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NEUROPHARMACOLOGY

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

Research & Development, Chiesi Farmaceutici, Parma, Italy (B.P.I., G.V., F.F., R.V.); Research & Innovation, Padova, Italy (E.D.G., D.C., A.D., M.D.C., A.L.); Department of Neurosciences, Neurology Section, University of Parma, Parma, Italy (V.P., M.F.B.); and Department for Molecular and Developmental Genetics, Vlaams Instituut voor Biotechnologie and Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium (L.S., B.D.S.)

Some nonsteroidal anti-inflammatory drugs has been shown to allosterically modulate the activity of -secretase, the enzymatic complex responsible for the formation of -amyloid (A). 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074) is a new -secretase modulator, devoid of anticyclooxygenase (COX) and Notch-interfering activities in vitro. We evaluated the effects of chronic CHF5074 treatment on brain A 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 A40 (–49.2 ± 9.2%, p = 0.017) and A42 (–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 A42 and A40 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.

Address correspondence to: Dr. Bruno P. Imbimbo, Research & Development, Chiesi Farmaceutici, via Palermo 26/A, 43100 Parma, Italy. E-mail: b.imbimbo{at}chiesigroup.com

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