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Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms

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Generation of Leads for γ-Secretase Modulation.

Mihirbaran Mandal¹, Alexei Buevich², John P Caldwell¹

¹Department of Medicinal Chemistry, Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.

Journal of Medicinal Chemistry

|August 14, 2020

Summary

Researchers developed novel oxadiazine-based gamma-secretase modulators (GSMs) to inhibit amyloid-beta 42 (Aβ42) production. Compound 11 and azepine 20 effectively reduced Aβ42 levels in rat cerebrospinal fluid.

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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.