Table 2. In Vitro Profiles of Compound 1.

	Ar	X	R	hNaV1.1 IC50 (μM)a	hNaV1.5 IC50 (μM)a	hNaV1.7 IC50 (μM)a	mNaV1.7 IC50 (μM)a	hERG inhibition at 100 μMa,b	Log Dc	Solubility (μM)d	Mouse PB free (%)d
1d	Ph	H	Me	80	79	0.33	2.7	17.1 ± 3.8	1.1	>660	<0.20
1f	2-F-C6H4	H	Me	NTe	100	5.9	12	NTf	NTf	NTf	NTf
1g	3-F-C6H4	H	Me	12	35	0.038	0.90	13.2 ± 6.0	1.2	600	<0.20
1h	4-F-C6H4	H	Me	52	42	0.19	2.8	5.6 ± 2.3	1.1	140	<0.20
1i	3-Cl-C6H4	H	Me	20	34	0.087	1.7	43.5 ± 11.9	1.8	620	<0.20
1j	4-Cl-C6H4	H	Me	>100	23	0.26	7.9	51.1 ± 7.6	1.8	26	NTf
1k	3-Me-C6H4	H	Me	39	NTf	0.058	1.6	51.0 ± 10.0	1.6	550	NTf
1l	3-MeO-C6H4	H	Me	79	71	0.19	2.1	18.9 ± 1.6	1.2	580	<0.20
1m	3-CF3-C6H4	H	Me	20	27	0.034	0.68	49.8 ± 8.2	1.7	>820	0.20
1n	3-F-C6H4	F	Me	>100	31	0.014	0.98	15.6 ± 2.6	0.8	430	<0.20
1o	3-CF3-C6H4	F	Me	>100	14	0.019	0.016	54.8 ± 15.2	1.5	230	0.40
1p	3-F-C6H4	H	c-Pr	4.8	14	0.032	0.81	42.1 ± 5.0	1.8	440	<0.20

^aData were obtained with a high-throughput electrophysiology system (IonWorks Quattro). Values are from a single experiment run in quadruplicate.

^bhERG inhibitory activity at 10, 30, and 100 μM was assessed, and the dose response was confirmed. Each value represents the mean ± SD.

^cDistribution coefficients (log D) were measured after partition between 1-octanol and PBS (pH = 7.4).

^dUnbound fractions (%) in mouse plasma.

^eAqueous thermodynamic solubility at pH 6.8.

^fNot tested.