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

PRODUCTION

Design of New HIV-Protease Inhibitors and Ritonavir Synth

esis

BY

Sathaporn Prutipanlai

Toxicology Program

Mahidol University

OUT LINEOUT LINEBackgroundContent: Processes of Ritonavir Synth

esis: Possibility for synthesis new P

IsConclusion

BACKGROUNDBACKGROUND

What is characteristic of HIV Protease enzyme.?

HIV Protease is one type of aspartic acid enzyme.

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)

HIV Protease Enzyme

BACKGROUND (Cont)BACKGROUND (Cont)

How does it work.?

HIV Protease works by homodimer that cleave gag/pol polypeptide

HIV Protease inhibitor developmentHIV Protease inhibitor development

Idea : How are enzyme and substrate interact.?

Construct more potent and novel structure of enzyme

Protease enzyme

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.

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

Ritonavir DevelopmentRitonavir Development

Peptidomimetic inhibitor

Substrate based inhibitor

C2 symmetry-based inhibitor

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

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.

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

CC2 2 Symmetric HIV PIsSymmetric HIV PIs

Kempf, D.J. et.al 1993

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

Linear, Nonsymmetric syntheses

Kempf,D.J. 1994

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

Effect of CEffect of C22-symmetric inhibitors to HIV -symmetric inhibitors to HIV

proteaseprotease

Processes of Ritonavir Synthesis

+

-aminoaldehyde

Scheme 1

vcl3

Zn

2-5-bis-N-((benzyl)oxy)carbonyl)amino-3, 4-diacydroxy-1, 6 diphenylhexane

(diols)Patent#5,846,987

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

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

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

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

Molecular structure of Ritonavir

Ritonavir and protease enzyme

Indinavir and Protease Enzyme

Indinavir

Saquinavir

Ritonavir

Nelfinavir

Possibility to design new prPossibility to design new protease inhibitorotease inhibitor

Factor : Hydrophobic : High oral bioavilability : Low hepatic clearance : Low toxicity

CONCLUSIONCONCLUSION

Factor that influence drug design

: Pharmacokinetic: Pharmacodynamic: Interaction between inhibitors and

HIV- protease enzyme

THANK YOU

Dr. Poonsak

Dr. Maria Kartalou

Dr. Suwit

CRI’s Staff

YOUR ATTENTION

THE END