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MW 315
HLM, Cl
int
, 9 µL/min/mg
clog P 3.6
h.heps, Cl
int
, 3 µL/min/million cells
Log D
7.4
0.6
CYP2D6, 3A4, 1A2, 2C9, 2C19 inh.,
H
HBD/HBA count 1/3
IC
50
>30 µM
pKa 10
CaCO-2, AB/BA 12/25
N
TPSA 32
MDCK-mdr1, AB/BA 16/43
O
K
+
, hERG, IC
50
20 µ
Μ
14
Cl
SRI, K
i
= 6 nM
Cl
NRI, K
i
= 21 nM
DRI, K
i
= 544 nM
Figure 12.11
In vitro profile of compound 14.
PF-184298 Peak Urethral Pressure
*
*
70
*
60
*
*
50
40
30
20
10
0
0 nM
0.5 nM
3.8 nM
7.5 nM
27 nM
103 nM
227 nM
Figure 12.12
Increases in PUP versus free plasma concentration of 14 in an anaes-
thetized dog model (i.v. infusion; n
¼
4). Significance relative to control
noted thus *; P
o
0.05.
regimen. The ratio obtained of 0.45 for 14 was clearly superior to the ratio of
0.1 observed for 13. Encouraged by these data and the overall promising in vitro
profile of 14, its performance was evaluated in the dog SUI ecacy model
(Figure 12.12). We were pleased to find that 14 elicited a robust dose-dependent
increase in urethral pressure in the model, confirming good blood-brain barrier
penetration. Additionally, at the estimated human therapeutic free plasma
concentration of duloxetine for SUI, i.e. 4 nM (corresponding to a dose of
40mg bid), 14 elicited a superior response to duloxetine, producing a 35%
increase in PUP compared to only 26% for duloxetine. Compound 14 also had
a superior haemodynamic profile. A slight increase in MAP of 2.5%, consistent
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