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

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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.

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