Discovery of an In Vitro and In Vivo Potent Nicotinic α7 Positive Allosteric Modulator Clinical Candidate Molecule (RGH-857)

While identifying α7 nACh receptor positive allosteric
modulators,
a novel scaffold (1,1-dioxo-thiadiazine core) emerged from our HTS
campaign, exhibiting unusually low lipophilicity compared to other
screening hits. During the hit-to-lead optimization, the importance
of different structural elements was evaluated. Upon combination of
the best building blocks, first a lead molecule (25),
then after a subsequent lead optimization, a clinical candidate compound
(51, RGH-857) was identified. Having the
most balanced physicochemical and in vitro pharmacological
profile combined with significant in vivo efficacy
in models of scopolamine-induced amnesia and natural forgetting, our
results suggest that cognitive enhancement through the positive modulation
of α7 nAChRs can be a viable approach to targeting cognitive
decline.