Table 1. Initial Modifications of Hit Compound 2.

compd	sc	R3	R2	Cavα2δ-1 (Ki, nM)a	CYP3A4 inhibition (%)b
1				19 ± 12	43
2	A	Et	2-methoxyethyl	1810 ± 82	37
11a	A	Pr	2-methoxyethyl	638 ± 345	67
11b	A	Me	2-methoxyethyl	4896 ± 1307	0
11c	A	H	2-methoxyethyl	>10 000c	6
11d	B	Pr	2-methoxyethyl	241 ± 246	94
11e	B	Et	2-methoxyethyl	761 ± 235	86
11f	B	Bu	2-methoxyethyl	1340 ± 856	97
11g	B	CyPrMe	2-methoxyethyl	413 ± 188	94
11h	A	Et	3-methoxypropyl	>10 000c	NDd
11i	B	Pr	benzyl	4816 ± 45	98
11j	B	Pr	2-furylmethyl	230 ± 101	99
11k	B	Pr	ethyl	36 ± 28	85
11l	B	Pr	methyl	73 ± 20	80

^aBinding affinity (K_i, 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.

^bPercentage 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.

^cLess than 50% inhibition at 10 μM.

^dNot determined.