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PRODUCTION
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Design of New HIV-Protease Inhibitors and Ritonavir Synth
esis
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BY
Sathaporn Prutipanlai
Toxicology Program
Mahidol University
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OUT LINEOUT LINEBackgroundContent: Processes of Ritonavir Synth
esis: Possibility for synthesis new P
IsConclusion
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BACKGROUNDBACKGROUND
What is characteristic of HIV Protease enzyme.?
HIV Protease is one type of aspartic acid enzyme.
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Protease enzymeProtease enzyme
Protease’s function exists as a C
2- symmetric homodimer.
Each monomeric unit contributes one of the conserved catalytic triads(Asp-Thr-gly)
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HIV Protease Enzyme
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BACKGROUND (Cont)BACKGROUND (Cont)
How does it work.?
HIV Protease works by homodimer that cleave gag/pol polypeptide
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HIV Protease inhibitor developmentHIV Protease inhibitor development
Idea : How are enzyme and substrate interact.?
Construct more potent and novel structure of enzyme
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Protease enzyme
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Inhibitors represent all three cateInhibitors represent all three categoriesgories
Based on peptide isosteres : statinExploitation the symmetrical pro
perties of the protease dimer.Based on enzyme structure.
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Type of Designing Protease InhibitorType of Designing Protease Inhibitor
Non hydrolyzable analog of peptide substrates.
Transition-state analogs.Pepstatin-Protease Complex.Two-fold symmetrical or Pseudo s
ymmetrical inhibitor.Structure-Based inhibitor Design
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Ritonavir DevelopmentRitonavir Development
Peptidomimetic inhibitor
Substrate based inhibitor
C2 symmetry-based inhibitor
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Ritonavir DevelopmentRitonavir 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
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Ritonavir Development(cont)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.
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CC22-symmetric inhibitor to HIV pro-symmetric inhibitor to HIV pro
tease enzymetease enzyme
Imposition of C2-symmetry axes on an asymmetric substrate or inhibitor
Kempf, D.J. et.al. 1993
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CC2 2 Symmetric HIV PIsSymmetric HIV PIs
Kempf, D.J. et.al 1993
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Synthesis of Symmetric InhibitSynthesis of Symmetric Inhibitor Core Unitsor Core Units
Three general categories. : Linear, nonsymmetric synthese
s : Symmetric combination of iden
tical halves : Bifunctionalization of a C2 sym
metric precursor
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Linear, Nonsymmetric syntheses
Kempf,D.J. 1994
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Synthesis of Symmetric InhibitSynthesis of Symmetric Inhibitor Core Units(cont)or Core Units(cont)
Three general categories. : Symmetric combination of ide
ntical halves : Bifunctionalization of a C2 sym
metric precursor
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Effect of CEffect of C22-symmetric inhibitors to HIV -symmetric inhibitors to HIV
proteaseprotease
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Processes of Ritonavir Synthesis
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+
-aminoaldehyde
Scheme 1
vcl3
Zn
2-5-bis-N-((benzyl)oxy)carbonyl)amino-3, 4-diacydroxy-1, 6 diphenylhexane
(diols)Patent#5,846,987
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Scheme 2
2-5-bis-N-((benzyl)oxy)carbonyl)amino-3, 4-diacydroxy-1, 6 diphenylhexane
bromoacetate
HydrolysisCyclization
Reduction
2-5-bis-N-((benzyl)oxy)carbonyl)amino)1, 6 diphenyl-3-hydroxyhexane Patent#5,846,987
2,5-Bis-(N(((benzyl)oxyl)carbonyl amino)-3-4-epoxy-1,6 diphenylhaxane
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Scheme 2 (cont)
2-5-bis-N-((benzyl)oxy)carbonyl)amino)1, 6 diphenyl-3-hydroxyhexane
hydrolysis
2, 5, -diamino-1, 6diphenyl-3-hydroxyhexane
Patent#5,846,987
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Scheme 3
acylation
Patent#5,846,987
2,5,-Diamino-1,6-diphenyl-3-hydroxyhexane
6(1-Amino-2-phenyl)-4-benzyl-2-phenyl-3-aza-2-boro-1-oxacyclohexane
5-(Thiazolyl)methyl)-(4-nitrophenyl)carbamate
5-Amino-2-(N-((5-thiazolyl)methoxy carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane
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Scheme 3 (cont)
Patent#5,846,987
5-Amino-2-(N-((5-thiazolyl)methoxy carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane
Coupling reaction
Ritonavir
N-((N-methyl-N-((2-isopropyl-4-thiazoyl methyl)amino)carbonyl-L-valine
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Molecular structure of Ritonavir
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Ritonavir and protease enzyme
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Indinavir and Protease Enzyme
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Indinavir
Saquinavir
Ritonavir
Nelfinavir
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Possibility to design new prPossibility to design new protease inhibitorotease inhibitor
Factor : Hydrophobic : High oral bioavilability : Low hepatic clearance : Low toxicity
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CONCLUSIONCONCLUSION
Factor that influence drug design
: Pharmacokinetic: Pharmacodynamic: Interaction between inhibitors and
HIV- protease enzyme
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THANK YOU
Dr. Poonsak
Dr. Maria Kartalou
Dr. Suwit
CRI’s Staff
YOUR ATTENTION
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THE END