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Maria Francesca Baroc - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Bruno P. Imbimbo, Elda Del Giudice, Davide Colavito, Maurizio Dalle Carbonare, Gino Villetti, Fabrizio Facchinetti, Roberta Volta, Vladimiro Pietrini, Antonello Darrigo, Maria Francesca BarocAbstract:Some nonsteroidal anti-inflammatory drugs has been shown to allosterically modulate the activity of γ-secretase, the enzymatic complex responsible for the formation of β-amyloid (Aβ). 1-(3′,4′-Dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-Cyclopropanecarboxylic Acid (CHF5074) is a new γ-secretase modulator, devoid of anticyclooxygenase (COX) and Notch-interfering activities in vitro. We evaluated the effects of chronic CHF5074 treatment on brain Aβ 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 Aβ40 (–49.2 ± 9.2%, p = 0.017) and Aβ42 (–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 Aβ42 and Aβ40 secretion, with an IC50 of 3.6 and 18.4 μM, respectively, values consistent with those measured in the brain of the CHF5074-treated Tg2576 mice (6.4 ± 0.4 μM). At 5 μM, 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.
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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
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Bruno P. Imbimbo, Elda Del Giudice, Davide Colavito, Antonello D’arrigo, Maurizio Dalle Carbonare, Gino Villetti, Fabrizio Facchinetti, Roberta Volta, Vladimiro Pietrini, Maria Francesca BarocAbstract:Some nonsteroidal anti-inflammatory drugs has been shown to allosterically modulate the activity of γ-secretase, the enzymatic complex responsible for the formation of β-amyloid (Aβ). 1-(3′,4′-Dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-Cyclopropanecarboxylic Acid (CHF5074) is a new γ-secretase modulator, devoid of anticyclooxygenase (COX) and Notch-interfering activities in vitro. We evaluated the effects of chronic CHF5074 treatment on brain Aβ 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 Aβ40 (–49.2 ± 9.2%, p = 0.017) and Aβ42 (–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 Aβ42 and Aβ40 secretion, with an IC50 of 3.6 and 18.4 μM, respectively, values consistent with those measured in the brain of the CHF5074-treated Tg2576 mice (6.4 ± 0.4 μM). At 5 μM, 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.
Bruno P. Imbimbo - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Bruno P. Imbimbo, Elda Del Giudice, Davide Colavito, Maurizio Dalle Carbonare, Gino Villetti, Fabrizio Facchinetti, Roberta Volta, Vladimiro Pietrini, Antonello Darrigo, Maria Francesca BarocAbstract:Some nonsteroidal anti-inflammatory drugs has been shown to allosterically modulate the activity of γ-secretase, the enzymatic complex responsible for the formation of β-amyloid (Aβ). 1-(3′,4′-Dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-Cyclopropanecarboxylic Acid (CHF5074) is a new γ-secretase modulator, devoid of anticyclooxygenase (COX) and Notch-interfering activities in vitro. We evaluated the effects of chronic CHF5074 treatment on brain Aβ 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 Aβ40 (–49.2 ± 9.2%, p = 0.017) and Aβ42 (–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 Aβ42 and Aβ40 secretion, with an IC50 of 3.6 and 18.4 μM, respectively, values consistent with those measured in the brain of the CHF5074-treated Tg2576 mice (6.4 ± 0.4 μM). At 5 μM, 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.
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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
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Bruno P. Imbimbo, Elda Del Giudice, Davide Colavito, Antonello D’arrigo, Maurizio Dalle Carbonare, Gino Villetti, Fabrizio Facchinetti, Roberta Volta, Vladimiro Pietrini, Maria Francesca BarocAbstract:Some nonsteroidal anti-inflammatory drugs has been shown to allosterically modulate the activity of γ-secretase, the enzymatic complex responsible for the formation of β-amyloid (Aβ). 1-(3′,4′-Dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-Cyclopropanecarboxylic Acid (CHF5074) is a new γ-secretase modulator, devoid of anticyclooxygenase (COX) and Notch-interfering activities in vitro. We evaluated the effects of chronic CHF5074 treatment on brain Aβ 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 Aβ40 (–49.2 ± 9.2%, p = 0.017) and Aβ42 (–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 Aβ42 and Aβ40 secretion, with an IC50 of 3.6 and 18.4 μM, respectively, values consistent with those measured in the brain of the CHF5074-treated Tg2576 mice (6.4 ± 0.4 μM). At 5 μM, 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.
Stephen G Kukolich - One of the best experts on this subject based on the ideXlab platform.
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microwave spectrum for a second higher energy conformer of Cyclopropanecarboxylic Acid and determination of the gas phase structure of the ground state
Journal of Physical Chemistry A, 2015Co-Authors: Aaron M Pejlovas, Stephen G KukolichAbstract:: Microwave spectra for a higher-energy conformer of Cyclopropanecarboxylic Acid (CPCA) were measured using a Flygare-Balle-type pulsed-beam Fourier transform microwave spectrometer. The rotational constants (in megahertz) and centrifugal distortion constants (in kilohertz) for this higher-energy conformer are A = 7452.3132(57), B = 2789.8602(43), C = 2415.0725(40), DJ = 0.29(53), and DJK = 2.5(12). Differences between rotational constants for this excited-state conformation and the ground state are primarily due to the Acidic OH bond moving from a position cis relative to the cyclopropyl group about the C1-C9 bond to the more stable trans conformation. Calculations indicate that the relative abundance of the higher-energy state should be 15% to 17% at room temperature, but the observed relative abundance for the supersonic expansion conditions is about 1%. The measurements of rotational transitions for the trans form of CPCA were extended to include all of the unique (13)C singly substituted positions. These measurements, along with previously measured transitions of the parent and -OD isotopologues, were used to determine a best-fit gas-phase structure.
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microwave spectra and structure of the Cyclopropanecarboxylic Acid formic Acid dimer
Journal of Chemical Physics, 2015Co-Authors: Aaron M Pejlovas, Stephen G KukolichAbstract:The rotational spectrum of the Cyclopropanecarboxylic Acid–formic Acid doubly hydrogen bonded dimer has been measured in the 4-11 GHz region using a Flygare-Balle type pulsed-beam Fourier transform microwave spectrometer. Rotational transitions were measured for the parent, four unique singly substituted 13C isotopologues, and a singly deuterated isotopologue. Splittings due to a possible concerted double proton tunneling motion were not observed. Rotational constants (A, B, and C) and centrifugal distortion constants (DJ and DJK) were determined from the measured transitions for the dimer. The values of the rotational (in MHz) and centrifugal distortion constants (in kHz) for the parent isotopologue are A = 4045.4193(16), B = 740.583 80(14), C = 658.567 60(23), DJ = 0.0499(16), and DJK = 0.108(14). A partial gas phase structure of the dimer was derived from the rotational constants of the measured isotopologues, previous structural work on each monomer units and results of the calculations.
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microwave measurements of Cyclopropanecarboxylic Acid and od isotopologue
Journal of Molecular Spectroscopy, 2015Co-Authors: Aaron M Pejlovas, Kexin Li, Stephen G KukolichAbstract:Abstract The microwave spectrum of Cyclopropanecarboxylic Acid has been measured in the 5–15 GHz region using a Flygare–Balle type, pulsed-beam Fourier-transform microwave spectrometer. These lower-frequency measurements are at a much higher resolution then the previous waveguide studies. The experimental rotational constants obtained in this study were A = 7625.0432(17) MHz, B = 2724.7672(8) MHz, and C = 2382.0755(5) MHz. The centrifugal distortion constants determined were Δ J = 0.4010(25) kHz, Δ JK = 3.04(17) kHz, Δ J = 0.0434(72) kHz, and Δ K = −11.32(24) kHz.
Yonghua Yang - One of the best experts on this subject based on the ideXlab platform.
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halogen effects in robinson gabriel type reaction of Cyclopropanecarboxylic Acid n substituted hydrazides with pph3 cx4
Tetrahedron Letters, 2005Co-Authors: Yonghua YangAbstract:We found that the reaction of Cyclopropanecarboxylic Acid N'- substituted -hydrazides with PPh3/CCl4 proceeded smoothly to give the corresponding normal Robinson-Gabriel type product 2-cyclopropyl-5-substituted-[1,3,4]-oxadiazoles in good yields. Using CBr4 or CI4 instead Of CCl4 in the above system, the ring opening of cyclopropane occurred after dehydration to give the corresponding 2-(3 -halopropyl) -5-substituted-[ 1, 3,4]-oxadiazoles (4 or 5) in good yields. (c) 2005 Elsevier Ltd. All rights reserved.
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Halogen effects in Robinson–Gabriel type reaction of Cyclopropanecarboxylic Acid N′-substituted-hydrazides with PPh3/CX4
Tetrahedron Letters, 2005Co-Authors: Yonghua YangAbstract:We found that the reaction of Cyclopropanecarboxylic Acid N'- substituted -hydrazides with PPh3/CCl4 proceeded smoothly to give the corresponding normal Robinson-Gabriel type product 2-cyclopropyl-5-substituted-[1,3,4]-oxadiazoles in good yields. Using CBr4 or CI4 instead Of CCl4 in the above system, the ring opening of cyclopropane occurred after dehydration to give the corresponding 2-(3 -halopropyl) -5-substituted-[ 1, 3,4]-oxadiazoles (4 or 5) in good yields. (c) 2005 Elsevier Ltd. All rights reserved.
Norbert De Kimpe - One of the best experts on this subject based on the ideXlab platform.
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stereoselective synthesis of both enantiomers of trans 2 diphenylmethylideneamino Cyclopropanecarboxylic Acid using a chiral pool approach and their incorporation in dipeptides
Tetrahedron, 2012Co-Authors: Tamara Meiresonne, Sven Mangelinckx, Norbert De KimpeAbstract:The stereoselective synthesis of (1R,2R)- and (1S,2S)-trans-2-(diphenylmethylideneamino)Cyclopropanecarboxylic Acid has been accomplished in six steps starting from (2S)- and (2R)-β-benzyl N-(tert-butoxycarbonyl)aspartate, respectively. The key-step in the reaction sequence is a stereoselective base-induced ring closure with a good trans diastereoselectivity. These novel trans-β-ACC derivatives could be incorporated in dipeptides employing a standard peptide coupling technique.
