Chemistry Reference
In-Depth Information
A
B
Vehicle
Compd
45
(1 mg/kg)
Vehicle
Compd
44
(1 mg/kg)
Compd
45
(3 mg/kg)
40
40
Compd
45
(10 mg/kg)
Compd
44
(3 mg/kg)
39
Compd
45
(30 mg/kg)
39
Compd
44
(10 mg/kg)
38
Compd
44
(30 mg/kg)
38
37
36
37
35
36
34
35
33
Time (min) post dosing
Time (min) post dosing
Figure 13.18
Effect on core body temperature of compounds 44 and 45. (A) Com-
pound 44 dosed at 1, 3, 10, 30mg kg
1
p.o. slightly decreased body
temperature with a maximum decrease of 0.6 1C occurring at 160min
post dosing in the 1mg kg
1
dosing group. (B) Compound 45 dosed at
0.3, 1, 3, 10, 30mg kg
1
p.o. significantly decreased body temperature
with a maximum decrease of 2.9 1C occurring at 160min post dosing.
Reprinted with permission of the American Society for Pharmacology
and Experimental Therapeutics from J. Pharmacol. Exp. Ther., 2008,
326, 218.
in mice (Figure 13.19). We found that compound 44 significantly blocked
capsaicin-induced flinching behavior, and produced statistically significant
ecacy in CFA- and skin incision-induced thermal hyperalgesia, and acetic
acid-induced writhing models.
The unique profile of compound 44 indicates that it is feasible to eliminate
hyperthermia while preserving antihyperalgesia by differential modulation of
distinct modes of TRPV1 activation. However, when tested at the human
TRPV1 receptor, compound 44 behaved as a ''profile B'' antagonist (blocking
all modes of activation: Figure 13.20) and would be expected to cause
hyperthermia in humans. Therefore, feasibility of ''profile C'' modulation
of both rat and human TRPV1 by a single small molecule is yet to be
demonstrated.
13.7 Summary
The information described above outlines the case study of the TRPV1
antagonist program conducted at Amgen, Inc., which started from an initial
high-throughput screening hit and culminated in the identification of two clinical
candidates, AMG 517 and AMG 628. Unfortunately, clinical studies of AMG
517 were discontinued due to the hyperthermia observed after exposure to
single and multiple doses of this molecule in healthy volunteers, and due to
marked and persistent hyperthermia after exposure to single doses of AMG 517
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