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AcHN
OH
CF
3
N
CF
3
S
O
H
N
NN
HN
O
NN
C
A
N
30
31
A
C
hTRPV1(Cap) IC
50
= 0.6 nM
hTRPV1(Cap) IC
50
= 0.9 nM
AcHN
CF
3
N
B
AcHN
S
O
CF
3
N
NN
S
O
AcHN
29
(AMG 517)
R
NN
N
Z
C
S
O
Y
HN
B
N
N
N
32
33
hTRPV1(Cap) IC
50
= 20 nM
Figure 13.11
Four approaches to reduce half-life and increase solubility of AMG
517.
AcHN
CF
3
AcHN
N
N
N
R
Introduce
S
O
S
O
N
Basic Amine
NN
N
N
29
(AMG 517)
Fill
Hydrophobic
Pocket
Block
Metabolism
34
: R = Me hTRPV1(Cap) IC
50
= 1,400 nM
hTRPV1(Cap) IC
50
= 0.8 nM
F
oral
= 48%
Rat t
1/2
= 31 h
Sol = 0.003 mg/mL (0.01N HCl)
35
: R = Ph hTRPV1(Cap) IC
50
= 13 nM
36
: R = 4-FPh
(AMG 628)
hTRPV1(Cap) IC
50
= 6.5 nM
F
oral
= 51%
Rat t
1/2
= 3.8 h
Sol
≥
200
μ
g/mL (0.01N HCl)
Sol = 7.4 mg/mL (phosphate salt (pH 3.2))
Figure 13.12
Key SAR leading to AMG 628, a second-generation TRPV1 antagonist
with increased solubility and reduce half-life.
In this investigation we demonstrated that replacement of the 4-(tri-
fluoromethyl)phenyl moiety with heterocycles was effective at increasing aqu-
eous solubility and modifying the pharmacokinetic properties of AMG 517.
Some of the key SAR milestones are illustrated in Figure 13.12. Initial repla-
cement of the 4-(trifluoromethyl)phenyl group with isopropylpiperazine resul-
ted in a compound with significantly increased solubility; however, TRPV1
potency was compromised (compound 34). We found that potency could be
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