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PRODUCTION

PRODUCTION. Design of New HIV-Protease Inhibitors and Ritonavir Synthesis . BY. Sathaporn Prutipanlai. Toxicology Program. Mahidol University. OUT LINE. Background Content : Processes of Ritonavir Synthesis : Possibility for synthesis new PIs Conclusion. BACKGROUND.

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PRODUCTION

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  1. PRODUCTION

  2. Design of New HIV-Protease Inhibitors and Ritonavir Synthesis

  3. BY Sathaporn Prutipanlai Toxicology Program Mahidol University

  4. OUT LINE • Background • Content • : Processes of Ritonavir Synthesis • : Possibility for synthesis new PIs • Conclusion

  5. BACKGROUND • What is characteristic of HIV Protease enzyme.? • HIVProtease is one type of aspartic acid enzyme.

  6. Protease enzyme • Protease’s function exists as a C2- symmetric homodimer. • Each monomeric unit contributes one of the conserved catalytic triads(Asp-Thr-gly)

  7. HIV Protease Enzyme

  8. BACKGROUND (Cont) • How does it work.? • HIV Protease works by homodimer that cleave gag/pol polypeptide

  9. HIV Protease inhibitor development • Idea : How are enzyme and substrate interact.? • Construct more potent and novel structure of enzyme

  10. Protease enzyme

  11. Inhibitors represent all three categories • Based on peptide isosteres • : statin • Exploitation the symmetrical properties of the protease dimer. • Based on enzyme structure.

  12. Type of Designing Protease Inhibitor • Non hydrolyzable analog of peptide substrates. • Transition-state analogs. • Pepstatin-Protease Complex. • Two-fold symmetrical or Pseudo symmetrical inhibitor. • Structure-Based inhibitor Design

  13. Ritonavir Development • Peptidomimetic inhibitor • Substrate based inhibitor • C2 symmetry-based inhibitor

  14. Ritonavir Development • Design of C2-symmetric inhibitor from an asymmetric substrate compose of 3 steps • First: Imposition an axis of symmetry on the peptide functionality in the substrate

  15. Ritonavir Development(cont) • Second: Arbitary deletion of either the N-terminal or C-terminal. • Third: C2 symmetry operation is applied to the remaining portion to generate a symmetric core unit.

  16. C2-symmetric inhibitor to HIV protease enzyme Imposition of C2-symmetry axes on an asymmetric substrate or inhibitor Kempf, D.J. et.al. 1993

  17. C2 Symmetric HIV PIs Kempf, D.J. et.al 1993

  18. Synthesis of Symmetric Inhibitor Core Units • Three general categories. • : Linear, nonsymmetric syntheses • : Symmetric combination of identical halves • : Bifunctionalization of a C2 symmetric precursor

  19. Linear, Nonsymmetric syntheses Kempf,D.J.1994

  20. Synthesis of Symmetric Inhibitor Core Units(cont) • Three general categories. • : Symmetric combination of identical halves • : Bifunctionalization of a C2 symmetric precursor

  21. Effect of C2-symmetric inhibitors to HIV protease

  22. Processes of Ritonavir Synthesis

  23. Scheme 1 vcl3 + Zn a-aminoaldehyde 2-5-bis-N-((benzyl)oxy)carbonyl)amino-3, 4-diacydroxy-1, 6 diphenylhexane (diols) Patent#5,846,987

  24. Scheme 2 bromoacetate 2-5-bis-N-((benzyl)oxy)carbonyl)amino-3, 4-diacydroxy-1, 6 diphenylhexane Cyclization Hydrolysis Reduction 2,5-Bis-(N(((benzyl)oxyl)carbonyl amino)-3-4-epoxy-1,6 diphenylhaxane 2-5-bis-N-((benzyl)oxy)carbonyl)amino)1, 6 diphenyl-3-hydroxyhexane Patent#5,846,987

  25. Scheme 2 (cont) hydrolysis 2-5-bis-N-((benzyl)oxy)carbonyl)amino)1, 6 diphenyl-3-hydroxyhexane 2, 5, -diamino-1, 6diphenyl-3-hydroxyhexane Patent#5,846,987

  26. Scheme 3 6(1-Amino-2-phenyl)-4-benzyl-2-phenyl-3-aza-2-boro-1-oxacyclohexane 2,5,-Diamino-1,6-diphenyl-3-hydroxyhexane acylation 5-(Thiazolyl)methyl)-(4-nitrophenyl)carbamate 5-Amino-2-(N-((5-thiazolyl)methoxy carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane Patent#5,846,987

  27. Scheme 3 (cont) 5-Amino-2-(N-((5-thiazolyl)methoxy carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane Coupling reaction N-((N-methyl-N-((2-isopropyl-4-thiazoyl methyl)amino)carbonyl-L-valine Ritonavir Patent#5,846,987

  28. Molecular structure of Ritonavir

  29. Ritonavir and protease enzyme

  30. Indinavir and Protease Enzyme

  31. Ritonavir Indinavir Saquinavir Nelfinavir

  32. Possibility to design new protease inhibitor • Factor • : Hydrophobic • : High oral bioavilability • : Low hepatic clearance • : Low toxicity

  33. CONCLUSION • Factor that influence drug design • : Pharmacokinetic • : Pharmacodynamic • : Interaction between inhibitors and HIV- protease enzyme

  34. THANK YOU Dr. Maria Kartalou Dr. Suwit Dr. Poonsak CRI’s Staff YOUR ATTENTION

  35. THE END

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