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.
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.
Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Yiu-Yin
YY
Cheung
Haibo
H
Yu
Kaiping
K
Xu
Beiyan
B
Zou
Meng
M
Wu
Owen B
OB
McManus
Min
M
Li
Craig W
CW
Lindsley
Corey R
CR
Hopkins
D000818:Animals; D001921:Brain / Q000378:metabolism*; D016208:Databases, Factual; D057166:High-Throughput Screening Assays; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008862:Microsomes, Liver / Q000378:metabolism; D010539:Permeability; D010654:Phenylbutyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C576050:2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)butanamide; D051658:KCNQ2 Potassium Channel; D010654:Phenylbutyrates; D026902:Potassium Channel Blockers; D011759:Pyrrolidines; D054852:Small Molecule Libraries