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 159

Table 7.5 Activity and lipophilicity of diphenyl ethers 63-70

NMe 2 NMe 2

X

N

O O

63-68, 70 69

Y SMe

SRI IC 50 (nM) a Compound Y X Selectivity over DRI Selectivity over NRI c log P log D

63 SMe SO 2 NH 2 4 633 218 2.8 1.5

64 SMe CONH 2 2 1351 320 3.2 2.2

65 SMe NHSO 2 Me 5 711 23 3.4 1.7

66 SMe CONHMe 12 197 27 3.4 -

67 SMe SO 2 NHMe 9 60 25 3.4 -

68 SMe 2 899 128 4.2 2.5

N

N N

69 - - 2 3600 500 3.1 1.5
70 SOMe SO 2 NH 2 41000 - - 1.0 o -2
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 appro-
priate transporters. All assay determinations are Zn ¼ 2.