Entecavir 0440120 周 雪 0440229 张学丽 0440218 孙婷婷 0440217 黄美花

1. Gospel for HBV Patients Entecavir0440120 周 雪 0440229 张学丽 0440218 孙婷婷 0440217 黄美花

2. The battle against the HBV • Human hepatitis B virus (HBV), remains a major agent of liver infection and a cause of liver disease throughout the world • HBV is estimated to infect more than 350 million people worldwide, and is responsible for 1 million deaths each year

3. Current efforts • Immunomodulators interferon-α---limited efficacy and frequent adverse effects • Nucleoside analogues lamivudine adefovir telbivudine…

4. 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

5. ABC of ETV A novel nucleoside analogue High potent and selective activity against HBV with little tolerance or toxicity

6. 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

7. ? Further Thinking May this anti-virus nucleoside analogue possess other anti-virus activity

8. Sure enough it was subsequently discovered that Entecavir is a highly potent inhibitor of HBV, with low toxicity

9. Loading…

10. 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 formsin mammalian cells by cellular enzymes

11. Illustration of activation in vivo enzyme Prodrug inactivity The activity form in vivo

12. Structure and Activity relationship (SAR) ※natural nucleosides (dNTP) materials of DNA or RNA synthesis β-D– dNTP β-L-dNTP ※unnatural (or synthesized) nucleosides Synthesize inactivity DNA or RNA Couldn’t prolong by used errorly Entecavir is β-L-2'-deoxynucleosides analog

13. Metabolicantagonism(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）.

14. Structure and Activity relationship (SAR) Guanine Entecavir

15. Structure and Activity relationship (SAR) Modify based on bioisosterism(生物电子等排 )

16. Structure and Activity relationship (SAR) Specificity Potency Toxicity

17. Structure and Activity relationship (SAR) A lack in the 3’-OH :possess anti-HBV activity a decrease in specificity

18. Structure and Activity relationship (SAR) R=F Cl Br Loss of specificity, Lower activity in anti-HIV & HBV

19. The Synthesis of entecavir

21. construct the chiral carbocyclic core introduce the guanine group to the position C1 of the core.

22. construct the chiral carbocyclic core chiral reagent Introducu different functional group key point Asymmetric synthesis (不对称合成) Chirality of 1,3,4-C • Wittig reaction • dehydration of hydroxymethyl (羟基脱水) Introduction of exocyclic methylene in 2-C

23. introduce the guanine group nucleophilic substitution Mitsunobu reaction SN2 nucleophilic substitution (亲核取代) R-configuration

25. The Synthesis of starting reagent

26. MECHANISM OF ACTION ETV phosphokinase ETV- TP • To affect 3 steps in the replication of the HBV

28. PHARMACOKINETICS • Absorption 1. be well absorbed orally .(Tmax , Cmax , Auc ) 2. be administered on an empty stomach . 3. Formulations

29. Metabolism • A small extent to glucuronide and sulfate forms • No oxidative or acetylated metabolites 3. not a substrate of the cytochrome P450 (CYP) enzyme system.

30. Elimination 1.primarily in the urine via glomerular filtration and tubular secretion (62%-73%) 2. remainder 3. Renal clearance 4. t1/2

31. Comparison of entecavir (ETV) and lamivudine (LVD) ETV 0.5 mg ,LVD 100 mg, hepatitis B e antigen-positive

32. ETV 0.5 mg ,LVD 100 mg, hepatitis B e antigen-negative

33. 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

34. ETV 1 mg ,LVD 100 mg, hepatitis B e antigen-positive , be refractory to LVD

35. Entecavir Resistance 1. Be naive to therapy with nucleoside antiviral agents 2. Patients with existing lamivudine resistance 3. More studies

36. Adverse Events • be comparable to those with lamivudine • 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%

37. Other Nucleoside Analogues for HBV • Adefovir • Emtricitabine • Tenofovir • Famciclovir

38. 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.

39. Direction of Treatment of HBV • Combination Chemotherapy • three advantages : • 1. Be additive orcomplementary to each other and reduce the duration of treatment • 2. Fewer side-effects • 3. Decrease the risk of viral mutations

40. Thank you !