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H
H
O
H
O
O
R1
N
N
N
11
12
Me
Cl
Block oxidation
Block
N
-dealkylation
R
Me
Cl
H
O
H
H
N
H
H
Me
Me
Cl
Me
Me
Cl
Oxidation
Major pathway
>80% Mediated by 2D6
Minor pathway
Mediated by 3A4
Major pathway >80%
Mediated by 2D6
Figure 12.9
Metabolic pathway of compounds 10 and 11 and strategy to design out
CYP2D6 metabolism.
MW 315
HLM, Cl
int
<7.6 µL/min/mg
clog P 3.3
h.heps, Cl
int
2.7 µL/min/million cells
H
Log D
7.4
0.8
CYP2D6 inh., IC
50
27.1 µM
HBD/HBA count 1/3
CYP1A2, 2C9, 2C19 inh., IC
50
>30 µM
O
N
pKa 9.4
CYP3A4 inhib., IC
50
17.9 µM
TPSA 32
CaCO-2, AB/BA 19/28
MDCK-mdr1, AB/BA 15/64
Cl
13
Cl
SRI, K
i
= 9 nM
K
+
, hERG, IC
50
24.7 µΜ
NRI, K
i
= 52 nM
DRI, K
i
= 640 nM
Dog pharmacokinetics:
T
1/2
5.7 h, Cl
s
1.1 mL/min/kg, V
d
0.5 L/kg
F 91%
Figure 12.10
In vitro and pharmacokinetic profile of compound 13.CaCO-2
¼
colo-
rectal adenocarcinoma cells.
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