The Discovery of UK-390957: the Challenge of Targeting a Short Half-life, Rapid T SSRI - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 154

38 has moderate SRI activity (25 nM), but insucient selectivity over NRI.
The 4-trifluoromethoxy derivative 39 is particularly interesting, as it combines
excellent potency (7 nM) with greater than 800-fold selectivity over DRI
and NRI.
NMe 2
X
O
29, 31-43
Y
Although a number of hydrophobic groups are well tolerated at the 4-
position of the phenoxy ring, we wished to explore the possibility of introducing
polarity at this position with the aim of potentially introducing polar sub-
stituents on both rings. We were encouraged to find that the sulfonamide 40 has
good potency (29 nM), excellent selectivity and is relatively polar (log D ¼ 0.5).
It therefore seemed like an ideal starting point for generating a low-volume and
potent SSRI. Unfortunately, we were unable to increase potency in this series,
as adding either polar or lipophilic substituents to the benzylamine ring resulted
in a loss of activity. The activity of 40 suggested that alternative polar sub-
stituents might be well tolerated on the phenoxy ring, but we were unable to find
any with sucient potency. For example, the amide 41 has activity of only
180 nM while the sulfoxide 42 and sulfone 43 are even less active.
7.4.2 Introducing Polarity in the Diphenyl Ether Template
Having explored the SAR around the phenoxy ring and the amine group, we
then investigated the effect of introducing polar groups onto the benzylamine
ring. 24,26 By analogy with the tetrahydronaphthalene template, we anticipated
that polar substitution would be well tolerated at the 5-position of the benzyl-
amine ring of the (2-phenoxybenzyl)amine template. We initially looked at
compounds with a trifluoromethyl or trifluoromethoxy substituent on the
phenoxy ring, as these substituents had shown good selectivity and were
anticipated to be metabolically stable, which at this stage we believed was
important (Table 7.4).
We were quickly able to show that adding small polar substituents, such
as primary S-linked sulfonamide (47), N-linked sulfonamide (44, 50) and pri-
mary amide (45, 51), led to highly potent and selective compounds. It is
interesting to note, however, that for the trifluoromethoxy-substituted series,
the primary amide 45 is nearly 5-fold more active than the methanesulfonamide