Brivudine, 溴夫定

5-(E)-(2-Bromovinyl)-2'-deoxyuridine

Anti-viral; thymidine analogue; DNA plymerase inhibitor

Pyrimidine nucleoside analog. Antiviral agent (IC50 values are 76 nM and 1.4 μM for herpesvirus and HIV respectively). Blocks DNA polymerase. Binds to heat shock protein HSPB1 and inhibits interaction with its binding partners. Shows anticancer effects in vivo. Orally active.

Brivudine is a thymidine analog and inhibitor of herpes simplex virus 1 (HSV-1) and varicella-zoster virus (VZV) viral replication. Following conversion to a 5'-triphosphate form by viral kinases, brivudine is incorporated into viral DNA, inhibiting viral DNA polymerases and inducing strand breakage. Brivudine (0.02-0.04 μg/ml) inhibits VZV replication in primary human fibroblasts and inhibits cytopathogenic effects of the KOS HSV-1 strain in a panel of cell lines (MIC50s = 0.007-0.4 μg/ml). It selectively inhibits cytopathogenicity induced by HSV-1 strains over HSV-2, vaccinia virus, vesicular stomatitis virus, or deoxythymidine kinase-deficient HSV-1 strains in E6SM cells (MIC50s = 0.02, 2-10, 7, >400, and 40 μg/ml, respectively). Brivudine (5 and 15 mg/kg twice per day) increases survival in a mouse model of disseminated HSV-1 infection.

Brivudine is a uridine derivative and nucleoside analog with pro-apoptotic and chemosensitizing properties. In vitro, bromovinyl-deoxyuridine (BVDU) has been shown to downregulate the multifunctional DNA repair enzyme APEX nuclease 1, resulting in the inhibition of DNA repair and the induction of apoptosis. In addition, this agent may inhibit the expression of STAT3 (signal transducer and activator of transcription 3), which may result in the downregulation of vascular endothelial growth factor (VEGF). BVDU has also been found to inhibit the upregulation of chemoresistance genes (Mdr1 and DHFR) during chemotherapy. Overall, the gene expression changes associated with BVDU treatment result in the decrease or prevention of chemoresistance. In addition, this agent has been shown to enhance the cytolytic activity of NK-92 natural killer cells towards a pancreatic cancer cell line in vitro.

Brivudine is used in the treatment of herpes zoster. Although not approved in the U.S. or Canada, it is approved in several European countries.

Title: Brivudine

CAS Registry Number: 69304-47-8

CAS Name: 5-[(1E)-2-Bromoethenyl]-2'-deoxyuridine

Additional Names: (E)-5-(2-bromovinyl)-2'-deoxyuridine; brivudin; BVDU

Trademarks: Brivex (Menarini); Brivirac (Menarini); Nervinex (Menarini); Zecovir (Guidotti); Zostex (Berlin-Chemie)

Molecular Formula: C11H13BrN2O5

Molecular Weight: 333.14

Percent Composition: C 39.66%, H 3.93%, Br 23.99%, N 8.41%, O 24.01%

Literature References: Analog of thymidine, q.v., with selective activity against herpes simplex virus type 1 and varicella-zoster virus. Prepn: A. S. Jones et al., DE 2915254; eidem, US 4424211 (1979, 1984 both to University of Birmingham and Rega Institut); and antiviral activity: E. De Clercq et al, Proc. Natl. Acad. Sci. USA 76, 2947 (1979). Mechanism of action studies: H. S. Allaudeen et al., ibid. 78, 2698 (1981); J. Balzarini, E. De Clercq, Methods Find. Exp. Clin. Pharmacol. 11, 379 (1989). Cytotoxic properties vs viral tumor cells: C. Grignet-Debrus et al., Cancer Gene Ther. 7, 215 (2000). CE determn in plasma and urine: J. Olgemöller et al., J. Chromatogr. B 726, 261 (1999). Clinical evaluation in herpetic keratitis: P. C. Maudgal, E. De Clercq, Curr. Eye Res. 10, Suppl., 193 (1991). Clinical comparison with acyclovir, q.v., in herpes zoster: S. W. Wassilew et al., Antiviral Res. 59, 49, 57 (2003). Review of pharmacology and clinical efficacy in herpes zoster: S. J. Keam et al., Drugs 64, 2091-2097 (2004); of antiviral activity, mechanism of action, and clinical efficacy: E. De Clercq, Med. Res. Rev. 25, 1-20 (2005).

Properties: White needles from methanol-water, mp 123-125° (dec). uv max: 253, 295 nm (e 13100, 10300).

Melting point: mp 123-125°

Absorption maximum: uv max: 253, 295 nm (e 13100, 10300)

Therap-Cat: Antiviral.

Keywords: Antiviral; Purines/Pyrimidinones.