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selective). Polar heterocycles such as triazole 18 also give potent SSRIs but
result in unacceptable levels of CYP2D6 inhibition, a problem that was not
seen with the other analogues prepared.
More than one polar substituent could be introduced onto the tetra-
hydronaphthalene ring to further reduce clog P, and this did give some SSRIs
with reasonable potency, such as amide/sulfonamide 24. This strategy was not
pursued further, partly because of the dicult syntheses involved and, more
importantly, because the high TPSA and HBD count were outside the targets
we had set to maximise the chance of achieving good CNS penetration.
7.3.1 Key Polar Analogues in the Tetrahydronaphthalene
Template
Compounds 10, 11, 14 and 15 were then selected for further progression into
permeability and CNS penetration studies based on their potency, selectivity
over DRI and NRI (at least 50-fold) and synthetic accessibility (Table 7.2). This
was despite 10 and 14 not meeting our goal of having
o
3 HBD, putting them at
risk of impaired brain penetration. As anticipated, it was found that incor-
porating a polar, strongly electron-withdrawing group onto the tetra-
hydronaphthalene core both attenuates the pK
a
of the amine and reduces the
log D, meeting the goals we had set. Despite the increased polarity, all of
the analogues tested show good flux and no eux in a Caco-2 assay. In fact,
like compound 3 they actually show a degree of influx, possibly indicating
apical-to-basal active transport across the membrane. In rat CNS penetration
studies, most of the analogues showed excellent brain exposure, with amide 10
and sulfonamide 14 displaying CSF (cerebrospinal fluid) to free blood levels of
1:1 and 2.6:1 respectively, despite both having 3 HBD and 14 having a TPSA of
81A
˚
2
, outside our original ''ideal'' target. While the N-methyl amide 11 also
showed good CSF levels, the N-methyl sulfonamide 15 showed somewhat
reduced CSF levels, despite being more lipophilic and having a HBD less than
14. This highlights that there are factors other than physicochemical properties,
perhaps such as transporter anity, which determine the level of CNS pene-
tration and following property guidelines too strictly (e.g. HBD
o
3) could lead
to interesting compounds being overlooked.
NHMe
R
2
3, 10, 11, 14, 15
Cl
Cl
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