Lobucavir

Lobucavir

Legal status
Legal status	US: Investigational New Drug
Identifiers
IUPAC name 2-amino-9-[(1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl]-1H-purin-6-one
JSmol)	Interactive image
SMILES C1[C@@H]([C@H]([C@@H]1N2C=NC3=C2N=C(NC3=O)N)CO)CO
InChI InChI=1S/C11H15N5O3/c12-11-14-9-8(10(19)15-11)13-4-16(9)7-1-5(2-17)6(7)3-18/h4-7,17-18H,1-3H2,(H3,12,14,15,19)/t5-,6-,7-/m1/s1 Key:GWFOVSGRNGAGDL-FSDSQADBSA-N

Lobucavir (previously known as BMS-180194, Cyclobut-G) is an

Lobucavir has been shown to exhibit antiviral activity against herpesvirus, hepatitis B, HIV/AIDS, and human cytomegalovirus.^[6] It reached phase III clinical trials for hepatitis B and herpesvirus, phase II clinical trials for cytomegalovirus, and underwent a pilot study for use in treating AIDs^[7][8] prior to discontinuation.

Adverse effects

In early clinical trials, Lobucavir was relatively well tolerated in subjects and was not subject to discontinuation due to adverse effects. Commonly reported effects included headache, fatigue, diarrhea, abdominal pain, and flu-like symptoms common with other nucleoside analogs.^[9] Other studies, however, identified Lobucavir-induced carcinogenesis associated with long-term use in mice that led to the drug's discontinuation in clinical trials in 1999.^[4]

Mechanism of action

Lobucavir is a guanine analog that interferes with viral DNA polymerase.^[6] It must be phosphorylated into its triphosphate form within infected cells via intracellular enzymes before it can demonstrate its anti-viral activity. In hepatitis B studies, Lobucavir has been found to inhibit viral primer synthesis, reverse-transcription, and DNA-dependent DNA polymerization by acting as a non-obligate chain terminator of the viral polymerase. Unlike traditional chain terminators that lack a 3'-OH group to prevent further DNA replication, Lobucavir is thought to cause a conformational change that blocks optimal polymerase activity two to three nucleotides downstream of its incorporation.^[1] Its mechanism of action has been found to be similar in use against human cytomegalovirus.^[6]

Pharmacokinetics

Lobucavir's bioavailability is 30-40% of the original oral dose and its half-life is approximately 10 hours, as demonstrated by pre-clinical testing^[10][11]

References