作者: Fokas, Demosthenes ; Tamvakopoulos, Constantin ; Sivolapenko, Gregory B. ; El Mubarak, Mohamed A. ; Rampias, Theodoros ; Papakyriakou, Athanasios ; Vassilatis, Demetrios K. ; Asvos, Xenophon ; Topouzis, Stavros ; Karampelas, Theodoros

We report the discovery of a Nurr1-RXRα heterodimer-selective rexinoid which emerged from the structural modification of aminopyrimidine XCT0135908. Although XCT0135908 demonstrated high selectivity for the Nurr1-RXRα heterodimer over other RXRα dimerization partners, its poor in vivo stability and limited brain penetration hindered its utility. Structure-activity relationship (SAR) studies alongside bioactivity evaluations of a diverse series of substituted pyrimidines led to BRF110, a brain-penetrant compound retaining the selective activation of the Nurr1-RXRα heterodimer. BRF110, as XCT0135908, protects dopaminergic cells against the Parkinson's disease-related toxin MPP⁺ and increases BDNF transcription in mice. Notably, BRF110, in contrast to the market-approved pan-RXR agonist bexarotene, did not elevate triglyceride levels, indicating that enhanced heterodimer selectivity can mitigate off-target in vivo side effects of rexinoids. These findings highlight the potential of heterodimer-selective scaffolds as a strategy for improving the therapeutic profile of rexinoids, addressing significant challenges in the clinical development of RXR-targeting molecules.

2017-04-11·Proceedings of the National Academy of Sciences1区 · 综合性期刊

Nurr1:RXRα heterodimer activation as monotherapy for Parkinson’s disease

1区 · 综合性期刊

Article

作者: Qing, Xiaobing ; Spathis, Athanasios D ; Schwamborn, Jens Christian ; Dalla, Christina ; Tamvakopoulos, Constantin ; Rideout, Hardy J ; Asvos, Xenophon ; Alexakos, Pavlos ; Cournia, Zoe ; Fokas, Demosthenes ; Smits, Lisa M ; Vassilatis, Demetrios K ; Topouzis, Stavros ; Karampelas, Theodoros ; Ziavra, Despina

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor α (RXRα) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement. We designed BRF110, a unique in vivo active Nurr1:RXRα-selective lead molecule, which prevents DAergic neuron demise and striatal DAergic denervation in vivo against PD-causing toxins in a Nurr1-dependent manner. BRF110 also protects against PD-related genetic mutations in patient induced pluripotent stem cell (iPSC)-derived DAergic neurons and a genetic mouse PD model. Remarkably, besides neuroprotection, BRF110 up-regulates tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), and GTP cyclohydrolase I (GCH1) transcription; increases striatal DA in vivo; and has symptomatic efficacy in two postneurodegeneration PD models, without inducing dyskinesias on chronic daily treatment. The combined neuroprotective and symptomatic effects of BRF110 identify Nurr1:RXRα activation as a potential monotherapeutic approach for PD.

2016-02-01·Molecular Diversity3区 · 化学

New insights into PDE4B inhibitor selectivity: CoMFA analyses and molecular docking studies

3区 · 化学

Article

作者: Bruno, Olga ; Guariento, Sara ; Cichero, Elena ; Fossa, Paola

PDE4 inhibitors have been largely studied because of their promising therapeutic effects concerning inflammation and neurodegenerative dysfunctions, such as depression, schizophrenia and Alzheimer's diseases. In this context, the PDE4B isoform proved to be particularly involved in the activation of inflammatory responses, while the PDE4D subfamily is more associated with neuropathologies. The clinical use of PDE4 inhibitors was restricted by the presence of prominent side effects probably due to their non-specific action across the different isoforms. Therefore, this work deals with the development of 3D-QSAR models, supported by molecular docking studies, to identify the key requirements underlying selective PDE4B or PDE4D inhibition. The results highlighted the ligand-based approach as a promising tool to guide the rational design of novel PDE4 inhibitors endowed with high affinity and selectivity profiles. The alignment of compound 1-85 and the model A statistical results are depicted.

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