Presented ByDeepakPI-292

NIPER (Hajipur)

Drug Like Property ConceptsIn Pharmaceutical Design

Li Di, Edward H. Kerns and Guy T. CarterCurrent Pharmaceutical Design, 2009, 15, 2184-2194

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CONTENTS

1. Introduction

2. Solubility

3. Permeability

4. Metabolism

5. Transporters

6. Conclusion

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Fail early Fail Fast Fail Cheap

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Bio assays

In vivo PK

Efficacy model

Development

Active

Acceptable PK

Good Efficacy

Bio assays

In vivo PK

Efficacy model

Development

Active

Acceptable PK

Good Efficacy

ADME/TOX Drug-like

PAST

PRESENT

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DRUG-LIKE MOLECULES

•What are drug like molecules ?•Molecules having the properties of being a possible

drug candidate is called drug like molecules.

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Drug like property concepts?

permeabilitysolub

ility

metabolic stabilitytransporter effects

oral bioavailability metabolism

toxicity

clearancein

vitro

pharm

acolo

gy

SOLUBILITY

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Development candidates issues (75%)

Class I (>50%) Class IV (>25%)

Enhance productivity Reduce cost

Increase success rate

Optimization

• Structural modification

• Prodrug approach

• Formulation development

Methods to enhance solubility

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STRUCTURALMODIFICATION

• Introducing an ionizable center is very effective for increasing solubility.

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PRODRUG &FORMULATION

• Formulation is another effective approach to improve solubility. Different additives can be added to bioassay media to maximize solubility.

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PERMEABILITY

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Development candidates issues (~35%)

Class III (<15%) Class IV (~25%)

Permeability issues (about 35%) Solubility issues (>75%)

lipophilicity Polarity

Hydrogen bonding capacity Size of the molecules

Permeability

Ester prodrug improved the cell membrane permeability of FT inhibitors

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METABOLISM

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Metabolism

ToxicityAccumulation of drug

Prolonged half life

Less efficacious

Clearance Oral bioavailability

Slow

Rapid Low

Species dependentUnique metabolizing

enzymes in the each species and gender

• Blocking the labile sites

• Removing the labile sites

• Reducing lipophilicity and

• Isosteric replacement of the labile groups.

Several methods to improve metabolic stability

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BLOCKING THE METABOLIC SITE

Metabolic stability of p38 drug candidates: blocking the site of metabolism improved metabolic stability, reduced clearance and enhanced oral bioavailability 15

ISOSTERIC REPLACEMENT

Phase II glucuronidation of opioid antagonists: Isosteric replacement of phenolic alcohol with amide improved Phase II metabolic stability, oral bioavailability and efficacy 16

Susceptible to Phase II

Glucuronidation

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TRANSPORTERS

Transporters

Pharmacokinetics EfficacySafety

Important property

INFLUX TRANSPORTERS

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EFFLUX TRANSPORTERS

• The ATP binding cassette (ABC) containing family of proteins have the greatest impact in drug discovery and development.

• Pgp is present in many important protective barriers, such as blood brain barrier, small and large intestines, liver, kidney, and skin. It reduces oral bioavailability and brain penetration and increases drug excretion through liver and kidney.

• Structure modification methods to reduce Pgp efflux are: decreasing basicity, reducing H-bond donors and reducing molecular weight.

MULTI DRUG RESISTANCE PROTEIN-2 (MRP2)

• MRP2 is a major determinant of biliary efflux of anionic drugs such as methotrexate. The major function of MRP2 is biliary excretion of drugs.

• Studies of 25 methotrexate analogues showed that hydrophobicity, negatively charged groups and aromatic rings are important for MRP2 transport.

• MRP2 inhibitors have: higher molecular weight, higher lipophilicity and higher aromaticity than non inhibitors, while the PSA and charge were similar.

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21central nervous system

Kidney into urine

Oral ab

sorpti

on

Hepato

cytes

into

bile

BCRP

CONCLUSIONS

• Drug-like property information provides an early alert to potential issues, guides structural modification, prioritizes chemical series.

• So, Drug-like properties have become an integrated part of the drug discovery process.

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Thank You

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