Related Experiment Video
Updated: May 29, 2026
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
Aminothiazoles as γ-secretase modulators
Thomas Lübbers1, Alexander Flohr, Synese Jolidon
1Discovery Chemistry, F. Hoffmann-La Roche Ltd, Grenzacher Strasse 124, 4070 Basel, Switzerland. thomas.luebbers@roche.com
Bioorganic & Medicinal Chemistry Letters
|September 20, 2011
Summary
Researchers discovered new aminothiazole compounds that reduce toxic amyloid beta (Aβ) peptide production without inhibiting γ-secretase. These novel modulators show promise in Alzheimer's disease research by decreasing harmful Aβ42 levels in vivo.
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Drug Discovery
Background:
- Amyloid beta (Aβ) peptides, particularly Aβ42, are implicated in Alzheimer's disease pathogenesis.
- γ-secretase plays a crucial role in amyloid precursor protein processing and Aβ production.
Purpose of the Study:
- To discover and characterize novel γ-secretase modulators (GSMs) with an aminothiazole core.
- To investigate the effect of these compounds on Aβ peptide production, focusing on reducing toxic Aβ42.
Main Methods:
- High-throughput screening (HTS) to identify initial hits.
- Chemical synthesis of novel aminothiazole derivatives.
- In vitro assays to measure Aβ peptide production.
- Structure-Activity Relationship (SAR) studies.
- In vivo studies in APPSwe transgenic mice.
Main Results:
- Discovery of a new class of γ-secretase modulators featuring an aminothiazole scaffold.
- Compounds exhibited moderate to good in vitro potency in reducing overall Aβ production.
- These modulators selectively shifted Aβ production from aggregating Aβ42 to smaller, non-aggregating forms, without inhibiting γ-secretase activity.
- Compound 15 demonstrated efficacy in reducing brain Aβ42 levels in vivo in a mouse model of Alzheimer's disease.
Conclusions:
- The novel aminothiazole-based compounds represent a promising new class of γ-secretase modulators.
- These compounds offer a potential therapeutic strategy for Alzheimer's disease by reducing toxic Aβ42 species.
- Further development of these GSMs could lead to effective treatments for Alzheimer's disease.
More Related Videos
Related Concept Videos
01:20Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein
Antiepileptic drugs, such as levetiracetam (Keppra) and brivaracetam (Briviact), have emerged as crucial tools in managing epilepsy. These medications exert their therapeutic effects by targeting the synaptic vesicle protein SV2A, a transmembrane glycoprotein primarily found in the brain.
SV2A is a transmembrane glycoprotein located predominantly in the brain, modulating the release of neurotransmitters for neuronal communication. Both levetiracetam and brivaracetam exhibit a high affinity for...
SV2A is a transmembrane glycoprotein located predominantly in the brain, modulating the release of neurotransmitters for neuronal communication. Both levetiracetam and brivaracetam exhibit a high affinity for...
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
01:29Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
01:18Antiepileptic Drugs: GABAergic Pathway Potentiators
γ-aminobutyric acid or GABA, plays a pivotal role as an inhibitory neurotransmitter in the brain. GABA pathway potentiators, also known as GABAergic drugs, are a class of pharmaceutical agents designed to enhance the functioning of the GABAergic system. These medications primarily treat epilepsy, a neurological disorder characterized by recurrent seizures.
The key GABA pathway potentiators used in epilepsy management are as follows.
Benzodiazepines are a well-known class of drugs used for their...
The key GABA pathway potentiators used in epilepsy management are as follows.
Benzodiazepines are a well-known class of drugs used for their...
01:18Indirect-Acting Cholinergic Agonists: Mechanism of Action
Indirect-acting cholinergic agonists work by interacting with an enzyme called acetylcholinesterase (AChE) in the synaptic cleft. They can be reversible or irreversible inhibitors and have different effects on the enzyme.
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex, leading to...
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex, leading to...
01:30Indirect-Acting Cholinergic Agonists: Pharmacological Actions
Indirect-acting cholinergic agonists, also known as anticholinesterases, exert their pharmacological effects by enhancing cholinergic transmission in various body parts, including the neuromuscular junction, autonomic cholinergic synapses, and the brain.
At the neuromuscular junction, these agents work by inhibiting the breakdown of acetylcholine, allowing it to remain bound to the receptor and bind to nearby receptors. This process leads to repetitive firing of the endplate, causing muscle...
At the neuromuscular junction, these agents work by inhibiting the breakdown of acetylcholine, allowing it to remain bound to the receptor and bind to nearby receptors. This process leads to repetitive firing of the endplate, causing muscle...