Development of α5-SOP002
We re-synthesised 6,6-dimethyl-3-(2-hydroxyethyl)
thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one that has
demonstrated selectivity for the benzodiazepine binding site and high
negative allosteric modulation for the α5 GABAAR
sub-type following its published route, from the parent compound (Atack,
2010; Sternfeld et al., 2004) to develop hybrid derivatives (parent
compound, shown in Figure 1 (A)), full details of the synthetic steps
are detailed in supplementary scheme 1 (B) (see also Sung, Lee, 1992).
There were two main sites for modification, which we explored via
replacement of the triazole moiety or the oxazole which enabled us to
explore late-stage modification in order to synthesise hybrid analogues
to improve potency as a negative allosteric modulator acting on α5
GABAA Rs.