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What is Ganciclovir?

Feb 10，2020

Ganciclovir is a potent inhibitor of herpes viruses, including CMV. It is a nucleoside analogue that suppresses the replication of herpes viruses and functions as a virustatic agent. Ganciclovir has been used systemically, in the form of intravitreal injections and implants for CMV infections of the eye. It is used for the treatment and suppression of the life-threatening or sight-threatening cytomegalovirus infections in immunocompromised patients, including those with acquired immunodeficiency syndrome and those with iatrogenic immunosuppression associated with organ transplantation or chemotherapy of neoplastic disease. More recently, topical ganciclovir has been shown to be effective against herpetic keratitis. Topical application of ganciclovir has also been shown to penetrate the corneal stroma and achieve therapeutic levels in the aqueous humour. It has been used in the treatment of CMV anterior uveitis, but its effectiveness has been reported in only a limited number of studies.[1]

Matthews and Boehme reported that the primary mechanism of ganciclovir action against cytomegalovirus is the inhibition of the replication of viral DNA by ganciclovir-5’-triphosphate. This inhibition includes a selective and potent inhibition of the viral DNA polymerase. Ganciclovir is metabolized to the triphosphate form by primarily three cellular enzymes:(1) a deoxyguanosine kinase induced by cytomegalovirus-infected cells;(2) guanylate kinase; and (3) phosphoglycerate kinase. Other nucleotidemetabolizing enzymes may be involved as well. The selective antiviral response associated with ganciclovir treatment is achieved because of the much weaker inhibition of cellular DNA polymerases by ganciclovir-5’-triphosphate. Activity and selectivity are also amplified by the accumulation of ganciclovir-5’-triphosphate in cytomegalovirus-infected cells.[2]

Concentration of ganciclovir equivalent to those achieved clinically have been shown to inhibit the growth of human bone marrow colonyforming cells in vitro. Ganciclovir exhibits a range of in vitro and in vivo immunological effects that indicate inhibition of immune responses associated with CMV infection and/or graft rejection (e.g. inhibition of CMV-induced antigen up-regulation, reduction in T-cell proliferation, release of soluble interleukin-2 receptor into serum, and immunosuppression in renal transplant recipients with active CMV infection). In vitro and in vivo studies also show that ganciclovir inhibits CMV-induced vascular smooth muscle cell and intimal proliferation, and that it prevents arteriosclerosis of CMV- infected aortic or cardiac allografts in rats These results are of clinical interest in relation to the prevention of CMV-induced arteriosclerotic graft rejection and loss.[3]

Ganciclovir is a polar hydrophilic compound with a solubility of 2.6mg/mL in water at 25°C and an n-octanol/water partition coefficient of 0.022. The pKa values for ganciclovir are 2.2 and 9.4. The n-octanol/water partition coefficient of ganciclovir is 0.022. [1]

Field et al. and Ashton et al. prepared ganciclovir 6 by treating 4-chloromethyl-1,3-dioxolane 1 with acetic acid anhydride, acetic acid, and zinc chloride, and the product, 1-chloro-2-acetoxymethoxy-3-acetoxy propane 2, was obtained. Treatment of compound 2 with potassium acetate in dimethylformamide gave 1,3-diacetyloxy-2-acetyoxymethyloxy propane 3. Compound 3 was fused with N2,9-diacetylguanine 4 at 155–170°C to give the triacetyl intermediate product 5. Treatment of compound 5 with 40% aqueous methylamine at 75°C produced ganciclovir 6 as illustrated in Scheme 1. [1]

References

1.Abdullah A. Al-Badr, Tariq D.S. Ajarim. Ganciclovir. Profiles of Drug Substances, Excipients, and Related Methodology, Volume 43. ISSN 1871-5125

2.Wong JXH et al. Efficacy and safety of topical ganciclovir in the management of cytomegalovirus (CMV)-related anterior uveitis[J]. Journal of Ophthalmic Inflammation and Infection, 2016, 6:10

3.Cvetkovic RS et al. Valganciclovir, A Review of its Use in the Management of CMV Infection and Disease in Immunocompromised Patients[J]. Drugs, 2005 65 (6): 859-878.