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.