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60 was profiled further and found to be 10-fold weaker than 50 (SRI IC
50
ΒΌ
49
nM) and to have a much longer half-life (
10 h in rat and dog) than 50.
Therefore, dosing with 50 would result in continued exposure to a serotonin re-
uptake inhibitor and, therefore, would not be significantly different to the use
of existing SSRIs for the treatment of PE.
B
NHMe
NHMe
H
MeSO
2
N
H
MeSO
2
O
O
60
59
OCF
3
CF
3
7.4.3 Strategies to Avoid Active Circulating Metabolites
We initially considered two strategies to overcome this problem of a long-lived,
active metabolite (Figure 7.7). One strategy was to modify the amine group
such that metabolism around the amine would not generate an active meta-
bolite. From our initial work varying the amine group, we knew that azetidines
61 retained SRI potency, but on investigating this further with polar sub-
stituents on the benzylamine ring we found that these analogues tend to be
weaker than desired and, in addition, have chemical stability issues.
27
We also
investigated cyclising the amine into a pyrrolidine ring to give the compounds
62. While this gives potent SSRIs,
28
the compounds made are also potent CYP
2D6 inhibitors. The introduction of a stereogenic centre made the synthesis of
analogues more complicated, and we chose not to pursue this strategy.
The second strategy was to introduce a metabolically vulnerable group onto
the template, so that metabolism would generate an inactive metabolite.
29
NMe
2
NMe
2
HN
N
N
X
X
MeSO
2
X
O
O
O
or
O
Modify amine
group
Introduce
metabolically
vulnerable group, Y
61
62
50
CF
3
Y
Y
Y
X = polar group
Figure 7.7
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