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

ArticleinJournal of Medicinal Chemistry 55(15):6975-9 · July 2012with59 Reads
Impact Factor: 5.45 · DOI: 10.1021/jm300700v · Source: PubMed

    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.