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

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

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!


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)


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


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


The concept of the maximum absorbable dose (MAD):


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


S = MAD / (Ka x SIWV x SITT)


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


N

OH

OH

O

HOOC

Lead Optimization

What can be modified?


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


N

OH

OH

O

HOOC

NH

OH

OH

O

HOOC

NH

OH

OH

O

HOOC

N

OH

OHHOOC

Lead Optimization

Modifications of amide group


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


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


N

OH

OH

O

HOOC

N

O

HOOC

OH

OH

N

O

HOOC

OH

OH

Lead Optimization

Modifications of chain length


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


The Topliss Tree A systematic lead optimization approach


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


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


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


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 IVFrom Peptides to Peptidomimetics

Fibrinogen binds to Fibrinogen receptor

=> Initiation of blood clotting

Binding is inhibited by Arg-Gly-Asp (RGD)-tripeptid


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


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

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


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


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


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


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


TechnologyThe Graffinity Approach

Small molecules are

immobilized on gold surface

Protein-Ligand Affinity is measured

via Surface-Plasmon Resonance


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


• Diversity in Microtiterplates

Technology

• LC/MS Quality control

• Daughter Microarrays

The Graffinity Approach: Library Synthesis


TechnologyThe Graffinity Approach: Library Synthesis


Technology

• Minimal Amounts of Protein

• Protein-Ligand Affinity Maps

• Surface-Plasmon Resonance

• No Assay Development

• Function-Blind

The Graffinity Approach: Detection


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


Technology

Immediate Rank-Order of Affinities

The Graffinity Approach: Detection


TechnologyThe Graffinity Approach: SAR Analysis

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