Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K(v)7.1 (KCNQ1) potassium channel activator.
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 (EC(50)=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.
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Margrith E
ME
Mattmann
Haibo
H
Yu
Zhihong
Z
Lin
Kaiping
K
Xu
Xiaofang
X
Huang
Shunyou
S
Long
Meng
M
Wu
Owen B
OB
McManus
Darren W
DW
Engers
Uyen M
UM
Le
Min
M
Li
Craig W
CW
Lindsley
Corey R
CR
Hopkins
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000819:agonists* / Q000378:metabolism*; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014105:Tosyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
C576869:(R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide; D051657:KCNQ1 Potassium Channel; D010880:Piperidines; D013844:Thiazoles; D014105:Tosyl Compounds