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. 2018 Jul 13;9(8):821–826. doi: 10.1021/acsmedchemlett.8b00215

Table 1. SAR and in Vitro ADME/DMPK Data for Disubstituted 5-Arylbenzimidazolones.

graphic file with name ml-2018-00215e_0006.jpg

Cmpd X R1 R2 GluA1/γ-8 pIC50a GluA1/γ-2 pIC50b HLM/RLM stabilityc MDCK-MDR1d (B-A)/(A-B) × 10–6cm/s Solubility (SGF/FaSSIF)e (μM) PPB,fub (h/r)f cLogP LLE
6 CH CH3 CH3 6.8 ± 0.1 <5 0.3/0.5 34/42 5/276 2.1/3.7 3.4 3.4
7 CH Cl CH3 7.3 ± 0.3 <5 <0.3/0.6 32/25 <4/146 0.9/1.4 3.7 3.6
8 CH Cl cPr 8.2 ± 0.2 <5 <0.3/0.5 18/10 <4/90 0.2/1.5 4.1 4.1
9 CH Cl Cl 7.3 ± 0.2 <5 <0.3/0.3 49/26 <4/69 0.5/0.6 3.9 3.4
10 N Cl Cl 6.6 ± 0.2 <5 <0.3/<0.2 83/16 42/52 2.9/2.7 2.6 3.9
11 CH Cl CN 6.6 ± 0.3 <5 <0.3/<0.2 70/14 <4/5 5.1/7.1 2.9 3.7
12 CH Cl CH2CN 8.0 ± 0.41 <51 <0.3/0.6 70/6.6 26/230 2.7/7.6 2.6 5.4
13 CH Cl OCH3 6.9 ± 0.2 <5 0.3/0.6 50/26 19/142 3.9/6.5 3.0 3.8
3 CH Cl OCF3 8.3 ± 0.31 <51 <0.3/0.3 24/22 <4/74 0.3/1.5 4.1 4.2
a

pIC50 measured in a FLIPR assay using HEK-293 cells expressing a human GluA1o-γ-8 fusion construct; all data are the result of at least three assays run in triplicate with the mean and standard deviation reported.

b

pIC50 measured in a FLIPR assay using HEK-293 cells expressing human GluA1-flop cotransfected with γ-2.

c

Stability in human and rat liver microsomes at 1 μM; data are reported as extraction ratios.

d

Apparent permeability in Madin–Darby canine kidney cells transfected with the MDR1 (P-gp) gene.

e

Thermodynamic solubility in simulated gastric fluid (pH = 1.6) and fasted state simulated intestinal fluid (pH = 6.5).

f

Human and rat plasma protein binding reported as fraction unbound (fub) at 1 μM. Details for all assay conditions are provided in the Supporting Information.