Discovery of an In Vitro and In Vivo Potent Nicotinic α7 Positive Allosteric Modulator Clinical Candidate Molecule...

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• Alpha-7 nicotinic acetylcholine receptors (α7 nAChRs) are key targets for cognitive enhancement.
• Identifying novel positive allosteric modulators (PAMs) for α7 nAChRs is crucial for treating cognitive decline.

Purpose of the Study:

• To discover and optimize novel α7 nAChR PAMs with favorable physicochemical properties.
• To identify a clinical candidate for treating cognitive deficits.

Main Methods:

• High-throughput screening (HTS) identified a novel 1,1-dioxo-thiadiazine scaffold.
• Hit-to-lead and lead optimization involved evaluating structural elements and combining building blocks.
• In vitro and in vivo studies assessed pharmacological profiles and efficacy in models of cognitive impairment.

Main Results:

• A novel scaffold with low lipophilicity was identified.
• Lead molecule 25 and clinical candidate 51 (RGH-857) were developed.
• RGH-857 demonstrated balanced physicochemical and in vitro properties, with significant in vivo efficacy in amnesia and natural forgetting models.

Conclusions:

• Positive modulation of α7 nAChRs is a viable strategy for cognitive enhancement.
• RGH-857 represents a promising clinical candidate for targeting cognitive decline.
• The novel thiadiazine scaffold offers a new chemical class for α7 nAChR PAM development.