2562
P. Ratcliffe et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2559–2563
Table 2
In vitro PK, hERG and plasma protein binding data for selected compounds
Compd
HLM CLint
l minÀ1 mgÀ1
RLM CLint
l minÀ1 mgÀ1
Rat Hep. CLint
l minÀ1106 cellsÀ1
hERG pKi
(% inhibition at 100 lM)
PPB%Bound
(Human)
PPB% Bound
(Rat Wistar)
(
l
)
(
l
)
(
l
)
2
<12
17
12
48
21
66
12
12
<12
<12
107
55
144
49
<6
<6
12
5.2
75
72.9
93.6
75.8
ND*
ND*
96.3
88.4
83.2
8c
8e
8f
8g
8h
8l
(75)
(86)
5.3
88.2
82.3
ND*
ND*
95.2
74.4
63.9
ND*
ND*
ND*
ND*
10
5.9
(59)
(83)
(69)
41
93
8n
*
ND—not determined.
Table 3
In vivo PK, for selected compounds. All compounds were dosed at 10 mg/kg (po) and 2 mg/kg (iv)
Compd
CL (ml minÀ1 kgÀ1
)
Vss (L kgÀ1
)
T1/2 (h)
po
po
%F
Cmax
(lM)
Tmax (h)
2
8e
8l
12.5
69
13.5
5.9
7.6
3.5
7.9
4.0
4.3
0.72
0.42
0.23
2
2
1.5
20
33
4
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Figure 4. The effects of po administration of 8e (3, 10, 30 lmol/kg) on paw
withdrawal latency (PWL) in the capsaicin Hargreaves assay.
of the acute inflammatory thermal response in the rat capsaicin
Hargreaves assay (p <0.01). We believe 8e will be a valuable tool
in exploring the potential role of TRPV1 antagonists in pain, and
in potentially elucidating and interpreting the relationship be-
tween TRPV1 antagonism and hyperthermia.
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Y.; Roughton, A.; Sammons, M.; Swanson, R.; Tracey, H.; Walker, G. Bioorg. Med.
Chem. Lett. 2011, 21, 892.
14. Ratcliffe, P. D.; Abernethy, L.; Ansari, N.; Cameron, K.; Clarkson, T.; Dempster,
M.; Dunn, D.; Easson, A-M.; Edwards, D.; Everett, K.; Feilden, H.; Ho, K.-K.;
Kultgen, S.; Littlewood, P.; McArthur, D.; McGregor, D.; MacLean, J.; McLuskey,
H.; Neagu, I.; Nimz, O.; Nisbet, L-A.; Ohlmeyer, M.; Palin, R.; Pham, Q.; Rong, Y.;
Roughton, A.; Sammons, M.; Swanson, R.; Tracey, H.; Walker, G. Bioorg. Med.
Acknowledgments
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).
References and notes
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NaCl, 4.5 mM KCl, 10 mM HEPES, 10 mM Glucose, 2 mM CaCl2, 1 mM MgCl2
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and 0.5 mM Probenecid), at room temperature for 1 h (25
this, 12.5 of test compound, prepared in assay buffer containing 4%
dimethylsulfoxide, was added by the FLIPR (Molecular Devices, Corp) to each
ll/well). Following
l
l