4-amino-7-chloroquinoline derivatives for treating Parkinson’s disease: implications for drug discovery

Kim, Chun-Hyung; Leblanc, Pierre; Kim, Kwangsoo

doi:10.1517/17460441.2016.1154529

Cited by 18 publications

(15 citation statements)

References 35 publications

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“…Aminoquinoline moiety is present in many biologically active compounds. Compounds bearing this sub-structure are described with anti-tuberculosis, 1 anti-leishmania 2 or antiinflammatory 3 , or antiviral (Ebola 4 ) activity or against Parkinson's disease 5 although an anti-malarial therapeutic indication is most well-known. The most used compounds of this family are chloroquine (CQ) and amodiaquine (AQ) ( Figure 1).…”

Section: -mentioning

confidence: 99%

New phenylaniline derivatives as modulators of amyloid protein precursor metabolism

Gay

Renault

Coevoet

et al. 2018

Bioorganic & Medicinal Chemistry

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The chloroquinoline scaffold is characteristic of anti-malarial drugs such as chloroquine (CQ) or amodiaquine (AQ). These drugs are also described for their potential effectiveness against prion disease, HCV, EBV, Ebola virus, cancer, Parkinson or Alzheimer diseases. Amyloid precursor protein (APP) metabolism is deregulated in Alzheimer's disease. Indeed, CQ modifies amyloid precursor protein (APP) metabolism by precluding the release of amyloid-beta peptides (Aβ), which accumulate in the brain of Alzheimer patients to form the so-called amyloid plaques. We showed that AQ and analogs have similar effects although having a higher cytotoxicity. Herein, two new series of compounds were synthesized by replacing 7chloroquinolin-4-amine moiety of AQ by 2-aminomethylaniline and 2aminomethylphenyle moieties. Their structure activity relationship was based on their ability to modulate APP metabolism, Aβ release, and their cytotoxicity similarly to CQ. Two compounds 15a, 16a showed interesting and potent effect on the redirection of APP metabolism toward a decrease of Aβ peptide release (in the same range compared to AQ), and a 3 to 10-fold increased stability of APP carboxy terminal fragments (CTFα and AICD) without obvious cellular toxicity at 100µM.

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Section: -mentioning

confidence: 99%

New phenylaniline derivatives as modulators of amyloid protein precursor metabolism

Gay

Renault

Coevoet

et al. 2018

Bioorganic & Medicinal Chemistry

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“…In particular, Nurr1 haploinsufficiency is associated with cognitive and language impairment in humans [15,16]. Furthermore, the intracellular transcription factor Nurr1 has been suggested as a therapeutic target since it undergoes alterations and is involved in the pathology of neurodegenerative diseases including Parkinson's disease (PD) and Alzheimer's disease (AD) [17][18][19][20][21][22][23]. Despite the fact that Nurr1 is considered an orphan nuclear receptor, the endogenous ligands for Nurr1 have not yet been identified [1,2,24].…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Stimulation of Nurr1 Promotes Cell Cycle Progression in Adult Hippocampal Neural Stem Cells

Moon

Jeon

Kim

et al. 2019

IJMS

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Nuclear receptor related-1 (Nurr1) protein performs a crucial role in hippocampal neural stem cell (hNSC) development as well as cognitive functions. We previously demonstrated that the pharmacological stimulation of Nurr1 by amodiaquine (AQ) promotes spatial memory by enhancing adult hippocampal neurogenesis. However, the role of Nurr1 in the cell cycle regulation of the adult hippocampus has not been investigated. This study aimed to examine changes in the cell cycle-related molecules involved in adult hippocampal neurogenesis induced by Nurr1 pharmacological stimulation. Fluorescence-activated cell sorting (FACS) analysis showed that AQ improved the progression of cell cycle from G0/G1 to S phase in a dose-dependent manner, and MEK1 or PI3K inhibitors attenuated this progression. In addition, AQ treatment increased the expression of cell proliferation markers MCM5 and PCNA, and transcription factor E2F1. Furthermore, pharmacological stimulation of Nurr1 by AQ increased the expression levels of positive cell cycle regulators such as cyclin A and cyclin-dependent kinases (CDK) 2. In contrast, levels of CDK inhibitors p27KIP1 and p57KIP2 were reduced upon treatment with AQ. Similar to the in vitro results, RT-qPCR analysis of AQ-administered mice brains revealed an increase in the levels of markers of cell cycle progression, PCNA, MCM5, and Cdc25a. Finally, AQ administration resulted in decreased p27KIP1 and increased CDK2 levels in the dentate gyrus of the mouse hippocampus, as quantified immunohistochemically. Our results demonstrate that the pharmacological stimulation of Nurr1 in adult hNSCs by AQ promotes the cell cycle by modulating cell cycle-related molecules.

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“…45 Nurr1 is also implicated in levodopa-induced dyskinesia, an adverse effect of dopamine replacement strategies in Parkinson's disease. 45 Two mechanisms for a potential interaction between AQ/ DEAQ and ATV/PG/CG can be hypothesized. A pharmacodynamic interaction could occur at the level of a brain target, such as the dopaminergic DA 2 receptors.…”

Section: Articlementioning

confidence: 99%

Unanticipated CNS Safety Signal in a Placebo‐Controlled, Randomized Trial of Co‐Administered Atovaquone‐Proguanil and Amodiaquine

Chalon

Chughlay

Abla

et al. 2021

Clin Pharma and Therapeutics

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Atovaquone-proguanil (ATV-PG) plus amodiaquine (AQ) has been considered as a potential replacement for sulfadoxine-pyrimethamine plus AQ for seasonal malaria chemoprevention in African children. This randomized, double-blind, placebo-controlled, parallel group study assessed the safety, tolerability, and pharmacokinetics (PKs) of ATV-PG plus AQ in healthy adult males and females of Black sub-Saharan African origin. Participants were randomized to four treatment groups: ATV-PG/AQ (n = 8), ATV-PG/placebo (n = 12), AQ/placebo (n = 12), and placebo/placebo (n = 12). Treatments were administered orally once daily for 3 days (days 1-3) at daily doses of ATV-PQ 1000/400 mg and AQ 612 mg. Co-administration of ATV-PG/AQ had no clinically relevant effect on PK parameters for ATV, PG, the PG metabolite cycloguanil, AQ, or the AQ metabolite N-desethyl-amodiaquine. Adverse events occurred in 8 of 8 (100%) of participants receiving ATV-PG/AQ, 11 of 12 (91.7%) receiving ATV-PG, 11 of 12 (91.7%) receiving AQ, and 3 of 12 (25%) receiving placebo. The safety and tolerability profiles of ATV-PG and AQ were consistent with previous reports. In the ATV-PG/AQ group, 2 of 8 participants experienced extrapyramidal adverse effects (EPAEs) on day 3, both psychiatric and physical, which appeared unrelated to drug plasma PKs or cytochrome P450 2C8 phenotype. Although rare cases are reported with AQ administration, the high incidence of EPAE was unexpected in this small study. Owing to the unanticipated increased frequency of EPAE observed, the combination of ATV-PQ plus AQ is not recommended for further evaluation in prophylaxis of malaria in African children.Most malaria deaths occur in African children under 5 years of age, and morbidity impedes child development and increases the susceptibility to other illnesses. 1 In particular, of the ~ 24 million African children under 5 years old infected with P. falciparum in 2018, 13.8 million were estimated to suffer from severe or moderate anemia. 2 Seasonal malaria chemoprevention (SMC) with sulfadoxinepyrimethamine (SP) plus amodiaquine (AQ) is recommended for

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4-amino-7-chloroquinoline derivatives for treating Parkinson’s disease: implications for drug discovery

Cited by 18 publications

References 35 publications

New phenylaniline derivatives as modulators of amyloid protein precursor metabolism

New phenylaniline derivatives as modulators of amyloid protein precursor metabolism

Pharmacological Stimulation of Nurr1 Promotes Cell Cycle Progression in Adult Hippocampal Neural Stem Cells

Unanticipated CNS Safety Signal in a Placebo‐Controlled, Randomized Trial of Co‐Administered Atovaquone‐Proguanil and Amodiaquine

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