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 enough

it was subsequently discovered that

Entecavir is a highly potent inhibitor of HBV, with low toxicity

ETV is prodrug

• Inhibition of hepaDNA viral replication is 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

Specificity

Potency

Toxicity

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 hydroxym

ethyl ( 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 agents

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 !