Discovery of a series of 2-phenyl- N -(2-(pyrrolidin-1-yl)phenyl)acetamides as novel molecular switches that modulate modes of K v7.2 (KCNQ2) channel pharmacology

Identification of (S)-2-phenyl- N -(2-(pyrrolidin-1-yl) phenyl)butanamide (ML252) as a potent, brain penetrant K v7.2 channel inhibitor

Yiu Yin Cheung, Haibo Yu, Kaiping Xu, Beiyan Zou, Meng Wu, Owen B. McManus, Min Li, Craig W. Lindsley, Corey R Hopkins

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

A potent and selective inhibitor of KCNQ2, (S)-5 (ML252, IC 50 = 69 nM), was discovered after a high-throughput screen of the MLPCN library was performed. SAR studies revealed a small structural change (ethyl group to hydrogen) caused a functional shift from antagonist to agonist activity (37, EC 50 = 170 nM), suggesting an interaction at a critical site for controlling gating of KCNQ2 channels.

Original languageEnglish (US)
Pages (from-to)6975-6979
Number of pages5
JournalJournal of Medicinal Chemistry
Volume55
Issue number15
DOIs
StatePublished - Aug 9 2012

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Acetamides
Libraries
Hydrogen
Pharmacology
Brain
2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)butanamide

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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title = "Discovery of a series of 2-phenyl- N -(2-(pyrrolidin-1-yl)phenyl)acetamides as novel molecular switches that modulate modes of K v7.2 (KCNQ2) channel pharmacology: Identification of (S)-2-phenyl- N -(2-(pyrrolidin-1-yl) phenyl)butanamide (ML252) as a potent, brain penetrant K v7.2 channel inhibitor",
abstract = "A potent and selective inhibitor of KCNQ2, (S)-5 (ML252, IC 50 = 69 nM), was discovered after a high-throughput screen of the MLPCN library was performed. SAR studies revealed a small structural change (ethyl group to hydrogen) caused a functional shift from antagonist to agonist activity (37, EC 50 = 170 nM), suggesting an interaction at a critical site for controlling gating of KCNQ2 channels.",
author = "Cheung, {Yiu Yin} and Haibo Yu and Kaiping Xu and Beiyan Zou and Meng Wu and McManus, {Owen B.} and Min Li and Lindsley, {Craig W.} and Hopkins, {Corey R}",
year = "2012",
month = "8",
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doi = "10.1021/jm300700v",
language = "English (US)",
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journal = "Journal of Medicinal Chemistry",
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publisher = "American Chemical Society",
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TY - JOUR

T1 - Discovery of a series of 2-phenyl- N -(2-(pyrrolidin-1-yl)phenyl)acetamides as novel molecular switches that modulate modes of K v7.2 (KCNQ2) channel pharmacology

T2 - Identification of (S)-2-phenyl- N -(2-(pyrrolidin-1-yl) phenyl)butanamide (ML252) as a potent, brain penetrant K v7.2 channel inhibitor

AU - Cheung, Yiu Yin

AU - Yu, Haibo

AU - Xu, Kaiping

AU - Zou, Beiyan

AU - Wu, Meng

AU - McManus, Owen B.

AU - Li, Min

AU - Lindsley, Craig W.

AU - Hopkins, Corey R

PY - 2012/8/9

Y1 - 2012/8/9

N2 - A potent and selective inhibitor of KCNQ2, (S)-5 (ML252, IC 50 = 69 nM), was discovered after a high-throughput screen of the MLPCN library was performed. SAR studies revealed a small structural change (ethyl group to hydrogen) caused a functional shift from antagonist to agonist activity (37, EC 50 = 170 nM), suggesting an interaction at a critical site for controlling gating of KCNQ2 channels.

AB - A potent and selective inhibitor of KCNQ2, (S)-5 (ML252, IC 50 = 69 nM), was discovered after a high-throughput screen of the MLPCN library was performed. SAR studies revealed a small structural change (ethyl group to hydrogen) caused a functional shift from antagonist to agonist activity (37, EC 50 = 170 nM), suggesting an interaction at a critical site for controlling gating of KCNQ2 channels.

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