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

Journal of Pharmacology and Experimental Therapeutics

Volumn 317, Issue 2, 2006, Pages 786-790

  Best, Jonathan D ^a   Jay, Mark T ^a   Otu, Franklin ^a   Churcher, Ian ^a   Reilly, Michael ^a   Morentin Gutierrez, Pablo ^a   Pattison, Christine ^a   Harrison, Tim ^a   Shearman, Mark S ^a,b   Atack, John R ^a  

^a NEUROSCIENCE RESEARCH CENTRE   (United Kingdom)

^b MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN[1-40]; GAMMA SECRETASE INHIBITOR; MRK 560; N [4 [(4 CHLOROPHENYL)SULFONYL] 4 (2,5 DIFLUOROPHENYL)CYCLOHEXYL] 1,1,1 TRIFLUOROMETHANESULFONAMIDE; UNCLASSIFIED DRUG; AMYLOID BETA PROTEIN; N (4 ((4 CHLOROPHENYL)SULFONYL) 4 (2,5 DIFLUOROPHENYL)CYCLOHEXYL) 1,1,1 TRIFLUOROMETHANESULFONAMIDE; N-(4-((4-CHLOROPHENYL)SULFONYL)-4-(2,5-DIFLUOROPHENYL)CYCLOHEXYL)-1,1,1-TRIFLUOROMETHANESULFONAMIDE; PEPTIDE FRAGMENT; PROTEINASE; PROTEINASE INHIBITOR; SECRETASE; SULFONAMIDE; SULFONE;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BRAIN LEVEL; COMPARATIVE STUDY; CONTROLLED STUDY; CORRELATION ANALYSIS; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG BRAIN LEVEL; DRUG CLEARANCE; DRUG EFFECT; DRUG HALF LIFE; ENZYME INHIBITION; IN VIVO STUDY; MALE; NONHUMAN; PRIORITY JOURNAL; PROTEIN CEREBROSPINAL FLUID LEVEL; RAT; ANIMAL; BLOOD; BRAIN; CEREBROSPINAL FLUID; ENZYMOLOGY; METABOLISM; ORAL DRUG ADMINISTRATION; SPRAGUE DAWLEY RAT;

ADMINISTRATION, ORAL; AMYLOID BETA-PROTEIN; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; BRAIN; DOSE-RESPONSE RELATIONSHIP, DRUG; ENDOPEPTIDASES; MALE; PEPTIDE FRAGMENTS; PROTEASE INHIBITORS; RATS; RATS, SPRAGUE-DAWLEY; SULFONAMIDES; SULFONES;

EID: 33645871592     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.105.100271     Document Type: Article

References (22)

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. 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.
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 after 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) gamma-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. Dovey HF, John V, Anderson JP, Chen LZ, de Saint Andrieu P, Fang LY, Freedman SB, Folmer B, Goldbach E, Holsztynska EJ, et al. (2001) Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem 76:173-181.
7. Grimwood S, Hogg J, Jay MT, Lad AM, Lee V, Murray F, Peachey J, Townend T, Vithlani M, Beher D, et al. (2005) Determination of guinea-pig cortical gamma-secretase activity ex vivo following the systemic administration of a gamma-secretase inhibitor. Neuropharmacology 48:1002-1011.
8. Haass C (2004) Take five-BACE and the γ-secretase quartet conduct Alzheimer's amyloid b-peptide generation. EMBO (Eur Mol Biol Organ) J 23:483-488.
9. Hardy J (1997) The Alzheimer family of diseases: many etiologies, one pathogenesis? Proc Natl Acad Sci USA 94:2095-2097.
10. Harrison T, Churcher I, and Beher D (2004) gamma-Secretase as a target for drug intervention in Alzheimer's disease. Curr Opin Drug Dis Dev 7:709-719.
11. 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.
12. 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.
13. 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.
14. Lanz TA, Hosley JD, Adams WJ, and Merchant KM (2004) Studies of αβ 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.
15. Lleó A, Waldron E, von Arnim CA, Herl L, Tangredi MM, Peltan ID, Strickland DK, Koo EH, Hyman BT, Pietrzik CU, et al. (2005) Low density lipoprotein receptor-related protein (LRP) interacts with presenilin 1 and is a competitive substrate of the amyloid precursor protein (APP) for γ-secretase. J Biol Chem 280:27303-27309.
16. Middendorp O, Luthi U, Hausch F, and Barberis A (2004) Searching for the most effective screening system to identify cell-active inhibitors of beta-secretase. Biol Chem 385:481-485.
17. 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.
18. Selkoe DJ (2001) Alzheimer's disease: genes, proteins and therapy. Physiol Rev 81:741-766.
19. Selkoe DJ and Schenk D (2003) Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol 43:545-584.
20. Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, et al. (2000) Clearance of Alzheimer's amyloid-β(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Investig 106:1489-1499.
21. Siemers E, Skinner M, Dean RA, Gonzales C, Satterwhite J, Farlow M, Ness D, and May PC (2005) Safety, tolerability and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin Neuropharmacol 28:126-132.
22. Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee H-JJ, et al. (2004) Chronic treatment with the γ-secretase inhibitor LY-411575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 279:12876-12882.