Chemistry Reference
In-Depth Information
NMe
2
H
2
NO
2
S
HLM T
1/2
= 40 min
RLM T
1/2
= 27 min
DLM T
1/2
= 13 min
Caco 2 flux (AB/BA) 40/41
pKa 8.4
logD 1.5
Rat PK
V
D
= 4 L/kg (V
DU
74 L/kg)
Cl
blood
= 19 mL/min/kg
T
1/2
= 3 h
T
max
= 0.5 h
CSF:free blood 0.9:1
Dog PK
V
D
= 4 L/kg (V
DU
144 L/kg)
Cl
blood
= 20 mL/min/kg
T
1/2
= 2.4 h
T
max
= 0.25 h
O
63
SMe
Figure 7.8
(Cl
blood
¼
19mLmin
1
kg
1
and 20mLmin
1
kg
1
), resulting in a relatively
short half-life of 3 hours and 2.4 hours in rat and dog, respectively. Total
clearance is moderate and bioavailability for 63 is high in both rat and dog,
despite its having relatively high turnover in microsomes and correspondingly
high unbound clearance (Cl
u
¼
377-730mLmin
1
kg
1
). This is thought to be
due to the protective effect of partitioning into red blood cells,
31
which reduces
the blood clearance and also protects against high first-pass clearance. Scaling
from rat and dog PK gave a human PK prediction of low V
D
(2-4 L kg
1
),
rapid T
max
0.5 h) and moderate blood clearance (4-8mLmin
1
kg
1
),
resulting in high predicted bioavailability (470%), a short half-life of 4-10 h,
and low predicted dose (
o
20mg), exactly in keeping with our goals. Sulf-
onamide 63 was profiled against a range of receptors, enzymes and ion-channels
(more than 30 Cerep assays) and was found to have no significant activity
(IC
50
410 mM except at dopamine D1, IC
50
¼
2.4 mM, and opiate receptors,
IC
50
¼
2.9 mM).
CNS penetration studies of 63 in the rat showed high drug levels in the
brain (CSF : free blood ratio of 0.9). CNS microdialysis studies in the rat
demonstrated that, after oral dosing, central serotonin levels rapidly increase
(Figure 7.9), reaching a peak within 1 h at 3mg kg
1
, a slightly later time than
the T
max
of 63 in the plasma. This is in marked contrast to the data obtained for
fluoxetine (Figure 7.1), where peak serotonin levels are not obtained until after
more than 5 h.
Drug metabolism studies showed that 63 is almost completely metabolised to
the sulfoxide 70 (490%) in human liver microsomes and also in vivo in rat and
dog. Not only is this compound completely inactive against all three mono-
amine transporters, but it is also essentially inactive in the CEREP screening
panel (all IC
50
410 mM). Compound 70 is extremely polar (log D
o
2) and is
rapidly cleared in vivo (t
1/2
o
4 h in rat and dog).
While, in theory, oxidation of the sulfur in 63 could be mediated by several
P450 isoforms, or by other oxidative enzymes such as flavin monooxygenases
(FMO),
32
drug metabolism studies showed that 63 is predominantly metabo-
lised by CYP2D6 and CYP2C9, with CYP2D6 appearing to be the major
metabolising enzyme (50-60%). Based on this it was anticipated that roughly a
2-fold increase in human half-life would be seen in patients who do not express
(
B
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