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Updated: Jun 1, 2026

Quantitative Measurement of &#947;-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms
06:40

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

Published on: January 25, 2018

Pyridazine-derived γ-secretase modulators.

Zehong Wan1, Adrian Hall, Yun Jin

  • 1Research and Development, GlaxoSmithKline Pharmaceuticals, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201023, China. zehong.2.wan@gsk.com

Bioorganic & Medicinal Chemistry Letters
|June 4, 2011
PubMed
Summary
This summary is machine-generated.

Researchers developed novel pyridazine compounds to modulate gamma-secretase. Compound 25 effectively reduced amyloid-beta 42 and 40 levels in vitro, showing good pharmacokinetics and brain penetration in rats.

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Saccharomyces cerevisiae Models of Alzheimer's Disease to Screen Genes, Mutations, and Chemicals Affecting Amyloid Beta Production by &#947;-Secretase
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Saccharomyces cerevisiae Models of Alzheimer's Disease to Screen Genes, Mutations, and Chemicals Affecting Amyloid Beta Production by γ-Secretase

Published on: June 24, 2025

Area of Science:

  • Medicinal Chemistry
  • Neuroscience
  • Pharmacology

Background:

  • Gamma-secretase plays a crucial role in amyloid precursor protein (APP) processing.
  • Dysregulation of gamma-secretase activity is implicated in Alzheimer's disease pathogenesis.
  • Developing selective gamma-secretase modulators is a key therapeutic strategy.

Purpose of the Study:

  • To describe the structure-activity relationship (SAR) of novel pyridazine-derived gamma-secretase modulators.
  • To identify potent and selective modulators with favorable pharmacokinetic properties.
  • To evaluate the in vitro and in vivo efficacy of lead compounds.

Main Methods:

  • Synthesis and chemical characterization of a series of pyridazine derivatives.
  • In vitro enzymatic assays to assess gamma-secretase modulatory activity.
  • Biochemical analysis to determine levels of amyloid-beta (Aβ) species (Aβ42, Aβ40, total Aβ).
  • Pharmacokinetic studies in rats, including assessment of central nervous system (CNS) penetration.

Main Results:

  • A novel series of pyridazine-derived gamma-secretase modulators was synthesized.
  • Compound 25 emerged as a potent modulator in vitro.
  • Compound 25 selectively reduced Aβ42 and Aβ40 levels while maintaining total Aβ levels.
  • Compound 25 exhibited favorable pharmacokinetic parameters and demonstrated good CNS penetration in rat models.

Conclusions:

  • The described pyridazine scaffold represents a promising starting point for developing gamma-secretase modulators.
  • Compound 25 is a potent and selective gamma-secretase modulator with desirable drug-like properties.
  • Further investigation of Compound 25 and related analogs is warranted for potential Alzheimer's disease therapeutics.