The Therapeutic Potential of GammaSecretase Modulators in Treating Alzheimers Disease


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1 : The Therapeutic Potential of g-Secretase Modulatorsin Treating Alzheimer’s Disease Bruno P. Imbimbo Research & Development Chiesi Farmaceutici Parma
2 : Amyloid precursor protein processingand b-amyloid accumulation Gandy. J Clin Invest 2005; 115: 1121-9
3 : ?-Secretase is a multi-protein complex Wolfe. Curr Top Med Chem 2008; 8: 2-8
4 : Presenilin is a nine-transmembrane domain protein
5 : Proposed mechanism of action of g-secretase inhibitors (DAPT) Morohashi et al, J Biol Chem 2006; 281: 14670-6 allosteric site catalytic site APP Asp DAPT
6 : The g-secretase inhibitor LY-450139 lowers Ab40 in the brain, CSF and plasma of guinea pigs Lanz et al, J Pharmacol Exp Ther 2006; 319: 924-33 Lanz et al, Ph Exp
7 : The g-secretase inhibitor DAPT improves contextual fear conditioning in Tg2576 mice Comery et al, J Neurosci 2005; 25: 8898-902
8 : ?-Secretase cleaves many other substrates other than APP Lleo Curr Top Med Chem 2008 (in press)
9 : g-Secretase inhibitors may cause thymus atrophy and intestinal goblet cell hyperplasia Hyde et al, J Pharmacol Exp Ther 2006; 319: 1133-43 LY-411575
10 : The g-secretase inhibitor LY-450139 lowers Ab40 in plasma of Alzheimer patients Siemers et al, Neurology 2006; 66: 602-4 thymus atrophy ? intestinal goblet cell hyperplasia?
11 : NSAIDs use and risk of Alzheimer’s disease Several case-control or population-based studies indicate that NSAIDs use is associated to reduced risk (- 30-40%) of developing AD. The protective effect of NSAIDs is greater in long-term users (relative risk = 0.27 for > 2 years) (Etminan et al, 2003). The protective effect of NSAIDs appears to be only in subjects with an APO e4 allele (hazard ratio = 0.34 for subjects with one or more e4 alleles (Szekely et al, 2008).
12 : Certain NSAIDs selectively lower A?42 secretion Weggen et al, Nature 2001; 414: 212-6
13 : Sulindac sulphide lowers Ab42and simultaneously increases Ab38 Weggen et al, Nature 2001; 414: 212-6
14 : Sulindac sulphide lowers A?42 independentlyfrom its anti-Cox activity Weggen et al, Nature 2001; 414: 212-6
15 : Sulindac sulphide is a non-competitive inhibitorof ?-secretase Takahashi et al, J Biol Chem 2003; 278: 18664-70 50 µM 75 µM 100 µM 25 µM 0 µM 100 µM
16 : Eriksen et al, J Clin Invest 2003; 112: 440-9 Effects of NSAIDs on Aß42 production in human neuroglioma cells
17 : Main A?42 lowering NSAIDs Flurbiprofen Fenoprofen Meclofenamic acid Sulindac sulfide Indomethacin Ibuprofen Diclofenac
18 : Molecular mechanism with which certain NSAIDs may allosterically modulate g-secretase Weggen Web Site Beher and Graham, Exp Opin Inv Drugs 2005; 14: 1385-1409
19 : Chemical moieties involved in A?42 modulation Peretto et al, J Med Chem 2005; 48: 5705-20. Ab40 Ab42
20 : In vivo studies showing A? lowering activityof certain NSAIDs
21 : In vivo studies showing behavioral effectsof certain NSAIDs
22 : R-flurbiprofen attenuates b-amyloid plaque deposition in Tg2576 mice Kukar et al, BMC Neurosci 2007; 8: 54-66
23 : R-flurbiprofen improves spatial learning ability in Tg2576 mice Kukar et al, BMC Neurosci 2007; 8: 54-66
24 : R-flurbiprofen (800 mg bid) delays functional decline of mild AD patients p = 0.059 R-Flurbiprofen (n = 48) Placebo (n = 46) 2 0 -2 -4 -6 -8 -10 -12 0 1 2 3 4 5 6 7 8 9 10 11 12 ADCS-ADL (change from baseline) Month 45% reduction Wilcock et al, 2005 Neuroscience Meeting
25 : 62% reduction p = 0.025 plasma concentrations > 307 mM (n = 29) plasma concentrations = 0 (n = 46) 2 0 -2 -4 -6 -8 -10 -12 0 1 2 3 4 5 6 7 8 9 10 11 12 ADCS-AD (change from baseline) Month The effects of R-flurbiprofen in mild AD patients correlate with drug plasma levels Wilcock et al, 2005 Neuroscience Meeting
26 : CHF5074 inhibits Ab42 secretion in human neuroglioma cells expressing hAPPswe Imbimbo et al, J Pharm Exp Ther 2007; 323: 822-30 Ab42 Ab40
27 : MALDI/TOF analysis of A? species in medium of H4-hAPPswe cells treated with CHF5074 0 10 20 30 40 50 42 40 39 38 37 36 34 33 32 29 28 27 24 21 18 17 14 DMSO DAPT (1 ?M) Flurbiprofen (250 ?M) CHF5074 (50 µM) CHF5074 (100 µM) Absolute abundance (%) A? species 0.0 0.5 1.0 1.5 2.0 2.5 DMSO DAPT 1 ?M Flurbiprofen 250 ?M CHF5074 50 ?M CHF5074 100 ?M A?42 Peretto et al, J Med Chem 2005; 48: 5705-20
28 : CHF5074 does not inhibit COX activityat Ab-relevant concentrations Imbimbo et al, Pharmacol Res 2007; 55: 318-28
29 : CHF5074 does not inhibit Notch cleavagein Notch?E-transfected HEK293 cells at non-cytotoxic concentrations Imbimbo et al, J Pharm Exp Ther 2007; 323: 822-30
30 : Oral CHF5074 (1 mg/kg) produces highand sustained drug plasma levels in rats Peretto et al, J Med Chem 2005; 48: 5705-20
31 : Short-term administration of CHF5074 dose-dependently reduces plasma Ab42 in Tg2576 mice Imbimbo et al, Pharmacol Res 2007; 55: 318-28
32 : Vehicle CHF5074 ** p < 0.01 * p < 0.05 Plaque Area Fraction Number of Plaques Mean Plaque Area CHF5074 attenuates b-amyloid burden in the hippocampus of Tg2576 mice Imbimbo et al, J Pharm Exp Ther 2007; 323: 822-30
33 : Plasma and brain CHF5074 concentrations are higher than IC50 on Ab42 secretion Ab42 IC50 Imbimbo et al, J Pharm Exp Ther 2007; 323: 822-30
34 : Mouse # 63 Mouse # 45 Globet cells Globet cells CHF5074 treatment does not affect globet cells in ileum tissues of Tg2576 mice Vehicle CHF5074 Imbimbo et al, J Pharm Exp Ther 2007; 323: 822-30
35 : Other g-secretase modulators Eisai IC50 = 56 nM Neurogenetics IC50 < 200 nM Hoffmann-La Roche (IC50 = 2.9 mM) Merck Sharpe & Dohme IC50 = ? Merck Sharp & Dohme IC50 = ? Cellzome IC50 < 1 mM Peretto et al, Curr Top Med Chem 2008; 8: 38-46
36 : Most promising g-secretase modulators Merck Sharp & Dohme WO 2007110667 Merck Sharp & Dohme WO 2007116228 Merck Sharp & Dohme GSM-1
37 : Most recent g-secretase modulators Eisai WO 2007135970 Eisai WO 2007135969
38 : Effects of GSM-1 on brain Ab in APP-Swe mice Page et al, J Biol Chem 2008; 283: 677-83
39 : Conclusions (1) Selected NSAIDs have been found to allosterically modulate g-secretase by binding at a site of presenilin different from that of the prototypical inhibitors. The allosteric modulation of g-secretase leads to a selective decrease in Ab42, the most toxic form of A? and a parallel increase in Ab38, the pharmacological consequences of which are unclear. Differently from traditional g-secretase inhibitors, these Ab42-lowering NSAIDs do not to interfere with the endoproteolysis of Notch. Long-term histopathological are available with these NSAIDs (mainly ibuprofen) but it is unclear if the observed in vivo effects on Ab brain pathology depend on their activity on g-secretase or on other biological targets.
40 : Conclusions (2) Limited behavioral studies are available with these of Ab-lowering NSAIDs. R-flurbiprofen belongs to this class of g-secretase modulators and is in an advanced stage of clinical development. Results of a first Phase 3 study will be available in late 2008. New potent, Notch-sparing g-secretase modulators have been recently described in patent literature an in a few congresses. Their in vivo activity is not fully described. In conclusion, g-secretase modulators are promising therapeutic agents and may efficiently test the b-amyloid hypothesis of AD.
41 : Acknowledgments and many thanks … Chiesi Farmaceutici Research & Innovation Gino Villetti Elda Del Giudice Fabrizio Facchinetti Flavia Miccichè Paola Puccini Davide Colavito Benedetta Riccardi Antonello D’Arrigo Marcello Biscaioli Maurizio Dalle Carbonare Roberta Volta Alberta Leon Valentina Cenacchi NiKem Research University of Parma Ilaria Peretto Maria Francesca Baroc Luca Raveglia Vladimiro Pietrini Giuseppe Giardina Nadia Moretto Simone Ottonello University of Leuven Bart De Strooper Lutgarde Seernels

 

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