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drug like property concepts in pharmaceutical design


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drug like property concepts in pharmaceutical design

  1. 1. Presented By Deepak PI-292 NIPER (Hajipur) Drug Like Property Concepts In Pharmaceutical Design Li Di, Edward H. Kerns and Guy T. Carter Current Pharmaceutical Design, 2009, 15, 2184-2194 1
  2. 2. CONTENTS 1. Introduction 2. Solubility 3. Permeability 4. Metabolism 5. Transporters 6. Conclusion 2
  3. 3.  Fail early Fail Fast Fail Cheap 3
  4. 4. 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 4
  5. 5. DRUG-LIKE MOLECULES •What are drug like molecules ? • Molecules having the properties of being a possible drug candidate is called drug like molecules. 5
  6. 6. 6 Drug like property concepts? clearance
  7. 7. SOLUBILITY 7 Development candidates issues (75%) Class I (>50%) Class IV (>25%) Enhance productivity Reduce cost Increase success rate Optimization
  8. 8. • Structural modification • Prodrug approach • Formulation development Methods to enhance solubility 8
  9. 9. STRUCTURAL MODIFICATION • Introducing an ionizable center is very effective for increasing solubility. 9
  10. 10. PRODRUG & FORMULATION • Formulation is another effective approach to improve solubility. Different additives can be added to bioassay media to maximize solubility. 10
  11. 11. PERMEABILITY 11 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
  12. 12. Ester prodrug improved the cell membrane permeability of FT inhibitors 12
  13. 13. METABOLISM 13 Metabolism Toxicity Accumulation of drug Prolonged half life Less efficacious Clearance Oral bioavailability Slow Rapid Low Species dependent Unique metabolizing enzymes in the each species and gender
  14. 14. • Blocking the labile sites • Removing the labile sites • Reducing lipophilicity and • Isosteric replacement of the labile groups. Several methods to improve metabolic stability 14
  15. 15. 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
  16. 16. 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
  17. 17. 17 TRANSPORTERS Transporters Pharmacokinetics EfficacySafety Important property
  19. 19. 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.
  20. 20. 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. 20
  21. 21. 21 BCRP
  22. 22. 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. 22
  23. 23. 23