Download ritonavir synthesis

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
 What
is characteristic of HIV
Protease enzyme.?
 HIV
Protease is one type of
aspartic acid enzyme.
Protease enzyme
 Protease’s
function exists as a
C2- symmetric homodimer.
 Each
monomeric unit
contributes one of the conserved
catalytic triads(Asp-Thr-gly)
HIV Protease Enzyme
BACKGROUND (Cont)
 How
 HIV
does it work.?
Protease works by
homodimer that cleave
gag/pol polypeptide
HIV Protease inhibitor development
 Idea
: How are enzyme and
substrate interact.?

Construct more potent and
novel structure of enzyme
Protease enzyme
Inhibitors represent all three
categories
 Based
on peptide isosteres
 : statin
 Exploitation the symmetrical
properties of the protease dimer.
 Based on enzyme structure.
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
Ritonavir Development
 Peptidomimetic
 Substrate
 C2
inhibitor
based inhibitor
symmetry-based inhibitor
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
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.
C2-symmetric inhibitor to HIV
protease enzyme
Imposition of C2-symmetry axes on an asymmetric substrate or
inhibitor
Kempf, D.J. et.al. 1993
C2 Symmetric HIV PIs
Kempf, D.J. et.al 1993
Synthesis of Symmetric
Inhibitor Core Units
 Three
general categories.
 : Linear, nonsymmetric
syntheses
 : Symmetric combination of
identical halves
 : Bifunctionalization of a C2
symmetric precursor
Linear, Nonsymmetric
syntheses
Kempf,D.J. 1994
Synthesis of Symmetric
Inhibitor Core Units(cont)
 Three
general categories.


: Symmetric combination of
identical halves
 : Bifunctionalization of a C2
symmetric precursor
Effect of C2-symmetric inhibitors to HIV
protease
Processes of Ritonavir
Synthesis
Scheme 1
+
a-aminoaldehyde
vcl3
Zn
2-5-bis-N((benzyl)oxy)carbonyl)amino-3,
4-diacydroxy-1, 6
diphenylhexane
(diols)
Patent#5,846,987
Scheme 2
bromoacetate
2-5-bis-N((benzyl)oxy)carbonyl)
amino-3, 4-diacydroxy1, 6 diphenylhexane
Cyclization
Hydrolysis
Reduction
2-5-bis-N-((benzyl)oxy)carbonyl)amino)1,
6 diphenyl-3-hydroxyhexane
2,5-Bis-(N(((benzyl)oxyl)carbonyl
amino)-3-4-epoxy-1,6 diphenylhaxane
Patent#5,846,987
Scheme 2 (cont)
hydrolysis
2-5-bis-N-((benzyl)oxy)carbonyl)amino)1,
6 diphenyl-3-hydroxyhexane
2, 5, -diamino-1, 6diphenyl3-hydroxyhexane
Patent#5,846,987
Scheme 3
2,5,-Diamino-1,6diphenyl-3hydroxyhexane
6(1-Amino-2phenyl)-4-benzyl2-phenyl-3-aza-2boro-1oxacyclohexane
acylation
5-(Thiazolyl)methyl)-(4nitrophenyl)carbamate
5-Amino-2-(N-((5-thiazolyl)methoxy
carbonyl)amino)-1,6-diphenyl-3hydroxyhexane
Patent#5,846,987
Scheme 3 (cont)
5-Amino-2-(N-((5thiazolyl)methoxy
carbonyl)amino)-1,6-diphenyl-3hydroxyhexane
Coupling reaction
N-((N-methyl-N-((2-isopropyl-4-thiazoyl
methyl)amino)carbonyl-L-valine
Ritonavir
Patent#5,846,987
Molecular structure of Ritonavir
Ritonavir and protease enzyme
Indinavir and Protease Enzyme
Ritonavir
Indinavir
Saquinavir
Nelfinavir
Possibility to design new
protease inhibitor
 Factor

: Hydrophobic
 : High oral bioavilability
 : Low hepatic clearance
 : Low toxicity
CONCLUSION

Factor that influence drug design
: Pharmacokinetic
 : Pharmacodynamic
 : Interaction between inhibitors and
HIV- protease enzyme

THANK YOU
Dr. Maria Kartalou
Dr. Suwit
Dr. Poonsak
CRI’s Staff
YOUR ATTENTION
THE END