3-azatetracyclo[5.2.1.15,8.01,5]undecane Derivatives

From wild-type inhibitors of the M2 ion channel of influenza A virus to derivatives with potent activity against the V27A mutant

Matias Rey-Carrizo, Eva Torres, Chunlong Ma, Marta Barniol-Xicota, Jun Wang, Yibing Wu, Lieve Naesens, William F. Degrado, Robert A. Lamb, Lawrence H. Pinto, Santiago Vázquez

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

We have synthesized and characterized a series of compounds containing the 3-azatetracyclo[5.2.1.15,8.01,5]undecane scaffold designed as analogues of amantadine, an inhibitor of the M2 proton channel of influenza A virus. Inhibition of the wild-type (WT) M2 channel and the amantadine-resistant A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Most of the novel compounds inhibited the WT ion channel in the low micromolar range. Of note, several compounds inhibited the A/M2 V27A mutant ion channel, one of them with submicromolar IC50. None of the compounds was found to inhibit the S31N mutant ion channel. The antiviral activity of three novel dual WT and A/M2-V27A channels inhibitors was confirmed by influenza virus yield assays.

Original languageEnglish (US)
Pages (from-to)9265-9274
Number of pages10
JournalJournal of Medicinal Chemistry
Volume56
Issue number22
DOIs
StatePublished - Nov 27 2013
Externally publishedYes

Fingerprint

Influenza A virus
Ion Channels
Amantadine
Xenopus
Orthomyxoviridae
Inhibitory Concentration 50
Oocytes
Antiviral Agents
Protons
Electrodes
undecane

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

3-azatetracyclo[5.2.1.15,8.01,5]undecane Derivatives : From wild-type inhibitors of the M2 ion channel of influenza A virus to derivatives with potent activity against the V27A mutant. / Rey-Carrizo, Matias; Torres, Eva; Ma, Chunlong; Barniol-Xicota, Marta; Wang, Jun; Wu, Yibing; Naesens, Lieve; Degrado, William F.; Lamb, Robert A.; Pinto, Lawrence H.; Vázquez, Santiago.

In: Journal of Medicinal Chemistry, Vol. 56, No. 22, 27.11.2013, p. 9265-9274.

Research output: Contribution to journalArticle

Rey-Carrizo, Matias ; Torres, Eva ; Ma, Chunlong ; Barniol-Xicota, Marta ; Wang, Jun ; Wu, Yibing ; Naesens, Lieve ; Degrado, William F. ; Lamb, Robert A. ; Pinto, Lawrence H. ; Vázquez, Santiago. / 3-azatetracyclo[5.2.1.15,8.01,5]undecane Derivatives : From wild-type inhibitors of the M2 ion channel of influenza A virus to derivatives with potent activity against the V27A mutant. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 22. pp. 9265-9274.
@article{eb84e6cb917f46c080cdac2fa3559c8f,
title = "3-azatetracyclo[5.2.1.15,8.01,5]undecane Derivatives: From wild-type inhibitors of the M2 ion channel of influenza A virus to derivatives with potent activity against the V27A mutant",
abstract = "We have synthesized and characterized a series of compounds containing the 3-azatetracyclo[5.2.1.15,8.01,5]undecane scaffold designed as analogues of amantadine, an inhibitor of the M2 proton channel of influenza A virus. Inhibition of the wild-type (WT) M2 channel and the amantadine-resistant A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Most of the novel compounds inhibited the WT ion channel in the low micromolar range. Of note, several compounds inhibited the A/M2 V27A mutant ion channel, one of them with submicromolar IC50. None of the compounds was found to inhibit the S31N mutant ion channel. The antiviral activity of three novel dual WT and A/M2-V27A channels inhibitors was confirmed by influenza virus yield assays.",
author = "Matias Rey-Carrizo and Eva Torres and Chunlong Ma and Marta Barniol-Xicota and Jun Wang and Yibing Wu and Lieve Naesens and Degrado, {William F.} and Lamb, {Robert A.} and Pinto, {Lawrence H.} and Santiago V{\'a}zquez",
year = "2013",
month = "11",
day = "27",
doi = "10.1021/jm401340p",
language = "English (US)",
volume = "56",
pages = "9265--9274",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "22",

}

TY - JOUR

T1 - 3-azatetracyclo[5.2.1.15,8.01,5]undecane Derivatives

T2 - From wild-type inhibitors of the M2 ion channel of influenza A virus to derivatives with potent activity against the V27A mutant

AU - Rey-Carrizo, Matias

AU - Torres, Eva

AU - Ma, Chunlong

AU - Barniol-Xicota, Marta

AU - Wang, Jun

AU - Wu, Yibing

AU - Naesens, Lieve

AU - Degrado, William F.

AU - Lamb, Robert A.

AU - Pinto, Lawrence H.

AU - Vázquez, Santiago

PY - 2013/11/27

Y1 - 2013/11/27

N2 - We have synthesized and characterized a series of compounds containing the 3-azatetracyclo[5.2.1.15,8.01,5]undecane scaffold designed as analogues of amantadine, an inhibitor of the M2 proton channel of influenza A virus. Inhibition of the wild-type (WT) M2 channel and the amantadine-resistant A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Most of the novel compounds inhibited the WT ion channel in the low micromolar range. Of note, several compounds inhibited the A/M2 V27A mutant ion channel, one of them with submicromolar IC50. None of the compounds was found to inhibit the S31N mutant ion channel. The antiviral activity of three novel dual WT and A/M2-V27A channels inhibitors was confirmed by influenza virus yield assays.

AB - We have synthesized and characterized a series of compounds containing the 3-azatetracyclo[5.2.1.15,8.01,5]undecane scaffold designed as analogues of amantadine, an inhibitor of the M2 proton channel of influenza A virus. Inhibition of the wild-type (WT) M2 channel and the amantadine-resistant A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Most of the novel compounds inhibited the WT ion channel in the low micromolar range. Of note, several compounds inhibited the A/M2 V27A mutant ion channel, one of them with submicromolar IC50. None of the compounds was found to inhibit the S31N mutant ion channel. The antiviral activity of three novel dual WT and A/M2-V27A channels inhibitors was confirmed by influenza virus yield assays.

UR - http://www.scopus.com/inward/record.url?scp=84889248905&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84889248905&partnerID=8YFLogxK

U2 - 10.1021/jm401340p

DO - 10.1021/jm401340p

M3 - Article

VL - 56

SP - 9265

EP - 9274

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 22

ER -