Chemistry Reference
In-Depth Information
A
B
Capsaicin-induced flinching
Plasma levels
Inhibition of hyperalgesia
Plasma levels
125
1000
60
10000
*
*
**
50
100
**
40
100
1000
75
**
30
50
20
10
100
25
10
0
0
1
10
0.01
0.1
1
10
100
0.001
0.01
0.1
1
10
Compound 29 (mg/kg, p.o.)
Compound 29 (mg/kg, p.o.)
Figure 13.9
(A) Compound 29 blocked capsaicin-induced flinch in rats. Compound
29 was administered p.o. to rats 60 min prior to capsaicin challenge. The
number of flinches in the first 1 min were counted and plotted against the
dose of compound 29. (B) AMG 517 blocked thermal hyperalgesia in
CFA model of pain. Significant reversal of CFA-induced thermal
hyperalgesia was observed at doses Z1mgkg
1
of compound 29.
Reproduced with permission of the American Society for Pharmacology
and Experimental Therapeutics from J. Pharmacol. Exp. Ther., 2007,
323, 128.
Human pharmacokinetic parameters were projected based on allometric
scaling and are presented in Table 13.1. Based on the allometric projection,
compound 29 was predicted to have a long half-life in humans (60-120 h). The
projected half-life in humans was expected to result in a 4-fold accumulation at
steady state, based on a QD dosing regimen, with minimal peak-to-trough
fluctuations and low variability.
In vivo evaluation of compound 29 showed that it was effective in a rodent on-
target biochemical challenge model (capsaicin-induced flinch, ED
50
¼
0.33mg
kg
1
p.o.) (Figure 13.9A). In the CFA pain model in rats, compound 29 showed
a dose-dependent inhibition of thermal hyperalgesia (MED
¼
0.3mg kg
1
, p.o.)
(Figure 13.9B).
In addition to reversing inflammation-induced pain behavior in rats, we
found that compound 29 also caused hyperthermia in rodents, dogs, and
monkeys (1-1.5 1C) but not in TRPV1 knockout mice, suggesting that TRPV1
is tonically activated in vivo and involved in body temperature regulation (rat
data shown in Figure 13.10A).
57,58
Interestingly, this hyperthermia was atte-
nuated with repeated dosing of antagonists to rats, dogs, and monkeys (mon-
key data shown in Figure 13.10B).
59
Other than the hyperthermic effect of
compound 29, it was well tolerated in preclinical safety studies, with safety
margins of 78-fold in 14-day rat toxicology studies (based on C
max
compared to
rat flinch EC
50
of 96 ngmL
1
). Because of its excellent pharmacokinetic
properties, in vivo ecacy, and good safety profile, compound 29 was selected
for further evaluation in human clinical trails for the treatment of inflammatory
pain and was redesignated AMG 517.
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