Herpes virus protease inhibitors

Hepatitis C virus NS3/NS4A protease inhibitors, 44 (2006) 65 Herpes virus, chemotherapy, 23 (1985) 67 Heterocyclic analogues of GABA,... 

Antibodies against the virus but also amantadine and derivatives, interfere with host cell penetration. There are nucleoside analogues such as aciclovir and ganciclovir, which interfere with DNA synthesis, especially of herpes viruses. Others like zidovudine and didanosine, inhibit reverse transcriptase of retroviruses. Recently a number of non-nucleoside reverse transcriptase inhibitors was developed for the treatment of HIV infections. Foscarnet, a pyrophosphate analogue, inhibits both reverse transcriptase and DNA synthesis. Protease inhibitors, also developed for the treatment of HIV infections, are active during the fifth step of virus replication. They prevent viral replication by inhibiting the activity of HIV-1 protease, an enzyme used by the viruses to cleave nascent proteins for final assembly of new vi-rons. 

Some phenylalanine-derived monocyclic azetidin-2-ones, for example, 564, have been reported as modest inhibitors of human cytomegalovirus (HCMV) serine protease <2004BML2253>. HCMV is a ubiquitous member of the herpes virus family. Severe manisfestations of HCMV can be seen in individuals with a weakened immune system due to late-stage cancer and AIDS, or by immunosuppressive therapy following organ transplantation. 

Antiviral drags come eleventh and seventeenth. They are an important research area, but progress has been slow. Acyclovir and related drags for herpes simplex and varicella-zoster are now well established. AIDS cannot be cured but its progression can be dramatically slowed by combination therapy of two reverse transcriptase inhibitors (e.g. azidothymidine and lamivudine) plus a protease inhibitor (e.g. saquinavir). Unfortunately, viruses have the ability to modify themselves in unpredictable ways. An... 

In this chapter, we have described the spectrum of antiviral activities that have been discovered beyond the world of nucleoside analogues, protease and fusion inhibitors. The compounds and mechanisms described here may one day add significantly to the armamentarium of antiviral agents, not only against Herpes Simplex, Hepatitis B and Human Immunodeficiency Virus, but also against Hepatitis C and Human Cytomegalovirus. 

Parallel synthesis is now established as an integral component of lead optimisation methodology and increasing numbers of reports on the use of this approach in medicinal chemistry programmes are appearing in the literature. Jarvest et al. [12] explored the structure activity relationship at the 2-position of benzoxazi-nones in the search for inhibitors of herpes simplex virus-1 protease. Reaction of anthranilic acids with excess isocyanate or chloroformate afforded the 2-amino or 2-alkoxy substituted derivatives (Figure 5). 

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