Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Editor

Personal info

View

About

Terms

Javascript disabled

Please enable Javascript support in your browser to use this application.

Instructions on how to enable JavaScript on different browsers can be found here: http://www.google.com/support/bin/answer.py?answer=23852.

[edit this page]

Chemical Compound Review:

AC1NUXVY 1-(2-methoxy-5,7- diazabicyclo[4.3.0]nona-1...

Synonyms: BMS-806, BMS806, CHEMBL337301, SureCN1288198, BMX 806, ...

Lin, P.F. et al., Yang, Z. et al., Madani, N. et al., Wang, H.G. et al., Wang, J. et al., et al.

Lin, Blair, Wang, Spicer, Guo, Zhou, Gong, Wang, Rose, Yamanaka, Robinson, Li, Fridell, Deminie, Demers, Yang, Zadjura, Meanwell, Colonno, Yang, Zadjura, D'Arienzo, Marino, Santone, Klunk, Greene, Lin, Colonno, Wang, Meanwell, Hansel,

Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of BMS-806

Further confirmation that BMS-378806 targets the envelope in infected cells was obtained through the isolation of resistant variants and the mapping of resistance substitutions to the HIV-1 envelope [1].
Together, the data show that BMS-378806 is a representative of a new class of HIV inhibitors that has the potential to become a valued addition to our current armamentarium of antiretroviral drugs [1].
BMS-378806 is selective for HIV-1 and inactive against HIV-2, SIV and a panel of other viruses, and exhibits no significant cytotoxicity in the 14 cell types tested (concentration for 50% reduction of cell growth, >225 microM) [1].

High impact information on BMS-806

Importantly, BMS-806 and related HIV-1 entry inhibitors bind gp120 and block the CD4 induction of HR1 exposure without significantly affecting CD4 binding [2].
BMS-378806 displays many favorable pharmacological traits, such as low protein binding, minimal human serum effect on anti-HIV-1 potency, good oral bioavailability in animal species, and a clean safety profile in initial animal toxicology studies [1].
We tested a panel of HIV-1 envelope glycoprotein mutants and identified several that were resistant to the antiviral effects of BMS-806 and #155 [3].
A putative binding site for BMS-806 and #155 between the gp120 receptor-binding regions and the inner domain, which is thought to interact with the gp41 transmembrane envelope glycoprotein, helps to explain the mode of action of these drugs [3].
Thus, inhibitors of the gp120-CD4 interaction have been detected (zintevir, FP-21399 and BMS-378806 in clinical trials) [4].

Biological context of BMS-806

BMS-378806 exhibits no significant cytotoxicity and displays many attractive pharmacological properties such as low protein binding, minimal serum effect on anti-HIV-1 potency, good oral bioavailability in animal species and a clean safety profile in initial animal toxicology studies [5].
The present work investigated the pharmacokinetics of BMS-378806 in rats, dogs and monkeys and assessed its in vitro permeability and metabolism [6].
This paper describes selected modification and structure-activity relationship of the small molecule HIV-1 inhibitor, 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2-(R)-methylpiperazine (BMS-378806) [7].

Anatomical context of BMS-806

In vitro, all three compounds inhibit infection of T cells and cervical tissue explants, and C52L acts synergistically with CMPD167 or BMS-378806 to inhibit infection of cell lines [8].
In human liver microsomes BMS-378806 was equally metabolized by cytochrome P450 1A2, 2D6 and 3A4 and did not inhibit major drug-metabolizing enzymes to a significant extent [6].

Gene context of BMS-806

Mechanism of action studies demonstrated that BMS-378806 binds to gp120 and inhibits the interactions of the HIV-1 envelope protein to cellular CD4 receptors [1].
BMS-378806 is a prototype of novel HIV attachment inhibitors that block the gp120 and CD4 interaction, the first step of HIV-1 entry into cells [6].

References

A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Lin, P.F., Blair, W., Wang, T., Spicer, T., Guo, Q., Zhou, N., Gong, Y.F., Wang, H.G., Rose, R., Yamanaka, G., Robinson, B., Li, C.B., Fridell, R., Deminie, C., Demers, G., Yang, Z., Zadjura, L., Meanwell, N., Colonno, R. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins. Si, Z., Madani, N., Cox, J.M., Chruma, J.J., Klein, J.C., Schön, A., Phan, N., Wang, L., Biorn, A.C., Cocklin, S., Chaiken, I., Freire, E., Smith, A.B., Sodroski, J.G. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
Localized changes in the gp120 envelope glycoprotein confer resistance to human immunodeficiency virus entry inhibitors BMS-806 and #155. Madani, N., Perdigoto, A.L., Srinivasan, K., Cox, J.M., Chruma, J.J., LaLonde, J., Head, M., Smith, A.B., Sodroski, J.G. J. Virol. (2004) [Pubmed]
Highly active antiretroviral therapy: current state of the art, new agents and their pharmacological interactions useful for improving therapeutic outcome. Barbaro, G., Scozzafava, A., Mastrolorenzo, A., Supuran, C.T. Curr. Pharm. Des. (2005) [Pubmed]
A novel class of HIV-1 inhibitors that targets the viral envelope and inhibits CD4 receptor binding. Wang, H.G., Williams, R.E., Lin, P.F. Curr. Pharm. Des. (2004) [Pubmed]
Preclinical pharmacokinetics of a novel HIV-1 attachment inhibitor BMS-378806 and prediction of its human pharmacokinetics. Yang, Z., Zadjura, L., D'Arienzo, C., Marino, A., Santone, K., Klunk, L., Greene, D., Lin, P.F., Colonno, R., Wang, T., Meanwell, N., Hansel, S. Biopharmaceutics & drug disposition. (2005) [Pubmed]
Modification and structure-activity relationship of a small molecule HIV-1 inhibitor targeting the viral envelope glycoprotein gp120. Wang, J., Le, N., Heredia, A., Song, H., Redfield, R., Wang, L.X. Org. Biomol. Chem. (2005) [Pubmed]
Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion. Veazey, R.S., Klasse, P.J., Schader, S.M., Hu, Q., Ketas, T.J., Lu, M., Marx, P.A., Dufour, J., Colonno, R.J., Shattock, R.J., Springer, M.S., Moore, J.P. Nature (2005) [Pubmed]

Contributions to this collaborative article are from individual authors of WikiGenes or mined by the WikiGenes Data Mining Engine from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.About WikiGenes Open Access Licence Privacy Policy Terms of Use apsburg

The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.