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CF
3
Blocked
Metabolism
H
N
H
N
O
N
O
O
Modified
para
-Substituent
and
Optimized
Amide Moiety
O
6
hTRPV1(Cap) IC
50
= 20 nM
7
hTRPV1(Cap) IC
50
= 4 nM
Figure 13.5
Initial cinnamide SAR development to block metabolism and increase
potency.
A
E
2.6 kcal/mo
l
Δ
H
N
O
O
O
NH
O
B
O
B
O
6
6
s-
trans
s-
cis
A
hTRPV1(Cap) IC
50
= 20 nM
O
V
Z
W
Y
O
X
hTRPV1 (Cap)
IC
50
(nM)
W
CH
CH
CH
CH
N
CH
CH
CH
N
N
N
N
X
CH
CH
CH
CH
CH
CH
CH
N
N
CH
CH
CH
CH
CH
Y
CH
CH
CH
CH
CH
CH
CH
N
N
N
N
Z
CH
CH
CH
CH
CH
N
CH
CH
N
CH
CH
CH
CH
V
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NMe
S
O
CH
2
10
:
N
>4000
120
650
>4000
>4000
44
>4000
3800
350
1700
>4000
250
>4000
1500
3800
740
O
11
:
12
:
13
:
14
O
O
8
:
hTRPV1(Cap) IC
50
= >4000 nM
15
:
16
:
17
:
18
:
19
:
N
20
:
O
:
22:
23:
24:
25:
21
O
O
9
hTRPV1(Cap) IC
50
= 2700 nM
Figure 13.6
Conformationally restricted analogs of the proposed bioactive s-cis
conformer of cinnamide 6.
To test this hypothesis we investigated a variety of replacements of the
acrylamide core (8-21; Figure 13.6).
54,55
First we examined the effect of
restricting the s-cis conformer of cinnamide 6 in two general ways: (1) by
connecting the amide nitrogen to the a-position of the cinnamide to form
lactam 8 and the corresponding dihydro isomer, pyridone 9 (cyclization A;
Figure 13.6); and (2) by incorporating the b-position of the cinnamide and the
amide carbonyl into various six-membered aromatic rings to give compounds
10-21 (cyclization B; Figure 13.6). Constraining cinnamide 6 in these two ways
allowed for the thorough evaluation of 14 different core replacements in which
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