drug like property concepts in pharmaceutical design
TRANSCRIPT
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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
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SOLUBILITY
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Development candidates issues (75%)
Class I (>50%) Class IV (>25%)
Enhance productivity Reduce cost
Increase success rate
Optimization
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• 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
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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
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• 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
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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
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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.
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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
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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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