1. 항바이러스제 Ritonavir 2013.03.29 양혜란

2. Ritonavir 화학명 1,3-Tiazol-5-ylmethyl[3-hydroxy-5-[3-methyl-2-[methyl-[(2-propan-2- yl-1,3-thiazole-4-yl)methyl]carbamoyl]-aminobutanoyl]amino-1,6- diphenylhexan-2-yl] aminoformate 분류항바이러스제, 항레트로바이러스제 약리 Nucleoside analog 로 HIV reverse transcriptase enzyme 저해 적응증 HIV 감염증 상품명 Norvir, Kaletra 개발회사 Abbott

3. HIV structure http://www.fattuesdayproductions.com/TIP620_1/rv_disease.html

4. HIV invasion of target cell The gp120 binds to the CD4 molecules. The CD4 receptor provokes change in gp120. Expose a portion of the gp41 protein Cause fusion of the viral envelope and the host cell envelope Enter HIV capsid to the target cell

5. Replication and Transcription of HIV Reverse transcriptase releases the single stranded RNA. Integrase enzyme is used to carry out the integration of the new DNA into the cell nucleus. Transcription - transfer of genetic information to the messenger RNA. Transcription - transfer of genetic information to the messenger RNA. Copy it into a complementary DNA strand Translation – the process of forming a protein. The protein is cleaved by the enzyme protease. Reconstruction of a new virus is underway.

6. Treatment http://www.fattuesdayproductions.com/TIP620_1/rv_disease.html

7. Ritonavir Ritonavir was originally developed as an inhibitor of HIV protease. It is now rarely used for its own antiviral activity, but remains widely used as a booster of other protease inhibitors. More specifically, ritonavir is used to inhibit a particular liver enzyme that normally metabolizes protease inhibitors, CYP 450-3A4 (CYP3A4). The drug's molecular structure inhibits CYP3A4, so a low dose can be used to enhance other protease inhibitors.

8. J. Med. Chem. 1998, 41, 602-617 Discovery of Ritonavir, a Potent Inhibitor of HIV Protease with High Oral Bioavailability and Clinical Efficacy Introduction Duplication of the N-terminus by a rotation about a C 2 axis bisecting the C-N single bond led to the Conceptualization of the symmetric or pseudo-symmetric core diamines 1 and 2.

9. J. Med. Chem. 1998, 41, 602-617 Introduction A-77003 - Oral BA↓ - adequate anti-HIV activity, aqueous solubility A-80987 - Oral BA↑ - T 1/2 ↓ Ritonavir (ABT-538) - rate of metabolism↓ - Oral BA ↑ * Primiarily metabolized and cleared through N-oxidation of one or Both of the pyridyl end group.

10. J. Med. Chem. 1998, 41, 602-617 Results Compound cytoxicity 5mg/kg, n=2, iv. 10mg/kg, n=3, oral. * A-80987 (5) → anti-HIV activity↑, rate of metabolism↓ A-80987 A-80613 * 6-alkylpyridines > unsubstituted pyridines * Ethyl > isopropyl, tert-butyl

11. J. Med. Chem. 1998, 41, 602-617 Results 25 (25-28) (29-33) (9-12) * Activity : 25-33 ≒ 9-12 * Pharmacokinetic profiles : 25-33 < 9-12 3-pyridyl2-pyridyl

12. J. Med. Chem. 1998, 41, 602-617 Results (34-37)(38-41) (42-45) * 34-45 : more active > A-80987 (methoxy group provided sufficient aqueous solubility) * 36 was the best properties.

13. J. Med. Chem. 1998, 41, 602-617 Results * 46-53 < A-80987 * 63 was 5-fold more potent than A-80987.

14. J. Med. Chem. 1998, 41, 602-617 Results * i-pr = t-Bu > Et > Me > H * 77, 79 (A=OH) > 76, 78 (B=OH) * 77 (A-83962) - 8-fold more potent than A-80987 - 20-fold more potent than A-80613 (6) A-83962 4-oxazolyl

15. J. Med. Chem. 1998, 41, 602-617 Results methoxymethyl 5-thiazole 5-oxazole 2-thiazole

16. J. Med. Chem. 1998, 41, 602-617 Results * 123 (ABT-538, Ritonavir) - potency 유지 (77, A-83962) - give plasma levels after oral administration >100-fold in excess of the EC50 - The rate of metabolism of ritonavir was 20-fold lower than that of A-80987(5). Ritonavir

17. J. Med. Chem. 1998, 41, 602-617 Results ○- rat (10mg/kg) ● - dog (10mg/kg) □ - mouse (25mg/kg) ■ - monkey (10mg/kg) rat dog mouse monkey * Levels were sustained in excess of the EC50 for >8h to >12h. * The extended pharmacokinetic profile of ritonavir correlated with a suppression of the rate of metabolism in vitro using dog liver microsomes.

18. J. Med. Chem. 1998, 41, 602-617 Discussion * Key to the discovery of ritonavir was the modification of chemical functionality within A-80987 to group more stable to oxidative metabolism by the CYP450 enzymes present in the intestine and liver. (pyridyl  less electron rich oxazolyl, thiazolyl) * Ritonavir has been shown to be not only metabolized by but also a potent inhibitor of the CYP 3A4.  It is likely that a combination of direct heme binding and chemical stability contributes to the favorable pharmacokinetic profile of ritonavir via potent inhibition of CYP in the liver and/or intestine. * The close interaction of the P3 isopropyl group with V82 also appears to affect the response of HIV to selective pressure during treatment with ritonavir. * Dual therapy with ritonavir and other protease inhibitors is under active investigation as an effective, convenient regimen.

19. Synthesis 1. protection 2. Claisen condensation 3. addition 4. reduction 5. Hydrogenolysis 6. Urethane 합성 7. Acylation

20. Synthesis 23 12

21. 34 5

22. 56

23. 67