Molecule of the Month

Author(s): Craig W. Lindsley.

Journal Name: Current Topics in Medicinal Chemistry

Volume 8 , Issue 2 , 2008

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Abstract:

CHF5074 - A novel NSAID-derived γ-secretase modulator that reduces brain β-amyloid pathology without peripheral toxicity. Some nonsteroidal ant-inflamatory drugs (NSAIDs) have been shown to decrease Aβ42 production, and upon long-term use, may delay or prevent the onset of Alzheimers disease (AD) in both transgenic mice and humans [1-3]. The mechanism proposed to account for this effect on Aβ42 is allosteric modulation of presenilin- 1, the major component of the γ-secretase complex responsible for the formation of Aβ [4,5]. Importantly, the inhibition of Aβ42 is independent of the anti-COX activity, and the γ-secretase modulator activity depends on the NSAID chemotype, with some NSAIDs (ibuprofen, indomethacin, flurbiprofen and sulindac) displaying activity and other not (naproxen, aspirin and celecoxib)[1,4,6]. Moreover, the Aβ42-lowering effects of NSAIDs differ from classical γ-secretase inhibitors as they do not inhibit γ-secretasemediate cleavage of APP at the η site or Notch-1; however, the application of NSAIDs for the treatment of AD has been hindered by the gastrointestinal toxicity of COX inhibition [1,7]. A recent manuscript from Imbimido, et.al. (J. Pharm Exp. Ther. 2007, 323, 822-830) presented the first demonstration that chronic administration of an NSAID-derived γ-secretase modulator (CHF 5074), devoid of both anticyclooxygenase (COX) and Notch-inter-fering activities, can significantly reduce the deposition of Aβ in the brain [8]. CHF5074 in human neuroglioma cells preferentially lowers Aβ42 (IC50 = 40 μM) without effect on COX-1 or COX-2 enzymes up to 300 μM, and also had no effect on the expression profile of several Notch intracellular domain-responsive genes when dosed at 100 μM. In addition, CHF5074 possessed good oral bioavailability in rats (%F = 50) and a long half-life (t1/2 = 20.7 h). In the study, aged Tg2576 mice were chronically dosed with CHF5074 (in diet 61 mg/kg/day) for 4 months, a well tolerated and safe dose [8]. Compared with controls, the area occupied by plaques and the number of plaques in cortex (-52% and -48%, respectively) and hippocampus (- 76% and -66%, respectively) were significantly reduced in CHF5074 treated animals. Furthermore, biochemical analysis demonstrated that CHF5074-tretaed animals displayed reduced total brain Aβ40 (-49%) and Aβ42 (-43%) levels. In a human neuroglioma cell line expressing the Swedish mutated form of APP (H4swe), CHF5074 reduced Aβ40 and Aβ42 secretion with IC50 values of 3.6 μM and 18.4 μM, respectively [8]. Histopathological examination of the GItract of the chronically treated Tg2567 mice produced no abnormal findings, further indicating the lack of COXrelated toxicity [8]. Based on these data, CHF5074 represents a promising new lead for the development of a potential therapeutic agent for the treatment of Alzheimers disease. REFERENCES [1] Weggen, S.; Eriksein, J.L.; Das, P.; Sagi, S.A.; Wang, R.; Pietrzik, C.U.; Findlay, K.A.; Smith, T.E.; Murphy, M.P.; Butler, T. Nature 2001, 414, 212-216. [2] Lim, G.P.; Yang, F.; Chu, T.; Chen, P.; Beech, W.; Teter, B.; Tran, T.; Ubeda, O.; Ashe, K.H.; Frautschy, S.A.; Cole, G.M. Neurobiol. Aging 2001, 22, 983-991. [3] Wilcock, D.M.; Jantzen, P.T.; Li, Q.; Morgan, D.; Gordon, M.N. Neuroscience 2007, 144, 9

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Article Details

VOLUME: 8
ISSUE: 2
Year: 2008
Page: [171 - 171]
Pages: 1
DOI: 10.2174/156802608783378819
Price: $58

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