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

  • J Med Chem. 2012 Aug 9;55(15):6975-9. doi: 10.1021/jm300700v.
Yiu-Yin Cheung  1 ,  Haibo Yu ,  Kaiping Xu ,  Beiyan Zou ,  Meng Wu ,  Owen B McManus ,  Min Li ,  Craig W Lindsley ,  Corey R Hopkins
Affiliations
  • 1. Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
PMID: 22793372 DOI: 10.1021/jm300700v
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.

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