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1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a novel gamma-secretase modulator, reduces brain beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease without causing peripheral toxicity.
J Pharmacol Exp Ther. 2007 Dec; 323(3):822-30.JP

Abstract

Some nonsteroidal anti-inflammatory drugs has been shown to allosterically modulate the activity of gamma-secretase, the enzymatic complex responsible for the formation of beta-amyloid (Abeta). 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074) is a new gamma-secretase modulator, devoid of anticyclooxygenase (COX) and Notch-interfering activities in vitro. We evaluated the effects of chronic CHF5074 treatment on brain Abeta pathology in Tg2576 transgenic mice. Twenty-eight animals of 9.5 to 10.5 months of age received CHF5074-medicated diet (375 ppm) or standard diet for 17 weeks. Compared with controls, CHF5074 treatment significantly reduced the area occupied by plaques and the number of plaques in cortex (-52.2 +/- 5.6%, p = 0.0003 and -48.9 +/- 6.6%, p = 0.0004, respectively) and hippocampus (-76.7 +/- 6.4%, p = 0.004 and -66.2 +/- 10.3%, p = 0.037, respectively). Biochemical analysis confirmed the histopathological measures, with CHF5074-treated animals showing reduced total brain Abeta40 (-49.2 +/- 9.2%, p = 0.017) and Abeta42 (-43.5 +/- 9.7%, p = 0.027) levels. In a human neuroglioma cell line expressing Swedish mutated form of amyloid precursor protein (H4swe), CHF5074 reduced Abeta42 and Abeta40 secretion, with an IC50 of 3.6 and 18.4 microM, respectively, values consistent with those measured in the brain of the CHF5074-treated Tg2576 mice (6.4 +/- 0.4 microM). At 5 microM, no effects were observed on Notch intracellular cleavage in human embryonic kidney 293swe cells. CHF5074 was well tolerated by Tg2576 mice. No abnormal findings were observed upon histopathological examination of the gastrointestinal tract, indicating the absence of COX-related toxicity. Semiquantitative histochemical evaluation of goblet cells in the ileum of vehicle- and CHF5074-treated animals yielded similar results, suggesting no effects on Notch pathway. CHF5074 is therefore a promising therapeutic agent for Alzheimer's disease.

Authors+Show Affiliations

Research & Development, Chiesi Farmaceutici, via Palermo 26/A, 43100 Parma, Italy. b.imbimbo@chiesigroup.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17895400

Citation

Imbimbo, Bruno P., et al. "1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic Acid (CHF5074), a Novel Gamma-secretase Modulator, Reduces Brain Beta-amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease Without Causing Peripheral Toxicity." The Journal of Pharmacology and Experimental Therapeutics, vol. 323, no. 3, 2007, pp. 822-30.
Imbimbo BP, Del Giudice E, Colavito D, et al. 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a novel gamma-secretase modulator, reduces brain beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease without causing peripheral toxicity. J Pharmacol Exp Ther. 2007;323(3):822-30.
Imbimbo, B. P., Del Giudice, E., Colavito, D., D'Arrigo, A., Dalle Carbonare, M., Villetti, G., Facchinetti, F., Volta, R., Pietrini, V., Baroc, M. F., Serneels, L., De Strooper, B., & Leon, A. (2007). 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a novel gamma-secretase modulator, reduces brain beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease without causing peripheral toxicity. The Journal of Pharmacology and Experimental Therapeutics, 323(3), 822-30.
Imbimbo BP, et al. 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic Acid (CHF5074), a Novel Gamma-secretase Modulator, Reduces Brain Beta-amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease Without Causing Peripheral Toxicity. J Pharmacol Exp Ther. 2007;323(3):822-30. PubMed PMID: 17895400.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a novel gamma-secretase modulator, reduces brain beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease without causing peripheral toxicity. AU - Imbimbo,Bruno P, AU - Del Giudice,Elda, AU - Colavito,Davide, AU - D'Arrigo,Antonello, AU - Dalle Carbonare,Maurizio, AU - Villetti,Gino, AU - Facchinetti,Fabrizio, AU - Volta,Roberta, AU - Pietrini,Vladimiro, AU - Baroc,Maria F, AU - Serneels,Lutgarde, AU - De Strooper,Bart, AU - Leon,Alberta, Y1 - 2007/09/25/ PY - 2007/9/27/pubmed PY - 2007/12/18/medline PY - 2007/9/27/entrez SP - 822 EP - 30 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 323 IS - 3 N2 - Some nonsteroidal anti-inflammatory drugs has been shown to allosterically modulate the activity of gamma-secretase, the enzymatic complex responsible for the formation of beta-amyloid (Abeta). 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074) is a new gamma-secretase modulator, devoid of anticyclooxygenase (COX) and Notch-interfering activities in vitro. We evaluated the effects of chronic CHF5074 treatment on brain Abeta pathology in Tg2576 transgenic mice. Twenty-eight animals of 9.5 to 10.5 months of age received CHF5074-medicated diet (375 ppm) or standard diet for 17 weeks. Compared with controls, CHF5074 treatment significantly reduced the area occupied by plaques and the number of plaques in cortex (-52.2 +/- 5.6%, p = 0.0003 and -48.9 +/- 6.6%, p = 0.0004, respectively) and hippocampus (-76.7 +/- 6.4%, p = 0.004 and -66.2 +/- 10.3%, p = 0.037, respectively). Biochemical analysis confirmed the histopathological measures, with CHF5074-treated animals showing reduced total brain Abeta40 (-49.2 +/- 9.2%, p = 0.017) and Abeta42 (-43.5 +/- 9.7%, p = 0.027) levels. In a human neuroglioma cell line expressing Swedish mutated form of amyloid precursor protein (H4swe), CHF5074 reduced Abeta42 and Abeta40 secretion, with an IC50 of 3.6 and 18.4 microM, respectively, values consistent with those measured in the brain of the CHF5074-treated Tg2576 mice (6.4 +/- 0.4 microM). At 5 microM, no effects were observed on Notch intracellular cleavage in human embryonic kidney 293swe cells. CHF5074 was well tolerated by Tg2576 mice. No abnormal findings were observed upon histopathological examination of the gastrointestinal tract, indicating the absence of COX-related toxicity. Semiquantitative histochemical evaluation of goblet cells in the ileum of vehicle- and CHF5074-treated animals yielded similar results, suggesting no effects on Notch pathway. CHF5074 is therefore a promising therapeutic agent for Alzheimer's disease. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/17895400/1__3'4'_Dichloro_2_fluoro[11'_biphenyl]_4_yl__cyclopropanecarboxylic_acid__CHF5074__a_novel_gamma_secretase_modulator_reduces_brain_beta_amyloid_pathology_in_a_transgenic_mouse_model_of_Alzheimer's_disease_without_causing_peripheral_toxicity_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17895400 DB - PRIME DP - Unbound Medicine ER -