Inhibitors of Hepatitis B Virus (HBV) - Adefovir dipivoxil (Hepsera™) (1) was approved in the US for the treatment of HBV on September 20th, 2002 and in the European Union on March 11th, 2003, providing a second small molecule antiviral to add to lamivudine (3TC) and the injectable protein IFNa as the only approved agents for treating HBV infection. Adefovir is an effective inhibitor of 3TC-resistant HBV caused by the rtM204l and rtL180M + rtM204V mutations in the reverse transcriptase (2) and resistance to adefovir has not been seen after 48 weeks of monotherapy (3,4).
A clinical study with entecavir (2), currently undergoing P3 trials, compared a dose of 0.1-1 mg/day of 2 to 3TC (100 mg/day) for 48 days in 181 patients previously unresponsive to 3TC treatment (5). Compared to 3TC, treatment with 2 resulted in lower overall viral loads, lower ALT levels and a higher proportion of patients with undetectable HBV DNA levels. Moreover, adverse events for 2 were less than those observed with 3TC. A separate P2 trial of 2 in 177 treatment-naive patients for 22 weeks at a dose of 0.5 mg/day showed that reduction in viral DNA levels was independent of baseline ALT levels, with treatment resulting in a 4.7-4.8 logio reduction in HBV DNA (6).
L-nucleosides represent a promising area of antiviral research (7). LdT (telbivudine, 3) is currently in P3 clinical trials designed to evaluate 1200 patients for safety and efficacy compared with standard treatment in HBeAg+ and HBeAg- patients (8). Recent P2b data was released from a trial involving 104 adults randomized to receive 3TC plus 3 or 3TC monotherapy once daily for 1 year. Viral load reductions of greater than 6 log™ were seen for all patients in the study arms containing 3 and no treatment-limiting or dose-related adverse events were reported. The mechanism of action of L-FMAU (clevudine) (4), currently in P1/P2 trials, is not firmly understood but recent molecular dynamics simulation experiments have suggested that the triphosphate derivative of 4 may act as a competitive inhibitor rather than as a substrate of HBV polymerase (9,10). Emtricitabine (Coviracil™) (5) is also currently in P3 clinical trials for the treatment of HBV. An NDA seeking approval to market 5 for the treatment of HIV was filed in September 2002 (9). Results from a P1/P2 clinical trial with ACH-126443 (elvucitabine, 6) have been released (11-13). In 36 HBV treatment-naive patients receiving single daily doses of 1-100 mg of 6, mean declines in plasma HBV DNA of up to 2.5 log™ were observed after 14 days of treatment. Furthermore, plasma levels in excess of the IC50 values for wild type and YMDD mutants were achieved in the low dose arms. It is therefore anticipated that 6 will be efficacious against 3TC resistant infections in an ongoing P2 trial.
LY-582563 (MCC-478, 7) is more potent than 3TC in HB611 cells, EC50 = 27 nM and 2.2 nM, respectively, and retains activity towards HBV carrying the recently identified G1896A mutation (14-16). This mutation, which arises in response to 3TC therapy, is found in the precore region and confers HBeAg negativity. The major metabolite of 7 formed in rat or human serum is the mono-ester, which is a more potent HBV inhibitor, ECso = 70 nM, than 3TC. It is postulated that the arylthio moiety is responsible for the specificity towards HBV and lower cytotoxicity than PMEA, the active component of adefovir dipivoxil. Additional analogs in this structural class have been prepared with the phenylthio- and 3-methoxyphenylthio ethers showing the most promise whilst other aromatic thioethers exhibited higher cytotoxicity (14,15).
Non-nucleoside inhibitors of HBV are beginning to emerge that are anticipated to show reduced cross-resistance with nucleoside analogues. AT130 (8) and its close analog AT61 are active against wild type HBV and the rtL180M, rtM204l, and rtL180M+rtL204V mutants (EC50 = 2-5 nM) in HepG2-derived cells (17,18). It has been postulated that 8 interferes with the packaging of pregenomic viral RNA resulting in inhibition of viral reverse transcription. Pyridinedicarboxamide 9 represents the first report of a non-nucleoside inhibitor of HBV reverse transcriptase (19). The unique mechanism of action of Bay 41-4109 (10), a potent HBV inhibitor in vitro, EC50 in HepG2.2.15 cells = 50 nM, has recently been elucidated (20,21). Only the (R)-
enantiomer of 10 is active in cell culture and appears to prevent proper formation of the viral nucleocapsid.
Inhibitors of Hepatitis C Virus (HCV) - Nearly 170 million individuals are infected with hepatitis C virus (HCV) worldwide and HCV infection is responsible for 8,000-10,000 deaths annually in the United States, a burden expected to increase significantly (22,23). A second pegylated interferon-a (IFN), Roche's Pegasys, was approved in 2003, both as mono therapy and in conjunction with ribavirin (11) (Copegus™) (24). However, safety concerns with combination therapy remain, as the accumulation of 11. in erythrocytes can lead to hemolytic anemia. This has prompted a search for safer interferon co-therapies which include the active enantiomer of 1_1, levovirin, and the prodrug viramidine (12), which improves liver at the expense of erythrocyte exposure (25,26).
The development of safe, efficacious, and HCV-specific antiviral agents remains an important goal and the development of subgenomic HCV replicons has dramatically enhanced the potential to identify inhibitors (27,28). A significant advance towards establishing a correlation between replicon inhibition and clinical efficacy was recently accomplished with the disclosure of preliminary clinical data for BILN-2061, a selective inhibitor of the NS3 serine protease of HCV that is structurally related to 13. This highly modified macrocylic tripeptide derivative is extremely potent in vitro, with Ki values of 0.3 nM and 0.66 nM towards HCV-1a and HCV-1b NS3 proteases, respectively (29). These figures are similar to the potency observed in cell culture in the cognate HCV replicons, EC5o = 4 nM and 3 nM, respectively (29). Antiviral efficacy was established in a study conducted with 10 patients with chronic HCV and significant liver fibrosis, where all patients treated with BILN-2061 (200 mg p.o. b.i.d.) displayed a decrease in serum HCV RNA levels of at least 2.0 log™ copies/mL after two days of treatment (30). Four of these patients recorded a reduction in viral load of more than 3 orders of magnitude and viral titers returned to baseline following cessation of therapy, with no drug-related safety issues identified (31).
The intensity of effort devoted towards the discovery of inhibitors of HCV NS3 has continued, with the focus largely on peptide-based molecules that are required to effectively complement the active site and proximal regions of the protease (32-34). The crystal structure of a macrocyclic inhibitor related to 13 bound to HCV protease has been disclosed and an acyclic tripeptidic inhibitor has been used to generate resistant subgenomic replicons in which mutations mapped to the protease (35,36). Amongst several strategies disclosed, the C-terminal carboxylate of peptide inhibitors may be replaced with an N-acyl sulfonamide moiety, as exemplified by 14 (37). Novel approaches to constrain or mimic the peptidic backbone are represented by macrocycle 15, the tetrahydroindolizine 16 (IC5o = 0.12 nM), the imidazolone 17 and
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