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

Table 3. Modification of Amine over 6-Bromo-2-butyl-3-ethyl Derivatives.

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compd NR4R4’ Cavα2δ-1 (Ki, nM)a CYP3A4 inhibition (%)b
11u piperazin-1-yl 76 ± 20 65
11v 4-methylaminopiperidin-1-yl 436 ± 60 83
11w 3,8-diazabicyclo[3.2.1]octan-1-yle 397 ± 161 74
11xRS (S)-3-methylpiperazin-1-yl 91 ± 15 73
11xRR (R)-3-methylpiperazin-1-yl 16 ± 15 51
11xSS (S)-3-methylpiperazin-1-yl 479 ± 324 33
11xSR (R)-3-methylpiperazin-1-yl >1000c 21
11yR (R)-3-ethylpiperazin-1-yl 123 ± 340 97
11zR 3,3-dimethylpiperazin-1-yl 1578 ± 1998 72
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.

e

Derivative with 6-H instead of 6-Br.