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In Vivo Characterization of ARN14140, a Memantine/Galantamine-Based Multi-Target Compound for Alzheimer ’ s Disease

View Article: PubMed Central - PubMed

ABSTRACT

Alzheimer’s disease (AD) is a chronic pathological condition that leads to neurodegeneration, loss of intellectual abilities, including cognition and memory, and ultimately to death. It is widely recognized that AD is a multifactorial disease, where different pathological cascades (mainly amyloid and tau) contribute to neural death and to the clinical outcome related to the disease. The currently available drugs for AD were developed according to the one-target, one-drug paradigm. In recent times, multi-target strategies have begun to play an increasingly central role in the discovery of more efficacious candidates for complex neurological conditions, including AD. In this study, we report on the in vivo pharmacological characterization of ARN14140, a new chemical entity, which was obtained through a multi-target structure-activity relationship campaign, and which showed a balanced inhibiting profile against the acetylcholinesterase enzyme and the NMDA receptor. Based on the initial promising biochemical data, ARN14140 is here studied in mice treated with the amyloidogenic fragment 25–35 of the amyloid-β peptide, a consolidated non-transgenic AD model. Sub-chronically treating animals with ARN14140 leads to a prevention of the cognitive impairment and of biomarker levels connected to neurodegeneration, demonstrating its neuroprotective potential as new AD agent.

No MeSH data available.


Related in: MedlinePlus

2D structure of ARN14140 (MW = 506.73) along with biological activities values against AChE and NMDAR as reported in Simoni et al.10.
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f1: 2D structure of ARN14140 (MW = 506.73) along with biological activities values against AChE and NMDAR as reported in Simoni et al.10.

Mentions: Because of its complexity, AD is the source of a major unmet medical need in neurology78. In response to this pluralism of causes and effects, one possible research strategy is to develop a multi-target approach, leading to a single molecule acting in concert on different targets of relevance for the disease. This should allow to gain a superior therapeutic profile, relative to single-target molecules alone, and to overcome the intrinsic conflict of combination therapies, where positive outcomes deriving from combating the disease on multiple fronts coexist with drug-drug interaction concerns9. We recently developed a novel class of multi-target compounds, obtained by linking together two commercially available drugs for AD, galantamine and memantine. These drugs modulate the cholinergic and glutamatergic pathways, respectively1011. ARN14140 was the endpoint of a mid-sized campaign of dual-target structure-activity relationship (SARs) studies. ARN14140 was the best compromise between pharmacological potency, molecular weight, and calculated logP. When tested in vitro, ARN14140 showed a fairly balanced profile against both targets. It was almost equipotent for acetylcholinesterase (AChE) and the NMDA receptor (NMDAR, Fig. 1).


In Vivo Characterization of ARN14140, a Memantine/Galantamine-Based Multi-Target Compound for Alzheimer ’ s Disease
2D structure of ARN14140 (MW = 506.73) along with biological activities values against AChE and NMDAR as reported in Simoni et al.10.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5016838&req=5

f1: 2D structure of ARN14140 (MW = 506.73) along with biological activities values against AChE and NMDAR as reported in Simoni et al.10.
Mentions: Because of its complexity, AD is the source of a major unmet medical need in neurology78. In response to this pluralism of causes and effects, one possible research strategy is to develop a multi-target approach, leading to a single molecule acting in concert on different targets of relevance for the disease. This should allow to gain a superior therapeutic profile, relative to single-target molecules alone, and to overcome the intrinsic conflict of combination therapies, where positive outcomes deriving from combating the disease on multiple fronts coexist with drug-drug interaction concerns9. We recently developed a novel class of multi-target compounds, obtained by linking together two commercially available drugs for AD, galantamine and memantine. These drugs modulate the cholinergic and glutamatergic pathways, respectively1011. ARN14140 was the endpoint of a mid-sized campaign of dual-target structure-activity relationship (SARs) studies. ARN14140 was the best compromise between pharmacological potency, molecular weight, and calculated logP. When tested in vitro, ARN14140 showed a fairly balanced profile against both targets. It was almost equipotent for acetylcholinesterase (AChE) and the NMDA receptor (NMDAR, Fig. 1).

View Article: PubMed Central - PubMed

ABSTRACT

Alzheimer’s disease (AD) is a chronic pathological condition that leads to neurodegeneration, loss of intellectual abilities, including cognition and memory, and ultimately to death. It is widely recognized that AD is a multifactorial disease, where different pathological cascades (mainly amyloid and tau) contribute to neural death and to the clinical outcome related to the disease. The currently available drugs for AD were developed according to the one-target, one-drug paradigm. In recent times, multi-target strategies have begun to play an increasingly central role in the discovery of more efficacious candidates for complex neurological conditions, including AD. In this study, we report on the in vivo pharmacological characterization of ARN14140, a new chemical entity, which was obtained through a multi-target structure-activity relationship campaign, and which showed a balanced inhibiting profile against the acetylcholinesterase enzyme and the NMDA receptor. Based on the initial promising biochemical data, ARN14140 is here studied in mice treated with the amyloidogenic fragment 25–35 of the amyloid-β peptide, a consolidated non-transgenic AD model. Sub-chronically treating animals with ARN14140 leads to a prevention of the cognitive impairment and of biomarker levels connected to neurodegeneration, demonstrating its neuroprotective potential as new AD agent.

No MeSH data available.


Related in: MedlinePlus