- From Leads to Developmental Candidates -

Präsentation zum Thema: "- From Leads to Developmental Candidates -"—  Präsentation transkript:

1 - From Leads to Developmental Candidates -
Lead Optimization - From Leads to Developmental Candidates -

2 Why do drugs fail in clinical development?
(Taken from Kennedy, Drug Discovery Today, 2 (10), 1997, )

3 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 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)

5 Water Solubility as a parameter for lead optimization
The concept of the maximum absorbable dose (MAD):

6 Water Solubility as a parameter for lead optimization
How soluble does a drug candidate have to be??? S = MAD / (Ka x SIWV x SITT)

7 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!

8 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 Lead Optimization What can be modified?

10 Lead Optimization Modifications of aromatic substituents

11 Lead Optimization  Modifications of amide group

12 Lead Optimization  Modifications of cyclohexyl group

13 Lead Optimization  Modifications of carboxyl group

14 Lead Optimization  Modifications of chain length

15 Lead Optimization  Modifications of aromatic substituents

16 The Topliss Tree A systematic lead optimization approach

17 Lead Optimization - Example I
hormone of the thyroidal gland agonist of thyroxine receptor bioisosterical replacements of iodo groups potent agonist of thyroxine receptor

18 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 Lead Optimization - Example III
analgesic drug activity due to COX inhibition no analgesic effect bioisosteric replacement of ester by amide failed!

20 Acetyl salicylic acid: Mechanism of Action
acetyl group is transferred to serine in active site of COX => labile ester group is required!

21 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

22 Lead Optimization - Example IV From Peptides to Peptidomimetics

23 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 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

25 The Prodrug concept - Example II
anti-hypertensive drug orally inactive Prodrug: orally active due to amino acid carrier degradation to Enalaprilat by esterases

26 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

27 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

28 Drug Discovery: What's next?

29 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 The Graffinity Approach
Technology Small molecules are immobilized on gold surface Protein-Ligand Affinity is measured via Surface-Plasmon Resonance

31 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

32 The Graffinity Approach: Library Synthesis
Technology Diversity in Microtiterplates LC/MS Quality control Daughter Microarrays

33 The Graffinity Approach: Library Synthesis
Technology

34 The Graffinity Approach: Detection
Technology Minimal Amounts of Protein Protein-Ligand Affinity Maps Surface-Plasmon Resonance No Assay Development Function-Blind

35 Principle of Surface Plasmon Resonance - a means to detect Protein-Ligand binding

36 The Graffinity Approach: Detection
Technology Immediate Rank-Order of Affinities

37 The Graffinity Approach: SAR Analysis
Technology