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. 2021 Oct 5;12(11):1802–1809. doi: 10.1021/acsmedchemlett.1c00416

Table 2. Modification of R1 over Compound 11k.

graphic file with name ml1c00416_0006.jpg

compd R1 Cavα2δ-1 (Ki, nM)a CYP3A4 inhibition (%)b
11m 6-Br 16 ± 28 95
11mR 6-Br 8 ± 2 94
11mS 6-Br 2903 ± 703 88
11n 6-CN 288 ± 139 70
11o 6-NHEt 44 ± 23 69
11p 6-(4-pyridinyl) 38 ± 13 92
11q 7-Br 15 ± 24 97
11r 7-(4-pyridinyl) 18 ± 24 97
11s 5-Br 66 ± 16 95
11t 8-Br >1000c NDd
a

Binding affinity (Ki, nM) in human α2δ-1 enriched membranes from hamster tumor CHO-K1 cells (Human Cav2.2/β3/α2δ1 Calcium Channel Cell Line, ChanTest) using [3H]-gabapentin as the radioligand. Each value is the mean ± SD of two determinations.

b

Percentage of inhibition after incubation at 1 μM with recombinant human CYP3A4 using BFC (7-benzyloxy-4-trifluoromethylcoumarin) as the CYP probe substrate and fluorescence detection.

c

Less than 50% inhibition at 1 μM.

d

Not determined.