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

doi:10.1021/jm300700v

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 journal › Article › peer-review

19 Scopus citations

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 language	English (US)
Pages (from-to)	6975-6979
Number of pages	5
Journal	Journal of medicinal chemistry
Volume	55
Issue number	15
DOIs	https://doi.org/10.1021/jm300700v
State	Published - Aug 9 2012
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

Access to Document

10.1021/jm300700v

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this

Cheung, Y. Y., Yu, H., Xu, K., Zou, B., Wu, M., McManus, O. B., Li, M., Lindsley, C. W., & Hopkins, C. R. (2012). 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. Journal of medicinal chemistry, 55(15), 6975-6979. https://doi.org/10.1021/jm300700v

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. / Cheung, Yiu Yin; Yu, Haibo; Xu, Kaiping et al.
In: Journal of medicinal chemistry, Vol. 55, No. 15, 09.08.2012, p. 6975-6979.

Research output: Contribution to journal › Article › peer-review

Cheung, YY, Yu, H, Xu, K, Zou, B, Wu, M, McManus, OB, Li, M, Lindsley, CW & Hopkins, CR 2012, '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', Journal of medicinal chemistry, vol. 55, no. 15, pp. 6975-6979. https://doi.org/10.1021/jm300700v

Cheung YY, Yu H, Xu K, Zou B, Wu M, McManus OB et al. 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. Journal of medicinal chemistry. 2012 Aug 9;55(15):6975-6979. doi: 10.1021/jm300700v

Cheung, Yiu Yin ; Yu, Haibo ; Xu, Kaiping et al. / 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. In: Journal of medicinal chemistry. 2012 ; Vol. 55, No. 15. pp. 6975-6979.

@article{c30cef8b3d94477cb79f6477567f17c0,

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 = aug,

day = "9",

doi = "10.1021/jm300700v",

language = "English (US)",

volume = "55",

pages = "6975--6979",

journal = "Journal of medicinal chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "15",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=84864927786&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864927786&partnerID=8YFLogxK

U2 - 10.1021/jm300700v

DO - 10.1021/jm300700v

M3 - Article

C2 - 22793372

AN - SCOPUS:84864927786

SN - 0022-2623

VL - 55

SP - 6975

EP - 6979

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

IS - 15

ER -