Lobucavir

Lobucavir (previously known as BMS-180194, Cyclobut-G) is an antiviral drug that shows broad-spectrum activity against herpesviruses, hepatitis B and other hepadnaviruses, HIV/AIDS and cytomegalovirus.^[1][2][3] It initially demonstrated positive results in human clinical trials against hepatitis B with minimal adverse effects but was discontinued from further development following the discovery of increased risk of cancer associated with long-term use in mice.^[4] Although this carcinogenic risk is present in other antiviral drugs, such as zidovudine and ganciclovir that have been approved for clinical use, development was halted by Bristol-Myers Squibb, its manufacturer.^[5]

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
CAS Number	127759-89-1
PubChem CID	135413519
DrugBank	DB12531
ChemSpider	54782
UNII	8U5PYQ1R2E
KEGG	D04757
ChEMBL	ChEMBL23550
CompTox Dashboard (EPA)	DTXSID40155063
Chemical and physical data
Formula	C11H15N5O3
Molar mass	265.273 g·mol−1
3D model (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

Medical use

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

1. Seifer M, Hamatake RK, Colonno RJ, Standring DN (December 1998). "In vitro inhibition of hepadnavirus polymerases by the triphosphates of BMS-200475 and lobucavir". Antimicrobial Agents and Chemotherapy. 42 (12): 3200–3208. doi:10.1128/aac.42.12.3200. PMC 106023. PMID 9835515.
2. Field AK, Tuomari AV, McGeever-Rubin B, Terry BJ, Mazina KE, Haffey ML, et al. (January 1990). "(+-)-(1 alpha,2 beta,3 alpha)-9-[2,3-bis(hydroxymethyl)-cyclobutyl] guanine [(+-)-BHCG or SQ 33,054]: a potent and selective inhibitor of herpesviruses". Antiviral Research. 13 (1): 41–52. doi:10.1016/0166-3542(90)90043-7. PMID 2159261.
3. Hoffman VF, Skiest DJ (February 2000). "Therapeutic developments in cytomegalovirus retinitis". Expert Opinion on Investigational Drugs. 9 (2): 207–220. doi:10.1517/13543784.9.2.207. PMID 11060672. S2CID 6621431.
4. Woicke J, Durham SK, Mense MG (November 2007). "Lobucavir-induced proliferative changes in mice". Experimental and Toxicologic Pathology. 59 (3–4): 197–204. doi:10.1016/j.etp.2007.09.002. PMID 17942294.
5. "Bristol-Myers Squibb Issues Statement On Lobucavir". www.pharmaceuticalonline.com. Retrieved 2020-03-14.
6. Tenney DJ, Yamanaka G, Voss SM, Cianci CW, Tuomari AV, Sheaffer AK, et al. (December 1997). "Lobucavir is phosphorylated in human cytomegalovirus-infected and -uninfected cells and inhibits the viral DNA polymerase". Antimicrobial Agents and Chemotherapy. 41 (12): 2680–2685. doi:10.1128/aac.41.12.2680. PMC 164188. PMID 9420038.
7. "Lobucavir". AdisInsight. Springer Nature Switzerland AG. Retrieved 2020-03-14.
8. Clinical trial number NCT00002352 for "A Study of Lobucavir in Patients With AIDS" at ClinicalTrials.gov
9. Mills J (1999). Antiviral chemotherapy : new directions for clinical application and research. Elsevier. ISBN 0-306-46107-2. OCLC 164814252.
10. Yamanaka G, Wilson T, Innaimo S, Bisacchi GS, Egli P, Rinehart JK, et al. (January 1999). "Metabolic studies on BMS-200475, a new antiviral compound active against hepatitis B virus". Antimicrobial Agents and Chemotherapy. 43 (1): 190–193. doi:10.1128/AAC.43.1.190. PMC 89048. PMID 9869593.
11. "AIDS Related Opportunistic Infections Report, 1998". Treatment Action Group. Retrieved 2020-03-14.