Chemistry Reference
In-Depth Information
Table 9.3
Incorporating polarity into the amide (endo-tropanes)
H
N
N
R
N
N
Binding
IC
50
(nM)
AV IC
90
(nM)
hERG
binding
a
HLM t
1/2
(min)
c
log D
b
Compound R
11
7
4.5
755 nM 3.0
100
O
12
5
27
(8%)
2.0
1
N
O
13
6
16
(87%)
12
O
O
14
0.8
1.5
410 mM 2.5
-
N
O
O
15
8
0.6
(0%)
2.7
77
O
O
a
hERG
¼
competition binding of [
3
H]dofetilide binding in membranes prepared from human
embryonic kidney (HEK293) cells stably expressing human ether-a-go-go related gene (HERG)
K
1
channels.
38
IC
50
(% inhibition at 300 nM).
b
Partition coecient measured in octan-1-ol/aqueous buffer at pH7.4.
c
HLM t
1/2
¼
half-life in human liver microsomes.
only the latter maintained stability in the presence of human liver microsomes
and showed good Caco-2 flux.
Given the initial in vitro profile, 15 was further progressed. It demonstrated a
slow off-rate from CCR5 (t
1/2
¼
3.5 h, as determined by radiolabelled washout
studies).
45
This was believed to be a significant finding, since slow receptor
disassociation could give a pharmacodynamic advantage in vivo by retaining
antiviral activity after free plasma levels had dropped below ecacious levels,
and could help explain the previously discussed discrepancy between binding
and antiviral assays in vitro.
When 15 was studied in vivo, the oral bioavailability in the dog was low
(
o
10%), which was ascribed to high first-pass clearance based upon clearance
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