Discovery of a series of 2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)acetamides as novel molecular switches that modulate modes of K(v)7.2 (KCNQ2) channel pharmacology: identification of (S)-2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)butanamide (ML252) as a potent, brain penetrant K(v)7.2 channel inhibitor.

Cheung YY, Yu H, Xu K, Zou B, Wu M, McManus OB, Li M, Lindsley CW, Hopkins CR
J Med Chem. 2012 55 (15): 6975-9

PMID: 22793372 · PMCID: PMC3530927 · DOI:10.1021/jm300700v

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.

MeSH Terms (15)

Animals Brain Databases, Factual High-Throughput Screening Assays Humans KCNQ2 Potassium Channel Microsomes, Liver Permeability Phenylbutyrates Potassium Channel Blockers Pyrrolidines Rats Small Molecule Libraries Stereoisomerism Structure-Activity Relationship

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