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A
B
Compd
29
(0.3 mg/kg)
Compd
29
(1 mg/kg)
Compd
Monkey Radiotelemetry
29
(3 mg/kg)
0 mg/kg/day
30 mg/kg/day
39.0
39
Vehicle
38.5
38.0
38
37.5
37.0
37
36.5
Treatment
36.0
36
0612 18
24 30 36
42 48 54
60 66
72
baseline
10
20
30
40
50
60
70
Time Post-dose (hours)
Treatment at 0, 24, 48, and 72 hours
Time (min)
Figure 13.10
Compound 29 effect on body temperature. (A) Body temperature of
rats administered with either vehicle or different doses of compound 29.
A significant increase in body temperature was seen 30-40min after
administration of compound 29. (B) Compound 29-induced hyper-
thermia attenuates after repeat dosing in female monkeys. Compound
29 caused an increase of approximately 1.1 1C on day 1 at 3 h post
administration but not on days 2-4. Reproduced with permission of the
American Society for Pharmacology and Experimental Therapeutics
from J. Pharmacol. Exp. Ther., 2007, 323, 128.
13.4.2 Identification of the Second-generation Clinical Candidate
AMG 628
As AMG 517 progressed into clinical development, we sought to identify a
second-generation TRPV1 antagonist with an improved profile as a potential
backup compound.
60
The two areas that we thought AMG 517 could be
improved upon were its half-life and solubility. In preclinical studies, AMG 517
was found to have very long half-lives in multiple species (Table 13.1). In
addition, AMG 517 has low aqueous solubility (
o
1 mgmL
1
in PBS or 0.01 N
HCl).
61
These two factors, although not critical for further progression of
AMG 517, presented challenges to the development of this candidate. There-
fore, our goal was to identify a novel second-generation clinical candidate with
a similar pharmacological profile to AMG 517 but with increased aqueous
solubility and a reduced half-life. Towards this end we examined four different
approaches, as illustrated in Figure 13.11: (1) alternatives to the benzothiazole
moiety,
62
(2) substitutions on the 2-position of the pyrimidine core,
63
(3) sub-
stitutions at the ortho-position of the 4-(trifluoromethyl)phenyl ring,
64
and (4)
replacements of the 4-(trifluoromethyl)phenyl group with various saturated aza
heterocycles (e.g., compound 33, where Y
¼
N and Z
¼
CH, O, or N) to create
the potential for salt formation.
60
Each of these approaches met with some
success (e.g., compounds 30-32 had good potency, improved solubility, and
decreased half-lives); however, it was the fourth approach of replacing of the 4-
(trifluoromethyl)phenyl group with saturated aza heterocycles which proved to
be the most successful and led to the backup candidate, AMG 628.
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