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A. Capsaicin-induced flinch
B. CFA-induced thermal hyperalgesia
Latency (sec)
Plasma concentration (
n
g/ml)
Number of flinches
Plasma concentration (ng/ml)
12
10000
14
10000
10
12
1000
1000
10
8
*
*
*
*
100
100
8
*
6
6
10
10
4
4
1
1
2
**
2
**
**
**
0
0.1
0
0.1
0.1
Compd
1
10
100
30
100
44
(mg/kg, p.o.)
Compd
44
(mg/kg, p.o.)
C. Incision-induced thermal hyperalgesia
D. Acetic acid-induced writhing
Latency (sec)
Plasma concentration (ng/ml)
Number of writhes
Plasma concentration (ng/ml)
50
14
10000
10000
12
40
1000
10
1000
30
100
8
*
*
*
*
*
100
6
*
10
1
20
4
10
10
2
0
0.1
0
1
30
100
10
30
100
Compd
44
(mg/kg, p.o.)
Compd
44
(mg/kg, p.o.)
Figure 13.19
In vivo ecacy of compound 44 in biochemical challenge as well as
inflammatory and surgical pain models. (A) Compound 44 significantly
decreased capsaicin-induced flinching behavior. (B) Compound 44
significantly reversed CFA-induced thermal hyperalgesia. (C) Com-
pound 44 significantly reversed skin incision-induced thermal hyper-
algesia. (D) Compound 44 reduced acetic acid-induced writhing in
mice. Note: compound 44 showed similar in vitro profiles at both rat
and mouse TRPV1. Reproduced with permission of the American
Society for Pharmacology and Experimental Therapeutics from J.
Pharmacol. Exp. Ther., 2008, 326, 218.
in subjects who underwent third-molar extraction. Although AMG 517 did not
progress to a successful registration, valuable lessons regarding hit identification,
metabolism, pharmacokinetics, toxicology, and pharmaceutics were encountered
in this ''near miss'' drug discovery effort. For example, in this study we used a
unique high-throughput functional assay to identify several high-quality leads
for medicinal chemistry optimization, and through extensive SAR investigations,
a good understanding of the pharmacophores needed for potent TRPV1 activity
was obtained. The lead optimization efforts also illustrated the effective utiliza-
tion of metabolite identification studies for the design of new derivatives and
resulted in the preparation of compounds with improved pharmacokinetic
profiles. Furthermore, we demonstrated that we could increase solubility and
reduced half-life by modulating the physiochemical properties of the compounds
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