A small‐molecule microtubule‐stabilizing agent safely reduces Aβ plaque and tau pathology in transgenic mouse models of Alzheimer's disease

Jun 17, 2024Alzheimer's & dementia : the journal of the Alzheimer's Association

A small drug that stabilizes cell structures safely lowers amyloid plaques and tau problems in mouse models of Alzheimer's disease

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Abstract

CNDR-51997 significantly reduced Aβ plaques in 5XFAD mice and in PS19 mice.

The compound also reduced axonal dystrophy and gliosis in a tauopathy mouse model.
Intermittent dosing with CNDR-51997 is associated with improvements in established mouse models of Alzheimer's disease.
The drug was well tolerated at doses exceeding those required for efficacy.
CNDR-51997 demonstrated a good safety pharmacology profile.

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INTRODUCTION: Intraneuronal inclusions composed of tau protein are found in Alzheimer's disease (AD) and other tauopathies. Tau normally binds (MTs), and its disengagement from MTs and misfolding in AD is thought to result in MT abnormalities. We previously identified triazolopyrimidine-containing MT-stabilizing compounds that provided benefit in AD mouse models and herein describe the characterization and efficacy testing of an optimized candidate, CNDR-51997.

METHODS: CNDR-51997 underwent pharmacokinetic, pharmacodynamic, safety pharmacology, and mouse tolerability testing. In addition, the compound was examined for efficacy in 5XFAD amyloid beta (Aβ) plaque mice and PS19 tauopathy mice.

RESULTS: CNDR-51997 significantly reduced Aβ plaques in 5XFAD mice and in PS19 mice, with the latter also showing attenuated axonal dystrophy and gliosis. CNDR-51997 was well tolerated at doses that exceeded efficacy doses, with a good safety pharmacology profile.

DISCUSSION: CNDR-51997 may be a candidate for advancement as a potential therapeutic agent for AD and/or other tauopathies. Highlights There is evidence of microtubule alterations (MT) in Alzheimer's disease (AD) brain and in mouse models of AD pathology. Intermittent dosing with an optimized, brain-penetrant MT-stabilizing small-molecule, CNDR-51997, reduced both Aβ plaque and tau inclusion pathology in established mouse models of AD. CNDR-51997 attenuated axonal dystrophy and gliosis in a tauopathy mouse model, with a strong trend toward reduced hippocampal neuron loss. CNDR-51997 is well tolerated in mice at doses that are meaningfully greater than required for efficacy in AD mouse models, and the compound has a good safety pharmacology profile.

Key numbers

1 mg/kg

Reduction of Insoluble Aβ42

Dose of CNDR-51997 that significantly decreased insoluble Aβ42 in 5XFAD mice.

50%

Reduction of Total Insoluble Tau

Approximate reduction in total insoluble tau in PS19 mice treated with CNDR-51997.

20 mg/kg

Well Tolerated Dose

Maximum tolerated dose of CNDR-51997 in mice without adverse effects.

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A small‐molecule microtubule‐stabilizing agent safely reduces Aβ plaque and tau pathology in transgenic mouse models of Alzheimer's disease

Abstract

Key numbers

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