH
N
Lead Optimization
Modifications of aromatic substituents
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
The Topliss Tree A systematic lead optimization approach
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
O
NH2
OH
I
I
I
COOHThyroxin
O
NH2
OH CH3
CH3
COOH
CH3
CH3
3,5-dimethyl-3'-isopropyl-thyronine
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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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
NH2OH
OH
Dopamine
NH
OH
OH
OH
CH3
Adrenaline
NH2
CH3
Amphetamine ("Speed")
NH
O
O CH3
CH3
MDMA ("Ecstasy")
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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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
O
O
COOH
Acetyl salicylic acid
NH
O
COOH
Amide derivative
• analgesic drug• activity due to COX inhibition
• no analgesic effect• bioisosteric replacement of ester by amide failed!
Lead Optimization - Example III
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
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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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
Lead Optimization - Example IVFrom 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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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
Lead Optimization - Example IVFrom Peptides to Peptidomimetics
O
NH
NH2
NH
H3N
O
NH
O
NH
O
O
O
Arg-Gly-Asp (RGD)
O
O
NH
N
N
N
N
O
HNH
O
NH
O
O
O
cyclo-(Arg-Gly-Asp-Phe-d-Val)
NH
N
N
N
N
O
CH3
NH
O
NH
O
O
O
S
O
S
NH
NH
N
COOHNH2
NH
O
O
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
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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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
The Prodrug concept - Example I
O
OH
OH
NCH3
Morphine
Drug:
O
O
O
NCH3
CH3
O
CH3
O
Diacetyl-morphine(Heroin)
Prodrug:
• 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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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
NH
N
O
O
O
CH3
OO
Enalapril-diester
The Prodrug concept - Example II
NH
N
O
OH
O
CH3
OHO
Enalaprilat
Drug:
NH
N
O
O
O
CH3
OHO
Enalapril
Prodrug:
• anti-hypertensive drug• orally inactive
• orally active due to amino acid carrier• degradation to Enalaprilat by esterases
NO
O
CH3
NO
O
Diketopiperazin derivative
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
The Prodrug concept - Example III
NH2OH
OH
Dopamine
Drug:
NH2OH
OHCOOH
L-Dopa
Prodrug:
• 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:
N
CH3
CH3
CH
Selegilin
• central MAO inhibitor• prevents dopamine oxidation
NNH
OH
OH
OH
OH
NH2
O
Benserazid
• peripheral decarboxylase inhib.• prevents L-Dopa decarboxylation
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
NH2 OH
O
GABA (gamma-amino butyric acid)
Drug:
N
Cl
F NH2
OOH
Progabid
Prodrug:
• anti-convulsive neurotransmitter• orally inactive• no penetration of blood-brain barrier
• orally active• rapid penetration of blood-brain barrier
The Prodrug concept - Example IV
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
Drug Discovery:
What's next?
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
Differences between leads and drugs
(Taken from Oprea et al., J. Chem. Inf. Comput. Sci. 2001, 41, 1308-1315)
Drugs compared to leads are heavier are more lipophilic have more ring systems, rotatable bonds, H-acceptors
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
TechnologyThe Graffinity Approach
Small molecules are
immobilized on gold surface
Protein-Ligand Affinity is measured
via Surface-Plasmon Resonance
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
100 200 300 400 500 600 Molweight
1,000,000
100,000
10,000
1,000
100
10
HTS of company pools
Library Sizedrug likelead like
The Graffinity Approach:Screening Scenarios
SAR by NMRCrystalLEAD
In-Silico Screens
Graffinity
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
• Diversity in Microtiterplates
Technology
• LC/MS Quality control
• Daughter Microarrays
The Graffinity Approach: Library Synthesis
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
TechnologyThe Graffinity Approach: Library Synthesis
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
Technology
• Minimal Amounts of Protein
• Protein-Ligand Affinity Maps
• Surface-Plasmon Resonance
• No Assay Development
• Function-Blind
The Graffinity Approach: Detection
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
Principle of Surface Plasmon Resonance - a means to detect Protein-Ligand binding
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
Technology
Immediate Rank-Order of Affinities
The Graffinity Approach: Detection
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Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002
TechnologyThe Graffinity Approach: SAR Analysis