The HCMV serine protease has been perceived as an attractive antiviral target. Recent crystal structure data demonstrated significant conformational flexibility in the S3 binding pocket of protein complexed with two peptidomimetic inhibtors (94). A series of frans-lactams, represented by 35 and 36, IC50 = 0.54 and 0.34 (iM, respectively, are derived from the same structural platform as the HCV NS3 inhibitor 22 but inhibit the HCMV serine protease with excellent selectivity (95-97). Mechanistic studies are consistent with acylation of the active site Seri32 of HCMV protease in a reversible and time-dependent manner.
All but one of the currently licensed drugs available to treat HSV act by inhibiting the viral DNA polymerase, providing a suitable backdrop for the emergence of resistant virus and a rationale for identifying inhibitors of other viral proteins (98,99). Two groups have reported novel thiazole-containing inhibitors of the HSV helicase-primase. BAY 57-1293 (37) is a leading pre-clinical candidate that is more potent (EC5o = 12 nM) than any anti-herpetic currently used to treat HSV infections (100,101). In a murine lethal challenge model of HSV-1 and HSV-2, 37 was protective with an ED5o value of 0.5 mg/kg, which compares with the much higher doses of 22 and 16 mg/kg for HSV-1 and HSV-2, respectively, required for acyclovir to show efficacy. Additional patent applications that extend this promising chemotype have appeared (102,103). A second series of HSV helicase-primase inhibitors, of which BILS-179 BS (38) is representative, has been disclosed (104). BILS 179 BS inhibits viral growth with an EC5o of 27 nM, displays an excellent therapeutic index of >2000 and reduces cutaneous HSV-1 and genital HSV-2 disease in a murine model when treatment is initiated 3 hours post-infection. Interestingly, when treatment was initiated 65 hours after infection, 38 reduced HSV-1 pathology by 75% and HSV-2 mortality by 75% (200 mg/Kg/day) when compared to acyclovir or untreated animals (104).
A series of 4-oxo-dihydroquinolone derivatives that are potent and broad spectrum non-nucleoside inhibitors of DNA polymerases of the herpesvirus family, including HCMV, HSV-1, HHV-8 and VZV, have been the subject of a number of recent disclosures (105). These compounds exhibit no significant inhibitory activity towards human a-, y-, or 8-polymerases. PNU-183792 (39) is an effective antiviral in cell culture, potently inhibiting HCMV (ECso = 0.69 nM), VZV (ECso = 0.37 ^M) and HSV (ECso = 0.58 nM), that is active towards ganciclovir- and cidofovir-resistant HCMV and acyclovir-resistant HSV (106). Excellent oral bioavailability and a protective effect in a murine CMV animal model were also reported. A series of related analogs have been reported in the recent patent literature (107,108).
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