Entecavir0440120 周 雪 0440229 张学丽 0440218 孙婷婷 0440217 黄美花
Gospel for HBV Patients
The battle against the HBV
• Human hepatitis B virus (HBV),
• HBV is estimated to infect more than 350
remains a major agent of liver infection and a cause of liver disease throughout the world
million people worldwide, and is responsible for 1 million deaths each year
Current efforts
• Immunomodulators
interferon-α---limited efficacy and frequent adverse effects
• Nucleoside analogues lamivudine adefovir telbivudine…
ETV--A new treatment option
• Wildly used as an accessory with other anti-HBV drugs ,such as lamivudine ,adfovir, especially when there are drug-resistance
A novel anti-HBV agent
• Commercially developed by Baraclude and Bristol-Myers Squibb • Approved by FDA in March 2005
ABC of ETV
A novel nucleoside analogue
High potent and selective activity against HBV with little tolerance or toxicity
Discovery
• First investigated as BMS-200475 / SQ-34676 , originally developed for the treatment of herpes complex virus infections ( 单纯性疱疹) with the guidance of CADD
• However,its moderate activity led to its discontinuation for this indication
?
May this anti-virus nucleoside analogue possess other anti-virus activity
Further Thinking
Sure enoughit was subsequently discovered that
Entecavir is a highly potent inhibitor of HBV, with low toxicity
ETV is prodrug• Inhibition of hepaDNA viral replication i
s presumed to occur through the triphosphate (TP) forms of ETV , with the nucleoside being converted to their respective TP forms in mammalian cells by cellular enzymes
Illustration of activation in Illustration of activation in vivovivo
HN
N N
N
O
H2N
OH
O P
O
O
OH
P O P
O O
OH OH
O
HN
N
O
H2NN
N
HO OH
enzyme
Prodrug inactivity The activity form in vivo
Structure and Activity Structure and Activity relationship (SAR)relationship (SAR)
※natural nucleosides (dNTP) materials of DNA or RNA synthesis
※unnatural (or synthesized) nucleosides
Couldn’t prolong by used errorly Synthesize inactivity DNA or RNA
Entecavir is β-L-2'-deoxynucleosides analog
β-D – dNTP
β-L-dNTP
MetabolicMetabolic antagonismantagonism(( 代谢拮抗代谢拮抗 )) As ETV is so structurally similar to the substrate of DNA polymerase,it interferes the later replication of virus DNA chain,thus leading to inhibition of HBV-virus, also called lethal synthesis (致死合成) .
Structure and Activity relationship (SAR)
NH
N
N
O
NH2N
O
HOH
HH
HH
HO
NH
N
N
O
NH2N
HOH
HH
HH
HO
Guanine Entecavir
Structure and Activity relationship (SAR)
O
HC CH
Modify based on bioisosterism ( 生物电子等排 )
Structure and Activity relationship (SAR)
O
HC CH
SpecificityPotencyToxicity
Structure and Activity relationship (SAR)
A lack in the 3’-OH :possess anti-HBV activity a decrease in specificity
Structure and Activity relationship (SAR)
R=F Cl Br Loss of specificity,Lower activity in anti-HIV & HBV
The Synthesis of entecavir
construct the chiral carbocyclic core
introduce the guanine group to the position C1 of the core.
chiral reagent
Introducu different functional group
construct the chiral carbocyclic core
key point
Chirality of 1,3,4-C
Introduction of exocyclic methylene in 2-C
Asymmetric synthesis ( 不对称合成 )
•Wittig reaction•dehydration of hydroxymethyl ( 羟基脱水 )
introduce the guanine group
Mitsunobu reaction
SN2 nucleophilic substitution ( 亲核取代 )
nucleophilic substitution
R-configuration
The Synthesis of starting reagent
MECHANISM OF ACTION
• ETV phosphokinase ETV- TP
• To affect 3 steps in the replication of the HBV
PHARMACOKINETICS
• Absorption
1. be well absorbed orally .(Tmax , Cmax , Auc )
2. be administered on an empty stomach .
3. Formulations
• Metabolism
1. A small extent to glucuronide and sulfate forms
2. No oxidative or acetylated metabolites
3. not a substrate of the cytochrome P450 (CYP) enzyme system.
1.primarily in the urine via glomerular filtration and tubular secretion (62%-73%)
2. remainder
3. Renal clearance
4. t1/2
•Elimination
Comparison of entecavir (ETV) and lamivudine (LVD)
ETV 0.5 mg ,LVD 100 mg, hepatitis B e antigen-positive
ETV 0.5 mg ,LVD 100 mg, hepatitis B e antigen-negative
• ETV has a more efficient curative effect on histologic
improvement, decreasing extent of HBV DNA and
ALT normalization.
• the emergence of resistance to LVD
• lamivudine-resistant strains of HBV are sensitive to
ETV
ETV 1 mg ,LVD 100 mg, hepatitis B e antigen-positive , be refractory to LVD
Entecavir Resistance 1. Be naive to therapy with nucleoside antiviral ag
ents
2. Patients with existing lamivudine resistance
3. More studies
Adverse Events1. be comparable to those with lamivudine
2. headache 17%-23%
upper respiratory tract infection 18%-20%
cough 12%-15%
nasopharyngitis 9%-14%
fatigue 10%-13%
dizziness 9%
upper abdominal pain 9%-10%
nausea 6%-8%
Other Nucleoside Analogues for HBV• Adefovir
• Emtricitabine
• Tenofovir
• Famciclovir
Conclusions• Entecavir is a new antiviral agent for the management of chronic HBV infection.
• Questions concern the ideal length of therapy, long-term efficacy, and resistance rates over time await the results of ongoing clinical trials.
Direction of Treatment of HBV
• Combination Chemotherapy three advantages :
1. Be additive or complementary to each other and reduce the duration of treatment
2. Fewer side-effects
3. Decrease the risk of viral mutations
Thank you !