Substituted N -(biphenyl-4′-yl)methyl (R)-2-acetamido-3- methoxypropionamides: Potent anticonvulsants that affect frequency (Use) dependence and slow inactivation of sodium channels

Hyosung Lee, Ki Duk Park, Robert Torregrosa, Xiao Fang Yang, Erik T. Dustrude, Yuying Wang, Sarah M. Wilson, Cindy Barbosa, Yucheng Xiao, Theodore Cummins, Rajesh Khanna, Harold Kohn

Research output: Contribution to journalArticle

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Abstract

We prepared 13 derivatives of N-(biphenyl-4′-yl)methyl (R)-2-acetamido-3-methoxypropionamide that differed in type and placement of a R-substituent in the terminal aryl unit. We demonstrated that the R-substituent impacted the compound's whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI = TD50/ED50) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent potently promoted Na+ channel slow inactivation and displayed frequency (use) inhibition of Na+ currents at low micromolar concentrations. The possible advantage of affecting these two pathways to decrease neurological hyperexcitability is discussed.

Original languageEnglish
Pages (from-to)6165-6182
Number of pages18
JournalJournal of Medicinal Chemistry
Volume57
Issue number14
DOIs
StatePublished - Jul 24 2014

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Sodium Channels
Anticonvulsants
Rodentia
Pharmacology
Pharmaceutical Preparations
diphenyl

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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Substituted N -(biphenyl-4′-yl)methyl (R)-2-acetamido-3- methoxypropionamides : Potent anticonvulsants that affect frequency (Use) dependence and slow inactivation of sodium channels. / Lee, Hyosung; Park, Ki Duk; Torregrosa, Robert; Yang, Xiao Fang; Dustrude, Erik T.; Wang, Yuying; Wilson, Sarah M.; Barbosa, Cindy; Xiao, Yucheng; Cummins, Theodore; Khanna, Rajesh; Kohn, Harold.

In: Journal of Medicinal Chemistry, Vol. 57, No. 14, 24.07.2014, p. 6165-6182.

Research output: Contribution to journalArticle

Lee, Hyosung ; Park, Ki Duk ; Torregrosa, Robert ; Yang, Xiao Fang ; Dustrude, Erik T. ; Wang, Yuying ; Wilson, Sarah M. ; Barbosa, Cindy ; Xiao, Yucheng ; Cummins, Theodore ; Khanna, Rajesh ; Kohn, Harold. / Substituted N -(biphenyl-4′-yl)methyl (R)-2-acetamido-3- methoxypropionamides : Potent anticonvulsants that affect frequency (Use) dependence and slow inactivation of sodium channels. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 14. pp. 6165-6182.
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abstract = "We prepared 13 derivatives of N-(biphenyl-4′-yl)methyl (R)-2-acetamido-3-methoxypropionamide that differed in type and placement of a R-substituent in the terminal aryl unit. We demonstrated that the R-substituent impacted the compound's whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI = TD50/ED50) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent potently promoted Na+ channel slow inactivation and displayed frequency (use) inhibition of Na+ currents at low micromolar concentrations. The possible advantage of affecting these two pathways to decrease neurological hyperexcitability is discussed.",
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AU - Lee, Hyosung

AU - Park, Ki Duk

AU - Torregrosa, Robert

AU - Yang, Xiao Fang

AU - Dustrude, Erik T.

AU - Wang, Yuying

AU - Wilson, Sarah M.

AU - Barbosa, Cindy

AU - Xiao, Yucheng

AU - Cummins, Theodore

AU - Khanna, Rajesh

AU - Kohn, Harold

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