2. Academic Validation
  3. 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

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

Affiliation

  • 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.

Figures
Products