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. 2019 May 8;10(6):929–935. doi: 10.1021/acsmedchemlett.9b00097

Table 1. Efficacy of RL-81 Analogues in Human Kv7 Channel Conductance Studiesa.

graphic file with name ml-2019-000972_0009.jpg

compd X Y R1 R2 R3 R4 R5 R6 R7 Kv7.2/3 EC2x ± SD [μM] Kv7.3/5 EC2x ± SD [μM] Kv7.4 EC2x ± SD [μM] Kv7.4/5 EC2x ± SD [μM] SI
FP CH CH F H H Nb H H Et 2.00 ± 0.69 1.58 ± 0.69 5.62 ± 1.86 3.50 ± 2.68 1.8
RG CH CH F H H H H H Et 0.33 ± 0.08 0.34 ± 0.04 ND ND ND
RL-81 CH CH CF3 H H F H H Et 0.26 ± 0.13 0.29 ± 0.06 0.10 ± 0.04 0.09 ± 0.04 0.3
RL-73 CH CH H CF3 H F H H Et 0.14 ± 0.05 0.20 ± 0.08 0.40 ± 0.13 0.66 ± 0.01 4.7
RL-02 CH CH H SF5 H F H H Et 0.36 ± 0.25 0.21 ± 0.11 0.65 ± 0.39 0.65 ± 0.28 1.8
RL-72 CH CH CF3 H H H F H Et 1.26 ± 0.31 >10 4.65 ± 0.95 >10 >7
RL-073 CH CH CF3 H H F CF3 H Et >10 >10 >10 >10 ND
RL-32 CH CH CF3 H H F H H i-Pr 0.16 ± 0.11 0.16 ± 0.10 0.19 ± 0.10 4.98 ± 1.12 31
RL-56 CH CH CF3 H H F H H c-Pr 0.11 ± 0.02 0.23 ± 0.10 0.38 ± 0.30 0.28 ± 0.03 2.5
RL-18 CF CH CF3 H H F H H Et 0.18 ± 0.11 0.34 ± 0.01 0.11 ± 0.04 0.30 ± 0.26 1.7
RL-35 CF CH CF3 H H F H H c-Pr 0.59 ± 0.08 0.47 ± 0.01 0.21 ± 0.19 0.35 ± 0.17 0.6
RL-36 CF CH CF3 H H F F H c-Pr 0.93 ± 0.21 >10 >10 >10 >10
RL-46 CF CH CF3 H H F H F c-Pr 1.47 ± 0.22 >10 0.55 ± 0.14 >10 >7
RL-50 CF CH CF3 H H F F F c-Pr >10 >10 >10 >10 ND
RL-31 N CH CF3 H H F H H Et 0.66 ± 0.25 0.79 ± 0.26 0.85 ± 0.14 0.59 ± 0.34 0.9
RL-68 N CH CF3 H H F H H c-Pr 0.79 ± 0.03 0.72 ± 0.05 0.90 ± 0.02 0.96 ± 0.05 1.2
RL-96 N CH CF3 H F F H H c-Pr 1.39 ± 0.20 >10 >10 >10 >7
RL-01 N CH CF3 H F F F H c-Pr >10 >10 >10 >10 ND
RL-12 N CH CF3 H F F H F c-Pr 1.00 ± 0.50 >10 >10 >10 >10
RL-23 N CCN CF3 H H F H H Et 1.60 ± 0.19 1.30 ± 0.16 2.17 ± 0.37 2.33 ± 0.89 1.5
RL-24 CH N CF3 H H F H H Et 0.61 ± 0.34 0.69 ± 0.35 0.95 ± 0.13 1.27 ± 0.05 2.1
RL-67 CH N CF3 H H F H H c-Pr 0.71 ± 0.23 0.69 ± 0.19 1.13 ± 0.72 1.36 ± 0.70 1.9
a

EC2x data were obtained from 10-point concentration curves and 2–5 individual assay determinations, with the exception of FP, for which 6–431 repeats were determined; SD = standard deviation; SI = selectivity index = EC2x(Kv7.4/5)/EC2x(Kv7.2/3); ND = not determined.

b

FP has a pyridine ring nitrogen at the R4-substituted carbon position.