Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1- tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K v7.1 (KCNQ1) potassium channel activator

Margrith E. Mattmann; Haibo Yu; Zhihong Lin; Kaiping Xu; Xiaofang Huang; Shunyou Long; Meng Wu; Owen B. McManus; Darren W. Engers; Uyen M. Le; Min Li; Craig W. Lindsley; Corey R. Hopkins

doi:10.1016/j.bmcl.2012.07.060

Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1- tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K _v7.1 (KCNQ1) potassium channel activator

Margrith E. Mattmann, Haibo Yu, Zhihong Lin, Kaiping Xu, Xiaofang Huang, Shunyou Long, Meng Wu, Owen B. McManus, Darren W. Engers, Uyen M. Le, Min Li, Craig W. Lindsley, Corey R. Hopkins

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

33 Scopus citations

Abstract

A high-throughput screen utilizing a depolarization-triggered thallium influx through KCNQ1 channels was developed and used to screen the MLSMR collection of over 300,000 compounds. An iterative medicinal chemistry approach was initiated and from this effort, ML277 was identified as a potent activator of KCNQ1 channels (EC₅₀ = 260 nM). ML277 was shown to be highly selective against other KCNQ channels (>100-fold selectivity versus KCNQ2 and KCNQ4) as well as against the distantly related hERG potassium channel.

Original language	English (US)
Pages (from-to)	5936-5941
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2012.07.060
State	Published - Sep 15 2012
Externally published	Yes

Keywords

KCNQ1 activator
ML277
MLPCN probe
Potassium channels
Voltage-gated ion channels

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmcl.2012.07.060

Cite this

Mattmann, M. E., Yu, H., Lin, Z., Xu, K., Huang, X., Long, S., Wu, M., McManus, O. B., Engers, D. W., Le, U. M., Li, M., Lindsley, C. W., & Hopkins, C. R. (2012). Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1- tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K _v7.1 (KCNQ1) potassium channel activator. Bioorganic and Medicinal Chemistry Letters, 22(18), 5936-5941. https://doi.org/10.1016/j.bmcl.2012.07.060

Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1- tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K _v7.1 (KCNQ1) potassium channel activator. / Mattmann, Margrith E.; Yu, Haibo; Lin, Zhihong et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 22, No. 18, 15.09.2012, p. 5936-5941.

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

Mattmann, ME, Yu, H, Lin, Z, Xu, K, Huang, X, Long, S, Wu, M, McManus, OB, Engers, DW, Le, UM, Li, M, Lindsley, CW & Hopkins, CR 2012, 'Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1- tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K _v7.1 (KCNQ1) potassium channel activator', Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 18, pp. 5936-5941. https://doi.org/10.1016/j.bmcl.2012.07.060

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title = "Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1- tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K v7.1 (KCNQ1) potassium channel activator",

abstract = "A high-throughput screen utilizing a depolarization-triggered thallium influx through KCNQ1 channels was developed and used to screen the MLSMR collection of over 300,000 compounds. An iterative medicinal chemistry approach was initiated and from this effort, ML277 was identified as a potent activator of KCNQ1 channels (EC50 = 260 nM). ML277 was shown to be highly selective against other KCNQ channels (>100-fold selectivity versus KCNQ2 and KCNQ4) as well as against the distantly related hERG potassium channel.",

keywords = "KCNQ1 activator, ML277, MLPCN probe, Potassium channels, Voltage-gated ion channels",

author = "Mattmann, {Margrith E.} and Haibo Yu and Zhihong Lin and Kaiping Xu and Xiaofang Huang and Shunyou Long and Meng Wu and McManus, {Owen B.} and Engers, {Darren W.} and Le, {Uyen M.} and Min Li and Lindsley, {Craig W.} and Hopkins, {Corey R.}",

note = "Funding Information: The authors would like to thank Tammy Santomango, Katrina Brewer and Kaustubh Kulkarni for technical assistance with the PK experiments and Nathan Kett and Sichen Chang for the purification of compounds. This work was supported, in whole or in part, by National Institutes of Health and MLPCN grants U54MH084659 (C.W.L.), U54MH084691 (M.L.), and 1R03MH090837-01 , 1R03MH090849-01 , and 1R03DA031670-01 (M.W.). Vanderbilt is a member of the MLPCN and houses the Vanderbilt Specialized Chemistry Center for Accelerated Probe Development. Johns Hopkins is a member of the MLPCN and houses the Johns Hopkins Ion Channel Center. ",

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AU - Yu, Haibo

AU - Lin, Zhihong

AU - Xu, Kaiping

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AU - Long, Shunyou

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AU - Engers, Darren W.

AU - Le, Uyen M.

AU - Li, Min

AU - Lindsley, Craig W.

AU - Hopkins, Corey R.

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