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eqn (7.1) and aiming for a half-life of
o
10 hours, this results in a target V
D
of
less than 9 Lkg
1
.
In addition to the pharmacokinetic (PK) targets above, our other project
goals were to find a potent, CNS penetrant SSRI with an SRI (serotonin re-
uptake inhibition) IC
50
o
10 nM and 4100-fold selectivity over dopamine
(DRI) and noradrenaline re-uptake inhibition (NRI). In addition, we required
the absence of significant off-target activity, as measured by screening against a
panel of other enzymes and receptors, no significant CYP inhibition,
1
and, in
order to avoid large exposure difference between individuals, the compound
should not be predominantly metabolised by CYP 2D6.
15
7.3 Reducing Volume Starting from a Precedented
SSRI Template
Our initial strategy to achieve the desired PK profile was to take one of the
marketed SSRIs as a starting point and seek to reduce its lipophilicity (clog P
and log D) by incorporating polar groups (Figure 7.2). While all of the factors
that underlie volume of distribution are not understood, it is clear that lipo-
philicity plays a significant role, as higher lipophilicity results in higher tissue
and membrane anity and therefore higher V
D
.
16
Non-basic electron-with-
drawing groups were particularly targeted as it was anticipated that these would
reduce the pK
a
of the basic nitrogen and potentially reduce membrane anity
by reducing the energetically favourable ionic interaction between the proto-
nated amine and the negatively charged phospholipid phosphate head-group.
By starting from a marketed drug, we knew that many of the properties we
would need (e.g. SRI potency, selectivity and CNS penetration) should be
achievable from that template. In addition, it was felt that starting with a
chemotype with clinical precedent would help mitigate development risks such
as toxicity. However, the known SSRIs are all highly lipophilic, and it was not
obvious that the polarity would be tolerated, either from a potency or CNS
penetration point of view. In terms of CNS penetration, we recognised the
critical need to balance our strategy of introducing polar groups to reduce V
D
NHMe
NHMe
R
R = polar and/or electron
withdrawing group
Cl
3
Cl
Cl
Cl
Figure 7.2
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