Ex vivo occupancy of γ-secretase inhibitors correlates with brain β-amyloid peptide reduction in Tg2576 mice

Journal of Pharmacology and Experimental Therapeutics

Volumn 323, Issue 1, 2007, Pages 102-108

  Goldstein, Margi E ^a   Cao, Yang ^a   Fiedler, Tracey ^a   Toyn, Jeremy ^a   Iben, Lawrence ^a   Barten, Donna M ^a   Pierdomenico, Maria ^a   Corsa, Jason ^a   Prasad, C V C ^a   Olson, Richard E ^a   Li, Yu Wen ^a   Zaczek, Robert ^a   Albright, Charles F ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 [1 [[(4 CHLOROPHENYL)SULFONYL](2,5 DIFLUOROPHENYL)AMINO]ETHYL] 5 FLUOROBENZENEPROPANOIC ACID; 2 [2 (3,5 DIFLUOROPHENYL) 2 HYDROXYACETAMIDO] N (3 METHYL 4 OXO 4,5 DIHYDRO 3H BENZO[D][1,2]DIAZEPIN 5 YL)PROPANAMIDE; 2 ISOBUTYL N1 (1 METHYL 2 OXO 5 PHENYL 2,3 DIHYDRO 1H BENZO[E][1,4]DIAZEPIN 3 YL) 3 PROPYLSUCCINAMIDE; AMYLOID BETA PROTEIN; BMS 299897; BMS 433796; GAMMA SECRETASE; GAMMA SECRETASE INHIBITOR; IN 973; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG PROTEIN BINDING; DRUG STRUCTURE; FEMALE; MALE; MOUSE; NONHUMAN; PEPTIDE SYNTHESIS; PRIORITY JOURNAL;

AMYLOID BETA-PROTEIN PRECURSOR; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; BINDING SITES; BRAIN; DOSE-RESPONSE RELATIONSHIP, DRUG; ENZYME INHIBITORS; LIGANDS; MICE; MICE, TRANSGENIC; MOLECULAR STRUCTURE; RADIOLIGAND ASSAY; TIME FACTORS;

EID: 34548830730     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.107.125492     Document Type: Article

References (45)

1. Anderson JJ, Holtz G, Baskin PP, Turner M, Rowe B, Wang B, Kounnas MZ, Lamb BT, Barten D, Felsenstein K, et al. (2005) Reductions in beta-amyloid concentrations in vivo by the gamma-secretase inhibitors BMS-289948 and BMS-299897. Biochem Pharmacol 69:689-698.
2. Andreasen N and Blennow K (2005) CSF biomarkers for mild cognitive impairment and early Alzheimer's disease. Clin Neurol Neurosurg 107:165-173.
3. Barten DM, Guss VL, Corsa JA, Loo A, Hansel SB, Zheng M, Munoz B, Srinivasan K, Wang B, Robertson BJ, et al. (2005) Dynamics of β-amyloid reductions in brain, cerebrospinal fluid, and plasma of β-amyloid precursor protein transgenic mice treated with a γ-secretase inhibitor. J Pharmacol Exp Ther 312:635-643.
4. Barten DM, Meredith JE Jr, Zaczek R, Houston JG, and Albright CF (2006) gamma-Secretase inhibitors for Alzheimer's disease: balancing efficacy and toxicity. Drugs R D 7:87-97.
5. Best JD, Jay MT, Otu F, Churcher I, Reilly M, Morentin-Gutierrez P, Pattison C, Harrison T, Shearman MS, and Atack JR (2006) In vivo characterization of Aβ(40) changes in brain and cerebrospinal fluid using the novel γ-secretase inhibitor N-[cis-4-[(4-chlorophenyl) sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) in the rat. J Pharmacol Exp Ther 317:786-790.
6. Best JD, Jay MT, Otu F, Ma J, Nadin A, Ellis S, Lewis HD, Pattison C, Reilly M, Harrison T, et al. (2005) Quantitative measurement of changes in amyloid-β (40) in the rat brain and cerebrospinal fluid following treatment with the γ-secretase inhibitor LY-411575 [N2-[(2S)-2-(3,5- difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide]. J Pharmacol Exp Ther 313:902-908.
7. Blanchard V, Czech C, Bonici B, Clavel N, Gohin M, Dalet K, Revah F, Pradier L, Imperato A, and Moussaoui S (1997) Immunohistochemical analysis of presenilin 2 expression in the mouse brain: distribution pattern and co-localization with presenilin 1 protein. Brain Res 758:209-217.
8. Christie RH, Bacskai BJ, Zipfel WR, Williams RM, Kajdasz ST, Webb WW, and Hyman BT (2001) Growth arrest of individual senile plaques in a model of Alzheimer's disease observed by in vivo multiphoton microscopy. J Neurosci 21:858-864.
9. Churcher I, Williams S, Kerrad S, Harrison T, Castro JL, Shearman MS, Lewis HD, Clarke EE, Wrigley JD, Beher D, et al. (2003) Design and synthesis of highly potent benzodiazepine gamma-secretase inhibitors: preparation of (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl) -4-hydroxy-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)butyramide by use of an asymmetric Ireland-Claisen rearrangement. J Med Chem 46:2275-2278.
10. Cirrito JR, May PC, O'Dell MA, Taylor JW, Parsadanian M, Cramer JW, Audia JE, Nissen JS, Bales KR, Paul SM, et al. (2003) In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. J Neurosci 23:8844-8853.
11. Clarke EE, Churcher I, Ellis S, Wrigley JD, Lewis HD, Harrison T, Shearman MS, and Beher D (2006) Intra- or intercomplex binding to the gamma-secretase enzyme. A model to differentiate inhibitor classes. J Biol Chem 281:31279-31289.
12. De Strooper B (2003) Aph-1, Pen-2, and nicastrin with presenilin generate an active gamma-secretase complex. Neuron 38:9-12.
13. Dolev I and Michaelson DM (2004) A nontransgenic mouse model shows inducible amyloid-β(Aβ) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade. Proc Natl Acad Sci U S A 101:13909-13914.
14. El Mouedden M, Vandermeeren M, Meert T, and Mercken M (2006) Reduction of Abeta levels in the Sprague Dawley rat after oral administration of the functional gamma-secretase inhibitor, DAPT: a novel non-transgenic model for Abeta production inhibitors. Curr Pharm Des 12:671-676.
15. Elder GA, Tezapsidis N, Carter J, Shioi J, Bouras C, Li HC, Johnston JM, Efthimiopoulos S, Friedrich VL Jr, and Robakis NK (1996) Identification and neuron specific expression of the S182/presenilin I protein in human and rodent brains. J Neurosci Res 45:308-320.
16. Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I, Wall A, Ringheim A, Langstrom B, and Nordberg A (2006) Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain 129:2856-2866.
17. Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS, Moore CL, Tsai JY, Rahmati T, Xia W, Selkoe DJ, and Wolfe MS (2000) Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1. Nat Cell Biol 2:428-434.
18. Goedert M and Spillantini MG (2006) A century of Alzheimer's disease. Science 314:777-781.
19. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, and Cole G (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274:99-102.
20. Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, et al. (1999) Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol Cell Neurosci 14:419-427.
21. Jankowsky JL, Slunt HH, Gonzales V, Savonenko AV, Wen JC, Jenkins NA, Copeland NG, Younkin LH, Lester HA, Younkin SG, et al. (2005) Persistent amyloidosis following suppression of Ab production in a transgenic model of Alzheimer disease. PLoS Med 2:e355.
22. Kim KS, Wegiel J, Sapienza V, Chen J, Hong H, and Wisniewski HM (1997) Immunoreactivity of presenilin-1 in human, rat and mouse brain. Brain Res 757:159-163.
23. Kobayashi DT and Chen KS (2005) Behavioral phenotypes of amyloid-based genetically modified mouse models of Alzheimer's disease. Genes Brain Behav 4:173-196.
24. Kornilova AY, Das C, and Wolfe MS (2003) Differential effects of inhibitors on the gamma-secretase complex. Mechanistic implications. J Biol Chem 278:16470-16473.
25. Lanz TA, Himes CS, Pallante G, Adams L, Yamazaki S, Amore B, and Merchant KM (2003) The γ-secretase inhibitor N-[N-(3,5- difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester reduces Aβ levels in vivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice. J Pharmacol Exp Ther 305:864-871.
26. Lanz TA, Hosley JD, Adams WJ, and Merchant KM (2004) Studies of Abeta pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576 mice using the γ-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S) -5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl] -L-alaninamide (LY-411575). J Pharmacol Exp Ther 309:49-55.
27. Laruelle M, Slifstein M, and Huang Y (2003) Relationships between radiotracer properties and image quality in molecular imaging of the brain with positron emission tomography. Mol Imaging Biol 5:363-375.
28. Lelas S, Wong H, Li Y-W, Heman KL, Ward KA, Zeller KL, Sieracki KK, Polino JL, Godonis HE, Ren SX, et al. (2004) Anxiolytic-like effects of the corticotropin-releasing factor1 (CRF1) antagonist DMP904 [4-(3-pentylamino)-2,7- dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] administered acutely or chronically at doses occupying central CRF1 receptors in rats. J Pharmacol Exp Ther 309:293-302.
29. Lin X, Koelsch G, Wu S, Downs D, Dashti A, and Tang J (2000) Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein. Proc Natl Acad Sci U S A 97:1456-1460.
30. Morohashi Y, Kan T, Tominari Y, Fuwa H, Okamura Y, Watanabe N, Sato C, Natsugari H, Fukuyama T, Iwatsubo T, et al. (2006) C-terminal fragment of presenilin is the molecular target of a dipeptidic γ-secretase-specific inhibitor DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]- S-phenylglycine t-butyl ester). J Biol Chem 281:14670-14676.
31. Moussaoui S, Czech C, Pradier L, Blanchard V, Bonici B, Gohin M, Imperato A, and Revah F (1996) Immunohistochemical analysis of presenilin-1 expression in the mouse brain. FEBS Lett 383:219-222.
32. Patel S, O'Malley S, Connolly B, Liu W, Hargreaves R, Sur C, and Gibson RE (2006) In vitro characterization of a γ-secretase radiotracer in mammalian brain. J Neurochem 96:171-178.
33. Prasad CVC, Zheng M, Vig S, Bergstrom C, Smith DW, Gao Q, Yeola S, Polson CT, Corsa JA, Guss VL, et al. (2007) Discovery of (S)-2-((S)-2- (3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z) -3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2] diazepin-5-yl) propanamide (BMS-433796): a γ-secretase inhibitor with A lowering activity in a transgenic mouse model of Alzheimer's disease. Bioorg Med Chem 17:4006-4011.
34. Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Dolios G, Hirotani N, Horikoshi Y, Kamentani F, Maeda M, Saido TC, Wang R, et al. (2005) Longer forms of amyloid β protein: implications for the mechanism of intramembrane cleavage by γ-secretase. J Neurosci 25:436-445.
35. Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, Cowie TF, Dickinson KL, Maruff P, Darby D, et al. (2007) Imaging beta-amyloid burden in aging and dementia. Neurology 68:1718-1725.
36. Seiffert D, Bradley JD, Rominger CM, Rominger DH, Yang F, Meredith JE, Wang Q, Roach AH, Thompson LA, Spitz SM, et al. (2000) Presenilin-1 and -2 are molecular targets for γ-secretase inhibitors. J Biol Chem 275:34086-34091.
37. Selkoe DJ (2001) Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 81:741-766.
38. Siman R and Salidas S (2004) gamma-Secretase subunit composition and distribution in the presenilin wild-type and mutant mouse brain. Neuroscience 129:615-628.
39. Smith DW, Munoz B, Srinivasan K, Bergstrom CP, Chaturvedula PV, Deshpande MS, Keavy DJ, Lau WY, Parker MF, Sloan CP, et al. (2000) inventors; Merck and Co., Inc., assignee. Novel sulfonamide compounds and uses thereof. World patent WO/2000/050391. 2000 Aug 31.
40. Tian G, Ghanekar SV, Aharony D, Shenvi AB, Jacobs RT, Liu X, and Greenberg BD (2003) The mechanism of gamma-secretase: multiple inhibitor binding sites for transition state analogs and small molecule inhibitors. J Biol Chem 278:28968-28975.
41. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, et al. (1999) beta-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735-741.
42. Wolfe MS (2006) The gamma-secretase complex: membrane-embedded proteolytic ensemble. Biochemistry 45:7931-7939.
43. Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, et al. (1999) Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature 402:533-537.
44. Yan X-X, Li T, Rominger CM, Prakash SR, Wong PC, Olson RE, Zaczek R, and Li Y-W (2004) Binding sites of γ-secretase inhibitors in rodent brain: distribution, postnatal development, and effect of deafferentation. J Neurosci 24:2942-2952.
45. Zhao G, Tan J, Mao G, Cui M-Z, and Xu X (2007) The same γ-secretase accounts for the multiple intramembrane cleavages of APP. J Neurochem 100:1234-1246.