Human cytomegalovirus inhibitor

Compound 13 is representative of a series of potent and selective human cytomegalovirus inhibitors (HCMV). This particular series has limited utility due to little or no oral bioavailability. Dihydroquinoline analog 14, however, maintains in vitro activity comparable to 13, but has acceptable bioavailability. Interestingly, the corresponding tetrahydroquinoline analog of 14 does not show any HCMV activity in vitro, suggesting that 14 has the optimal amount of flexibility, planarity, and stability for in vitro and in vivo potency. Further optimization of this series led to 15, which has a >7-fold increase in in vitro potency with oral bioavailability equal to 23% and 60% when dosed at 5mg/kg and 50mg/kg, po, respectively. 

Chan, L., Stefanac, T., Turcotte, N. et al. Design and evaluation of dihydroisoquinolines as potent and orally bioavailable human cytomegalovirus inhibitors. Bioorg. Med. Chem. Lett. 2000, 10, 1477-1480. 

Stuyver LJ, McBrayer TR, Thamish PM, Qark J, HoUecker L, Lostia S, Nachman T, Grier J, Bennett MA, Xie M-Y, Schinazi RE, Morrey JD, Inlander JL, Eurman PA, Otto MJ (2006) Inhibition of hepatitis C repUcon RNA synthesis by P-D-2 -deoxy-2 -fluoro-2 -C-methylcytidine a specific inhibitor of hepatitis C virus replication. Antiviral Chem Chemother 17 79-87 Sullivan V, Talarico CL, Stanat SC, Davis M, Coen DM, Biron KK (1992) A protein kinase homo-logue controls phosphorylation of ganciclovir in human cytomegalovirus-infected cells. Nature 359 85... 

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. 

Siegel, M.M., Tabei, K., Bebemitz, G.A., Baum, F.Z. Rapid methods for screening low molecular mass compounds non-covalently bound to proteins using size exclusion and mass spectrometry applied to inhibitors of human cytomegalovirus proteases. J. Mass Spectrom. 1998, 33, 264-273. 

In order to identify novel lead compounds with antiviral effects, methanol and aqueous extracts of some medicinal plants in the Zingiberaceae family were screened for inhibition of proteases from human immunodeficiency virus type 1 (HIV-1), hepatitis C virus (HCV) and human cytomegalovirus (HCMV). By bioassay-guided fractionation, eight fiavones were isolated from the black rhizomes of Kaempferia parviflora Wall, ex Baker. The most effective inhibitors, 5-hydroxy-7-methoxyfiavone and 5,7-dimethoxyflavone, inhibited HIV-1 protease, with an inhibitory concentration 50 (IC50) values of 19 0,M. Moreover, 5-hydroxy-3,7-dimethoxyflavone inhibited HCV protease and HCMV protease, with IC50 values of 190 and 250 pM, respectively. 

A range of chiral (ly)-proline derivatives, for example 211, have been shown to be active serine protease inhibitors and are active antivirals of human cytomegalovirus (HCMV) <2003JME4428>. 

Very recently, (3-lactam antibiotics have been shown to offer neuroprotection by increasing glutamate transporters expression via gene activation [15] in addition, the discoveries of new biologically active (3-lactams such as cholesterol acyl transferase inhibitors [16-18], thrombin inhibitors [19], human cytomegalovirus protease inhibitors [20], matrix-metallo protease inhibitors [21], inhibitors of human leukocyte elastase (HLE) [22, 23] and cysteine protease [24, 25], and apoptosis inductors [26, 27] have provided much needed motivation for continuous development of new (3-lactam systems. 

Another approach to a-ketoamide peptide mimetics was employed by Xu et al. [33] for the preparation of a human cytomegalovirus protease inhibitor library. In this case the oxidizable -OH group, protected as formate, belonged to the starting isocyanides. Thus, the reaction between N-acylated a-amino acids, amines, aldehydes, and isocyanides 42 afforded the a-hydroxyamides 43 in modest yields. Cleavage of the O-formyl bond was accomplished during the reaction by employing two... 

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. 

Abstract The inhibitory action of polyanionic substances on virus replication was reported more than 50 years ago. Seaweeds, marine invertebrates, and higher plants represent abundant sources of novel compounds of proved antiviral activity. Natural sulfated polysaccharides (SPs) are potent in vitro inhibitors of a wide variety of enveloped viruses, such as herpes simplex virus (HSV) types 1 and 2, human immunodeficiency virus (HIV), human cytomegalovirus (HCMV), dengue virus (DENV), respiratory syncytial virus (RSV), and influenza A virus. Several polysulfate compounds have the potential to inhibit virus replication by blocking the virion binding to the host cell. In contrast, their in vivo efficacy in animal and human systemic infections has undesirable draw-... 

Human cytomegalovirus (HCMV) disease is the most common life-threatening opportunistic viral infection in the inmunocompromised. HCMV protease, a serine protease, plays a critical role in capsid assembly and viral maturation and is an attractive target for antiviral chemotherapy. Slater et al investigated the interaction of various 1,4-naphthoquinones derivatives with HCMV protease. They identified potent irreversible naphthoquinones inhibitors of HCMV protease which covalently modify... 

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