Generation of Leads for γ-Secretase Modulation

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Drug Discovery

Background:

• Gamma-secretase modulators (GSMs) are investigated for Alzheimer's disease treatment.
• Amyloid-beta 42 (Aβ42) is a key protein implicated in Alzheimer's pathology.
• Oxadiazine scaffolds offer a novel structural basis for GSM development.

Purpose of the Study:

• To design and synthesize novel GSMs based on an oxadiazine scaffold.
• To evaluate the efficacy of these GSMs in inhibiting Aβ42 generation in vitro and in vivo.
• To address potential reactivity concerns associated with earlier GSM analogues.

Main Methods:

• Synthesis of structurally differentiated oxadiazine analogues (Series I, II, and III).
• In vitro assays to measure inhibition of Aβ42 generation.
• In vivo studies in rats to assess the effect of GSMs on cerebrospinal fluid (CSF) Aβ42 levels.

Main Results:

• Series I analogues with α-oriented substituents potently inhibited Aβ42 generation in vitro.
• Novel GSMs with endocyclic double bonds (Series II) or lacking olefinic moieties (Series III) were successfully designed.
• Compound 11 and azepine 20 demonstrated significant reduction of CSF Aβ42 in rats at a 30 mg/kg oral dose.

Conclusions:

• The oxadiazine scaffold is a viable platform for developing potent GSMs.
• Structural modifications can mitigate potential reactivity issues while maintaining efficacy.
• Promising GSM candidates, 11 and 20, warrant further investigation for Alzheimer's disease therapeutic potential.