Lobucavir

Short description: Chemical compound

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

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

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]

## Contents

* 1 Medical use
* 2 Adverse effects
* 3 Mechanism of action
* 4 Pharmacokinetics
* 5 References

## 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. ↑ 1.0 1.1 "In vitro inhibition of hepadnavirus polymerases by the triphosphates of BMS-200475 and lobucavir". Antimicrobial Agents and Chemotherapy 42 (12): 3200–3208. December 1998. doi:10.1128/aac.42.12.3200. PMID 9835515.
2. ↑ "(+-)-(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. January 1990. doi:10.1016/0166-3542(90)90043-7. PMID 2159261.
3. ↑ "Therapeutic developments in cytomegalovirus retinitis". Expert Opinion on Investigational Drugs 9 (2): 207–220. February 2000. doi:10.1517/13543784.9.2.207. PMID 11060672.
4. ↑ 4.0 4.1 "Lobucavir-induced proliferative changes in mice". Experimental and Toxicologic Pathology 59 (3–4): 197–204. November 2007. doi:10.1016/j.etp.2007.09.002. PMID 17942294.
5. ↑ "Bristol-Myers Squibb Issues Statement On Lobucavir". https://www.pharmaceuticalonline.com/doc/bristol-myers-squibb-issues-statement-on-lobu-0001.
6. ↑ 6.0 6.1 6.2 "Lobucavir is phosphorylated in human cytomegalovirus-infected and -uninfected cells and inhibits the viral DNA polymerase". Antimicrobial Agents and Chemotherapy 41 (12): 2680–2685. December 1997. doi:10.1128/aac.41.12.2680. PMID 9420038.
7. ↑ "Lobucavir". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800002213.
8. ↑ Clinical trial number NCT00002352 for "A Study of Lobucavir in Patients With AIDS" at ClinicalTrials.gov
9. ↑ Antiviral chemotherapy : new directions for clinical application and research. Elsevier. 1999. ISBN 0-306-46107-2. OCLC 164814252.
10. ↑ "Metabolic studies on BMS-200475, a new antiviral compound active against hepatitis B virus". Antimicrobial Agents and Chemotherapy 43 (1): 190–193. January 1999. doi:10.1128/AAC.43.1.190. PMID 9869593.
11. ↑ "AIDS Related Opportunistic Infections Report, 1998" (in en-US). https://www.treatmentactiongroup.org/publication/the-oi-report-1998/.

* v
* t
* e

DNA virus antivirals (primarily J05, also S01AD and D06BB)

Baltimore I|

| Herpesvirus|

| DNA-synthesis
inhibitor|

| TK activated|

| Purine analogue|

* guanine (Aciclovir#/Valaciclovir
* Ganciclovir/Valganciclovir#
* Penciclovir/Famciclovir)

* adenine (Vidarabine)

|

Pyrimidine analogue|

* uridine (Idoxuridine
* Trifluridine (+tipiracil)
* Edoxudine)

* thymine
* Brivudine
* Sorivudine

* [[Chemistry:Cytocytosine (Cytarabine|Cytarabine]])

Not TK activated|

* Foscarnet

Other|

* Docosanol
* early protein (Fomivirsen)
* Tromantadine

HPV/MC|

* Imiquimod/Resiquimod
* Podophyllotoxin

Vaccinia|

* assembly: Rifampicin

Poxviridae|

* Methisazone

Hepatitis B (VII)|

* Nucleoside analogues/NARTIs: Entecavir#
* Lamivudine
* Telbivudine
* Clevudine

* Nucleotide analogues/NtRTIs: Adefovir
* Tenofovir disoproxil
* Tenofovir alafenamide

Multiple/general|

| Nucleic acid inhibitors|

* Cidofovir

|

Interferon|

* Interferon alfa 2b
* Peginterferon alfa-2a

Multiple/unknown|

* Ribavirin#/Taribavirin†
* Moroxydine

* #WHO-EM
* ‡Withdrawn from market
* Clinical trials:
* †Phase III
* §Never to phase III

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