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

Why do drugs fail in clinical development? (Taken from Kennedy, Drug Discovery Today, 2 (10), 1997, 436-444)

Water Solubility as a parameter for lead optimization Is there a relationship between bioavailability and water solubility? Yes, there is. It's called MAD!

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)

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

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

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!

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

Lead Optimization What can be modified?

Lead Optimization Modifications of aromatic substituents

Lead Optimization  Modifications of amide group

Lead Optimization  Modifications of cyclohexyl group

Lead Optimization  Modifications of carboxyl group

Lead Optimization  Modifications of chain length

Lead Optimization  Modifications of aromatic substituents

The Topliss Tree A systematic lead optimization approach

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

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

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

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

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

Lead Optimization - Example IV From Peptides to Peptidomimetics

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

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

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

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

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

Drug Discovery: What's next?

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

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

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 100 200 300 400 500 600 Molweight

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

The Graffinity Approach: Library Synthesis Technology

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

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

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

The Graffinity Approach: SAR Analysis Technology