P. Ratcliffe et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4652–4657
4657
Table 4
In vitro pharmacokinetic data for selected compounds
Compound Solkin
(mg LÀ1
HLM CLint
l minÀ1 mgÀ1
RLM CLint
l minÀ1 mgÀ1
hERG pKi (% inhibition at
100 M)
PPB %bound
(Human)
PPB %bound (Rat
Wistar)
17
)
(
l
)
(
l
)
l
1
19a
21a
<1
73
82
<12/<12
<12/27
<12/<12
<12/<12
<12/27
<12/<12
Inactivea
(71%)
5.2 (81%)
99.0
91.9
75.0
99.3
90.9
72.9
Abbreviations: HLM CLint: intrinsic clearance in human liver microsomes; RLM CLint: intrinsic clearance in rat liver microsomes; hERG pKi: inhibition constant in a hERG
channel binding assay (dofetilide); PPB %bound: percentage of compound bound to plasma protein.18
a
Apparent inactivity may have been a result of low solubility under the assay conditions.
Table 5
In vivo pharmacokinetic data for compound 21a
Compound
CL (ml minÀ1 kgÀ1
)
Vss (L kgÀ1
)
T1/2 (h)
po
Tmax (h)
%F
Cmax
(lM)
AUClast (h
2728
l )
g LÀ1
21a
12.5
5.9
7.9
0.72
2
20
Abbreviations: CL: plasma clearance; Vss: steady state volume of distribution; T1/2: biological half-life; Cmax: peak plasma concentration after oral administration; AUClast: area
under the curve at final tested concentration; %F: oral bioavailability.
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Vehicle
30µmol/kg
Figure 3. Reversal of induced hyperalgesia by 21a in the Capsaicin Hargreaves
model. Paw withdrawal latency (PWL) is shown on the y-axis.
Acknowledgements
We would like to thank our colleagues in the Analytical section
for structure and purity determination of all compounds, through-
out the duration of the work described in this article (2007–2008).
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