Table 1. Selected in Vitro Screening Data of 1a, 1b, and 1c(42).
| compound | 1a | 1b | 1c | |
|---|---|---|---|---|
| cLogP | 1.4 | 2.8 | 0.27 | |
| FLIPR rat α7 (EC50, nM)a | 9.3 ± 5.3 | 11 ± 6 | 23 ± 10 | |
| rat α7 | BTXb binding (Ki, nM) | 4.8 | 3.3 | |
| human α7 | BTXb binding (Ki, nM) | 1.3 | 8.1 | |
| rat α7 nAChR electrophysiology | ||||
| peak Ymax, area Ymax (%) | 40, 54 | 13, 49 | 27, 67 | |
| area EC50 (nM) | 140 | 0.49 | 100 | |
| human α7 nAChR electrophysiology | ||||
| peak Ymax, area Ymax (%) | 26, 62 | 24, 78 | ||
| area EC50 (nM) | 240 | 300 | ||
| nicotinic ACh-related receptors (EC50, μM)c | >100 | >100 | ||
| HEK293 human 5-HT3A (IC50, nM)a | 480 ± 160 | 9200 ± 1400 | 8100 ± 2300 | |
| metabolic stability, % remaining (human, rat, mouse, dog, monkey) | 96, 1, 89, 74, 78 | 91, 95, 93, 98, 100 | ||
| CYP inhibition, IC50 (μM)d | >40 | >30 | ||
| hERG, patch clamp assay (IC50, μM) | 3.2 | 4.0 | >30e | |
| plasma free fraction, % free (human, rat, mouse, dog, monkey) | 25, 27, 23, 44, 35 | 87, 87, 84, 93, 87 | ||
| Caco-2, efflux ratio | 1.1 | 2.5 | ||
a
n ≥ 4.
b
[125I]-bungarotoxin binding.
c
Panel of nicotinic acetylcholine receptors α1β1δε, α3β4, and α4β2
d
Panel of human CYP isozymes: 3A4-BFC, 3A4-BZR, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6.
e
12% inhibition at 10 μM and 38% inhibition at 30 μM concentrations