The novel γ secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]- 4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) reduces amyloid plaque deposition without evidence of notch-related pathology in the Tg2576 mouse

Journal of Pharmacology and Experimental Therapeutics

Volumn 320, Issue 2, 2007, Pages 552-558

  Best, Jonathan D ^a,j   Smith, David W ^a,c   Reilly, Michael A ^a,d   O'Donnell, Ruth ^a   Lewis, Huw D ^a,e   Ellis, Semantha ^a,f   Wilkie, Neil ^a,g   Rosahl, Thomas W ^a,d   Laroque, Philippe A ^b   Boussiquet Leroux, Christine ^b   Churcher, Ian ^a,e   Atack, John R ^a,h   Harrison, Timothy ^a,i   Shearman, Mark S ^a,d  

^a NEUROSCIENCE RESEARCH CENTRE   (United Kingdom)

^b Dohme Chibret Centre de Recherche Riom   (France)

^c AMGEN INC   (United States)

^d MERCK RESEARCH LABORATORIES   (United States)

^e GLAXOSMITHKLINE   (United Kingdom)

^f Cellzome Ltd   (United Kingdom)

^g ITI Life Sciences   (United Kingdom)

^h JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

ⁱ Almac Sciences   (United Kingdom)

^j VASTox plc   (United Kingdom)

more..

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID; GAMMA SECRETASE INHIBITOR; MRK 560; N [CIS 4 [(4 CHLOEOPHENYL)SULFONYL] 4 (2,5 DIFLUOROPHENYL)CYCLOHEXYL] 1,1,1 TRIFLUOROMETHANESULFONAMIDE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BRAIN CORTEX; CONTROLLED STUDY; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG EFFECT; FEMALE; GLIOSIS; HISTOPATHOLOGY; ILEUM; IN VIVO STUDY; MALE; MORPHOMETRICS; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEGRADATION; SPLEEN; THYMUS;

ALZHEIMER DISEASE; AMYLOID BETA-PROTEIN; AMYLOID BETA-PROTEIN PRECURSOR; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; BRAIN; FEMALE; MALE; MICE; PROTEASE INHIBITORS; RECEPTORS, NOTCH; SULFONAMIDES; SULFONES;

EID: 33846451755     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.106.114330     Document Type: Article

References (39)

1. 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.
2. 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.
3. 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.
4. Churcher I and Beher D (2005) γ-secretase as a therapeutic target for the treatment of Alzheimer's disease. Curr Pharm Des 11:3363-3382.
5. Churcher I, Beher D, Best JD, Castro JL, Clarke EE, Gentry A, Harrison T, Hitzel L, Kay E, Kerrad S, et al. (2006) 4-substituted cyclohexyl sulfones as potent, orally active γ-secretase inhibitors. Bioorg Med Chem Lett 16:280-284.
6. Doerfler P, Shearman MS, and Perlmutter RM (2001) Presenilin-dependent γ-secretase activity modulates thymocyte development. Proc Natl Acad Sci USA 98:9312-9317.
7. Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, et al. (2003) NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ 42 in vivo. J Clin Investig 112:440-449.
8. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, et al. (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature (Lond) 373:523-527.
9. Haass C (2004) Take five-BACE and the γ-secretase quartet conduct Alzheimer's amyloid β-peptide generation. EMBO (Eur Mol Biol Organ) J 23:483-488.
10. Hadland BK, Manley NR, Su D, Longmore GD, Moore CL, Wolfe MS, Schroeter EH, and Kopan R (2001) γ-Secretase inhibitors repress thymocyte development. Proc Natl Acad Sci USA 98:7487-7491.
11. Hardy J and Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science (Wash DC) 297:353-356.
12. Harrison T, Churcher I, and Beher D (2004) γ-Secretase as a target for drug intervention in Alzheimer's disease. Curr Opin Drug Discov Dev 7:709-719.
13. Hartmann D, Tournoy J, Saftig P, Annaert W, and De Strooper B (2001) Implication of APP secretases in Notch signaling. J Mol Neurosci 17:171-181.
14. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, and Cole G (1996) Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science (Wash DC) 274:99-102.
15. Ida N, Hartmann T, Pantel J, Schroder J, Zerfass R, Forstl H, Sandbrink R, Masters CL, and Beyreuther K (1996) Analysis of heterogeneous A4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay. J Biol Chem 271:22908-22914.
16. Janus C and Westaway D (2001) Transgenic mouse models of Alzheimer's disease. Physiol Behav 73:873-886.
17. Jarrett JT, Berger EP, and Lansbury PT Jr (1993) The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry 32:4693-4697.
18. Johnson-Wood K, Lee M, Motter R, Hu K, Gordon G, Barbour R, Khan K, Gordon M, Tan H, Games D, et al. (1997) Amyloid precursor protein processing and A β42 deposition in a transgenic mouse model of Alzheimer disease. Proc Natl Acad Sci USA 94:1550-1555.
19. Kawarabayashi T, Younkin LH, Saido TC, Shoji M, Ashe KH, and Younkin SG (2001) Age-dependent changes in brain, CSF, and plasma amyloid (β) protein in the Tg2576 transgenic mouse model of Alzheimer's disease. J Neurosci 21:372-381.
20. Kim KS, Miller DL, Sapienza VJ, Chen C-MJ, Bai C, Grundke-Iqbal I, Currie JR, and Wisniewski HM (1988) Production and characterization of monoclonal antibodies reactive to synthetic cerebrovascular amyloid peptide. Neurosci Res Commun 2:121-130.
21. Lanz TA, Fici GJ, and Merchant KM (2005) Lack of specific amyloid-β(1-42) suppression by nonsteroidal anti-inflammatory drugs in young, plaque-free Tg2576 mice and in guinea pig neuronal cultures. J Pharmacol Exp Ther 312:399-406.
22. Lewis HD, Beher D, Smith D, Hewson L, Cookson N, Reynolds DS, Dawson GR, Jiang M, Van der Ploeg LH, Qian S, et al. (2004) Novel aspects of accumulation dynamics and Aβ composition in transgenic models of AD. Neurobiol Aging 25:1175-1185.
23. Lewis HD, Perez Revuelta BI, Nadin A, Neduvelil JG, Harrison T, Pollack SJ, and Shearman MS (2003) Catalytic site-directed gamma-secretase complex inhibitors do not discriminate pharmacologically between Notch S3 and beta-APP cleavages. Biochemistry 42:7580-7586.
24. Maggio JE, Stimson ER, Ghilardi JR, Allen CJ, Dahl CE, Whitcomb DC, Vigna SR, Vinters HV, Labenski ME, and Mantyh PW (1992) Reversible in vitro growth of Alzheimer disease β-amyloid plaques by deposition of labeled amyloid peptide. Proc Natl Acad Sci USA 89:5462-5466.
25. Milano J, McKay J, Dagenais C, Foster-Brown L, Pognan F, Gadient R, Jacobs RT, Zacco A, Greenberg B, and Ciaccio PJ (2004) Modulation of notch processing by γ-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci 82:341-358.
26. Mudher A and Lovestone S (2002) Alzheimer's disease-do tauists and baptists finally shake hands? Trends Neurosci 25:22-26.
27. Oddo S, Caccamo A, Kitazawa M, Tseng BP, and LaFerla FM (2003) Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease. Neurobiol Aging 24:1063-1070.
28. Price DL and Sisodia SS (1998) Mutant genes in familial Alzheimer's disease and transgenic models. Annu Rev Neurosci 21:479-505.
29. Savage MJ, Trusko SP, Howland DS, Pinsker LR, Mistretta S, Reaume AG, Greenberg BD, Siman R, and Scott RW (1998) Turnover of amyloid β-protein in mouse brain and acute reduction of its level by phorbol ester. J Neurosci 18:1743-1752.
30. Searfoss GH, Jordan WH, Calligaro DO, Galbreath EJ, Schirtzinger LM, Berridge BR, Gao H, Higgins MA, May PC, and Ryan TP (2003) Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional γ-secretase inhibitor. J Biol Chem 278:46107-46116.
31. Selkoe DJ (1999) Translating cell biology into therapeutic advances in Alzheimer's disease. Nature (Lond) 399:A23-A31.
32. Selkoe DJ (2000) Toward a comprehensive theory for Alzheimer's disease. Hypothesis: Alzheimer's disease is caused by the cerebral accumulation and cytotoxicity of amyloid β-protein. Ann NY Acad Sci 924:17-25.
33. Serneels L, Dejaegere T, Craessaerts K, Horre K, Jorissen E, Tousseyn T, Hebert S, Coolen M, Martens G, Zwijsen A, et al. (2005) Differential contribution of the three Aph1 genes to γ-secretase activity in vivo. Proc Natl Acad Sci USA 102:1719-1724.
34. van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H, Cozijnsen M, Robine S, Winton DJ, Radtke F, et al. (2005) Notch/γ- secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature (Lond) 435:959-963.
35. Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, Findlay KA, Smith TE, Murphy MP, Bulter T, et al. (2001) A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature (Lond) 414:212-216.
36. Weggen S, Eriksen JL, Sagi SA, Pietrzik CU, Ozols V, Fauq A, Golde TE, and Koo EH (2003) Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid β 42 production by direct modulation of γ-secretase activity. J Biol Chem 278:30748-30754.
37. Wolfe MS and Kopan R (2004) Intramembrane proteolysis: themes and variations. Science (Wash DC) 305:1119-1123.
38. Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ, et al. (2004) Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 279:12876-12882.
39. Zlokovic BV (2004) Clearing amyloid through the blood-brain barrier. J Neurochem 89:807-811.