Multiparameter Optimization of Naphthyridine Derivatives as Selective α5-GABA_A Receptor Negative Allosteric...

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Drug Discovery

Background:

• Selective α5-GABA_A receptor modulators are sought for cognitive disorders.
• Existing compounds often face challenges with metabolic stability, safety, or intellectual property.

Purpose of the Study:

• To discover and characterize novel naphthyridine derivatives as selective α5-GABA_A receptor negative allosteric modulators (NAMs).
• To optimize these compounds for improved potency, selectivity, ADME, and safety profiles.
• To establish in vivo proof of concept for the novel scaffold in models of cognitive impairment.

Main Methods:

• Scaffold-hopping strategy to design and synthesize fused [6 + 6] bicyclic compounds.
• Structure-activity relationship (SAR) studies involving relocation of functional groups and property modulation.
• In vitro assays for receptor activity and selectivity.
• In vivo studies in animal models of cognitive impairment associated with schizophrenia (CIAS).

Main Results:

• Identification of 1,6-naphthyridinones as potent and selective α5-GABA_AR NAMs with favorable metabolic stability and cardiac safety.
• Optimization led to novel 1,6-naphthyridines with enhanced potency, selectivity, ADME, and safety.
• Compound 20 demonstrated in vivo proof of concept in two CIAS animal models.

Conclusions:

• Novel 1,6-naphthyridine derivatives represent a promising new scaffold for developing α5-GABA_AR NAMs.
• These compounds exhibit a balanced profile suitable for further development.
• The findings support the therapeutic potential of targeting α5-GABA_A receptors for cognitive dysfunction.