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 153

Table 7.3 Potency and selectivity SAR for the phenoxy ring of diphenyl
ethers.

SRI IC 50
(nM) a

Selectivity
over DRI

Selectivity
over NRI Compound Y X

29 3,4-Cl 2 H 11 12 26
31 2-Cl H 293 14 0.2
32 3-Cl H 192 4.7 0.3
33 4-Cl H 22 4.7 8.5
34 4-F H 136 NT NT
35 4-Et H 6 1067 361
36 4-SMe H 9 324 71
37 4-CF 3 H 32 600 93
38 4-OMe H 25 192 28
39 4-OCF 3 H 7 827 956
40 4-SO 2 NH 2 H 29 1722 788
41 4-CONH 2 H 180 28 3.5
42 4-SOMe b F 599 46 26
43 4-SO 2 Me F 744 NT NT
a The inhibitory potency at human serotonin, dopamine and noradrenaline transporters was
quantified through measurement of a compound's ability to inhibit transport and subsequent
intracellular accumulation of radiolabelled ligand in an in vitro radiometric assay using HEK-293
cells stably expressing the appropriate transporters. All assay determinations are Zn ¼ 2.
b Racemic mixture of sulfoxide enantiomers.

Before embarking on optimisation of polar substitution on the benzylamine
ring, however, we quickly explored the SAR around the benzylamine and the
phenoxy ring (Table 7.3). It soon became apparent that little variation of the
amine group was tolerated and that the dimethylamine is generally optimal for
potency. Monomethylamines are only slightly less active, but activity tends to
drop off rapidly if larger alkyl groups are present. For example, mono-
ethylamine loses more than 10-fold in potency. Cyclic amines were also
investigated, and while azetidine is well tolerated, pyrrolidine and morpholine
derivatives are essentially inactive.
Simple chloro substitution on the phenoxy ring highlighted some interesting
trends, with both the 2-chloro 31 and 3-chloro 32 derivatives showing poor SRI
IC 50 values, 293 nM and 192 nM, respectively. They are in fact selective inhi-
bitors of noradrenaline re-uptake. Reasonable activity (22 nM) is achieved with
the 4-chloro isomer 33, but this compound has significant activity against the
other two monoamine transporters. Better selectivity over DRI and NRI can be
achieved, to varying degrees, by placing slightly larger hydrophobic sub-
stituents at the 4-position of the phenoxy ring. The 4-ethyl derivative 35 is very
potent (6 nM) and has greater than 300-fold selectivity over DRI and NRI. The
4-methylsulfanyl system 36 is less selective over NRI (71-fold), but again has
excellent SRI activity (9 nM). The 4-trifluoromethyl compound 37 has good
levels of selectivity over DRI and NRI, but somewhat disappointing SRI
activity (32 nM). The smaller 4-fluoro substituted analogue 34 has much
less SRI activity, with an IC 50 value of only 136 nM. The 4-methoxy analogue