In vitro and in vivo profiling of CHF5022 and CHF5074

Imbimbo, Bruno P.; Giudice, Elda Del; Cenacchi, Valentina; Volta, Roberta; Villetti, Gino; Facchinetti, Fabrizio; Riccardi, Benedetta; Puccini, Paola; Moretto, Nadia; Grassi, Francesca; Ottonello, Simone; Leon, Alberta

doi:10.1016/j.phrs.2006.12.010

Cited by 41 publications

(55 citation statements)

References 34 publications

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“…This led to the theory that the SALAs acted via the modulation of Ab production through a shift in the site of c-secretase cleavage from position 42 to 38. In turn, the Ab 1-42 /Ab 1-38 ratio has been used as an optimization criterion in drug discovery (Narlawar et al 2006;Peretto et al 2005;Imbimbo et al 2007aImbimbo et al ,b, 2009. Drugs were identified, such as fenofibrate and celecoxib, which showed an opposite effect on the Ab 1-42 /Ab 1-38 peptide fragment ratio (for ease of reference we term these agents SARAs).…”

Section: Discussionmentioning

confidence: 99%

Selective modulation of amyloid‐β peptide degradation by flurbiprofen, fenofibrate, and related compounds regulates Aβ levels

Abdul-Hay

Edirisinghe

Thatcher

2009

Journal of Neurochemistry

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Gamma‐secretase modulators (GSMs) include selected non‐steroidal anti‐inflammatory drugs such as flurbiprofen that selectively lowers the neurotoxic amyloid‐β peptide Aβ1–42. GSMs are attractive targets for Alzheimer’s disease, in contrast to ‘inverse GSMs,’ such as fenofibrate, which selectively increase the level of Aβ1–42. A methodology for screening of Aβ modulating drugs was developed utilizing an Aβ‐producing neuroblastoma cell line stably transfected with mutant human amyloid precursor protein, immunoprecipitation of Aβ peptides, and mass spectroscopic quantitation of Aβ1–37/Aβ1–38/Aβ1–40/Aβ1–42 using an Aβ internal standard. The unexpected conclusion of this work was that in this system, drug effects are independent of γ‐secretase. The methodology recapitulated reported results for modulation of Aβ by GSMs. However, control experiments in which exogenous Aβ1–40/Aβ1–42 was added (i) to drug‐treated wild‐type cells or (ii) to conditioned media from these wild‐type cells, gave comparable patterns of Aβ modulation. These results, suggesting that drugs modulate the ability of cell‐derived factors to degrade Aβ, was interrogated by adding protease inhibitors and performing molecular weight cut‐off fractionation. The results confirmed that modulation of Aβ1–40/Aβ1–42 was mediated by selective proteolysis. Treatment of N2a cells with flurbiprofen or fenofibric acid selectively enhanced Aβ1–42 clearance by extracellular proteolysis; treatment with HCT‐1026 or fenofibrate (esters of flurbiprofen and fenobric acid) inhibited clearance of Aβ1–40 and Aβ1–42.

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Section: Discussionmentioning

confidence: 99%

Selective modulation of amyloid‐β peptide degradation by flurbiprofen, fenofibrate, and related compounds regulates Aβ levels

Abdul-Hay

Edirisinghe

Thatcher

2009

Journal of Neurochemistry

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“…1) proved to be of major interest. In human neuroglioma cells (H4swe), CHF5074 preferentially lowers A␤42 secretion, with an IC 50 of 40 M (Imbimbo et al, 2007). CHF5074 does not display inhibitory activity on COX-1 and COX-2 enzymes when used at concentrations up to 100 and 300 M, respectively (Imbimbo et al, 2007).…”

mentioning

confidence: 99%

“…In human neuroglioma cells (H4swe), CHF5074 preferentially lowers A␤42 secretion, with an IC 50 of 40 M (Imbimbo et al, 2007). CHF5074 does not display inhibitory activity on COX-1 and COX-2 enzymes when used at concentrations up to 100 and 300 M, respectively (Imbimbo et al, 2007). At 100 M, CHF5074 does not alter the expression profile of several Notch intracellular domain-responsive genes (Imbimbo et al, 2007).…”

mentioning

confidence: 99%

“…CHF5074 does not display inhibitory activity on COX-1 and COX-2 enzymes when used at concentrations up to 100 and 300 M, respectively (Imbimbo et al, 2007). At 100 M, CHF5074 does not alter the expression profile of several Notch intracellular domain-responsive genes (Imbimbo et al, 2007). In rats, CHF5074 is orally well absorbed (50%), and it is slowly eliminated from plasma (t 1/2 ϭ 20.7 h) (Peretto et al, 2005).…”

mentioning

confidence: 99%

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1-(3′,4′-Dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic Acid (CHF5074), a Novel γ-Secretase Modulator, Reduces Brain β-Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease without Causing Peripheral Toxicity

Imbimbo¹,

Giudice²,

Colavito³

et al. 2007

J Pharmacol Exp Ther

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“…Chemically, CHF5074 is a nonsteroidal antiinflammatory drugs (NSAID) derivative but it is devoid of inhibitory activity on cyclooxygenase up to 300 lM concentrations (Imbimbo et al, 2007b). We then investigate whether CHF5074 modulatory effects on microglia transcription were reproduced by NSAIDs, the cyclooxygenase inhibitor ibuprofen, or the NSAID derivative R-flurbiprofen devoid of cyclooxygenase inhibitory activity.…”

Section: Chf5074 Reduces Pro-inflammatory Transcription and Increasesmentioning

confidence: 99%

CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 mice and primary glial cultures exposed to beta-amyloid

et al. 2015

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Abstract-Activation of microglia associated with neuroinflammation and loss of phagocytic activity is considered to play a prominent role in the pathogenesis of Alzheimer's disease (AD). CHF5074 (CSP-1103) has been shown to improve cognition and reduce brain inflammation in patients with mild cognitive impairment (MCI). CHF5074 was also found to reverse impairments in recognition memory and improve hippocampal long-term potentiation when administered to plaque-free Tg2576 mice (5-month-old) for 4 weeks. Though, no investigation has focused on the consequence of CHF5074 treatment on microglia polarization yet. In this study we evaluated the effect of CHF5074 administration (375 ppm in the diet) to 5-month-old Tg2576 mice on the expression of pro-inflammatory (M1) genes, Interleukin 1 beta (IL-1b), Tumor Necrosis Factor alpha (TNFa) and inducible Nitric Oxide Synthase (iNOS), and anti-inflammatory/ phagocytic (M2) markers Mannose Receptor type C 1 (MRC1/CD206), Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Chitinase 3-like 3 (Ym1). No changes of pro-inflammatory gene transcription but a reduced expression of MRC1/CD206, TREM2 and Ym1 were detected in the hippocampus of young Tg2576 mice receiving normal diet, when compared to wild-type littermates. CHF5074 did not affect the pro-inflammatory transcription but significantly increased the expression of MRC1/CD206 and Ym1. CHF5074 effects appeared to be hippocampus-specific, as the M2 transcripts were only slightly modified in the cerebral cortex. In primary cultures of mouse astrocyte-microglia, CHF5074 totally suppressed the expression of TNF-a, IL-1b and iNOS induced by 10 lM b-amyloid 1-42 (Ab 42 ). Moreover, CHF5074 significantly increased the expression of antiinflammatory/phagocytic markers MRC1/CD206 and TREM2, reduced by the Ab 42 application alone. The effect of CHF5074 was not reproduced by ibuprofen (3 lM or 500 lM) or R-flurbiprofen (3 lM or 100 lM), as both compounds limited the pro-inflammatory gene expression but did not modify the anti-inflammatory/phagocytic transcription. These data show that CHF5074 specifically drives the expression of microglia M2 markers either in young Tg2576 hippocampus or in primary astrocyte-microglia cultures, suggesting its potential therapeutic efficacy as microglial modulator in the early phase of AD.

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In vitro and in vivo profiling of CHF5022 and CHF5074

Cited by 41 publications

References 34 publications

Selective modulation of amyloid‐β peptide degradation by flurbiprofen, fenofibrate, and related compounds regulates Aβ levels

Selective modulation of amyloid‐β peptide degradation by flurbiprofen, fenofibrate, and related compounds regulates Aβ levels

1-(3′,4′-Dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic Acid (CHF5074), a Novel γ-Secretase Modulator, Reduces Brain β-Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease without Causing Peripheral Toxicity

CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 mice and primary glial cultures exposed to beta-amyloid

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