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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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1 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Lead Optimization - From Leads to Developmental Candidates -

2 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, )

3 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!

4 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 The concept of the maximum absorbable dose (MAD): MAD = S x K a x SIWV x SITT Swater solubility at pH 6.5 (mg/ml) K a transintestinal absorption rate constant (1/min) SIWVsmall intestinal water volume (~ 250 ml) SITTsmall intestinal transit time (~ 270 min) Water Solubility as a parameter for lead optimization Ranges typical for drug candidates: K a = min -1 (50-fold) S = mg/ml (10 6 -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

5 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Water Solubility as a parameter for lead optimization The concept of the maximum absorbable dose (MAD):

6 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 How soluble does a drug candidate have to be??? Water Solubility as a parameter for lead optimization S = MAD / (K a x SIWV x SITT)

7 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Azithromycin Water Solubility as a parameter for lead optimization Very poor absorption (K a = min -1) Very high water solubility (S = 50 mg/ml) MAD = 3375 mg Good oral bioavailability!

8 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

9 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Lead Optimization What can be modified?

10 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Modifications of aromatic substituents Lead Optimization

11 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Lead Optimization Modifications of amide group

12 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Lead Optimization Modifications of cyclohexyl group

13 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Lead Optimization Modifications of carboxyl group

14 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Lead Optimization Modifications of chain length

15 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Lead Optimization Modifications of aromatic substituents

16 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 The Topliss Tree A systematic lead optimization approach

17 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Lead Optimization - Example I hormone of the thyroidal gland agonist of thyroxine receptor bioisosterical replacements of iodo groups potent agonist of thyroxine receptor

18 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 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

19 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 analgesic drug activity due to COX inhibition no analgesic effect bioisosteric replacement of ester by amide failed! Lead Optimization - Example III

20 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Acetyl salicylic acid: Mechanism of Action Ø acetyl group is transferred to serine in active site of COX => labile ester group is required!

21 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Lead Optimization - Example IV From Peptides to Peptidomimetics Ø Fibrinogen binds to Fibrinogen receptor => Initiation of blood clotting Ø Binding is inhibited by Arg-Gly-Asp (RGD)-tripeptid

22 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Lead Optimization - Example IV From Peptides to Peptidomimetics

23 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

24 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 The Prodrug concept - Example I Drug: 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

25 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 The Prodrug concept - Example II Drug: Prodrug: anti-hypertensive drug orally inactive orally active due to amino acid carrier degradation to Enalaprilat by esterases

26 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 The Prodrug concept - Example III Drug: 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: central MAO inhibitor prevents dopamine oxidation peripheral decarboxylase inhib. prevents L-Dopa decarboxylation

27 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Drug: 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

28 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Drug Discovery: What's next?

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

30 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Technology The Graffinity Approach ØSmall molecules are immobilized on gold surface ØProtein-Ligand Affinity is measured via Surface-Plasmon Resonance

31 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/ Molweight 1,000, ,000 10,000 1, HTS of company pools Library Size drug likelead like The Graffinity Approach:Screening Scenarios SAR by NMR CrystalLEAD In-Silico Screens Graffinity

32 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

33 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Technology The Graffinity Approach: Library Synthesis

34 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

35 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Principle of Surface Plasmon Resonance - a means to detect Protein-Ligand binding

36 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Technology ØImmediate Rank-Order of Affinities The Graffinity Approach: Detection

37 Dr. Hans Briem Einführung in die Arzneimittelforschung - Vorlesung WS 2001/2002 Technology The Graffinity Approach: SAR Analysis


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