|
|
|
|
|---|---|---|---|
| 13: Daiichi Sankyo47 | 14: AstraZeneca69 | 15: Amgen | |
| hNaV1.1 IC50 | >100 μMb,c | — | — |
| hNaV1.5 IC50 | >100 μMb,c | >30 μMb,m | 1.1 μMe,n,70 |
| hNaV1.7 IC50 | 5.2 μMb,l | 0.41 μMb,g | 0.17 μMe,n,70 |
| Rodent NaV1.7 IC50 | 11.8 μM (mouse)b,l | 1.6 μM (rat)b,g | 0.39 μM (rat)e,n,71 |
| Rodent PPBf | 98.96% (mouse) | 86.8 % (rat) | 97.3% (rat)71 |
| Free plasma concentration | 2.7 nM@30 mg kg−1i (mouse PK) | 400 nM@43 mg kg−1 (rat formalin) | 14, 38 nM@3, 10 mg kg−1 (rat formalin)70 |
| 67 nM@10 mg kg−1 (rat CFA)71 | |||
| NaV1.7 coverage in plasma@efficacious dosagea | 0.000025-Fold@3.3 mg kg−1i (PSNL mouse) | 0.25-Fold@43 mg kg−1 (rat formalin) | 0.035-, 0.097-fold@3, 10 mg kg−1 70 (rat formalin) |
| 0.17-Fold@10 mg kg−1 71 (rat CFA) |
a
NaV1.7 coverage = free plasma concentration/in vitro NaV1.7 IC50.
b
Value in the automated patch-clamp assay.
c
Value in an inactivated state.
d
Value at Vhold = −60 mV.
e
Value in the manual patch-clamp assay.
f
Plasma protein binding.
g
Value at Vhold = −65 mV.
h
Plasma concentration.
i
Calculated from Cmax of the PK study.
j
Value at Vhold = −120 mV.
k
Value in a slow-inactivated state induced by prolonged depolarisation to −20 mV.
l
Value at Vhold = −30 mV.
m
Value at Vhold = −90 mV.
n
Value when approximately 20% of the channels were inactivated.