Pharmacodynamics and pharmacokinetics of the γ-secretase inhibitor PF-3084014

Journal of Pharmacology and Experimental Therapeutics

Volumn 334, Issue 1, 2010, Pages 269-277

  Lanz, Thomas A ^a   Wood, Kathleen M ^a   Richter, Karl E G ^a   Nolan, Charles E ^a   Becker, Stacey L ^a   Pozdnyakov, Nikolay ^a   Martin, Barbara Anne ^a   Du, Ping ^a   Oborski, Christine E ^a   Wood, Douglas E ^a   Brown, Tracy M ^a   Finley, James E ^a   Sokolowski, Sharon A ^a   Hicks, Carol D ^a   Coffman, Karen J ^a   Geoghegan, Kieran F ^a   Brodney, Michael A ^a   Liston, Dane ^a   Tate, Barbara ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN[1-40]; AMYLOID BETA PROTEIN[1-42]; NOTCH RECEPTOR; PF 3084014;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; B LYMPHOCYTE; CELL MATURATION; CONTROLLED STUDY; ENZYME LINKED IMMUNOSORBENT ASSAY; FEMALE; GUINEA PIG; HUMAN; HUMAN CELL; IC 50; IMMUNOPRECIPITATION; MALE; MASS SPECTROMETRY; MOUSE; NONHUMAN; OSMOTIC PUMP; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; PROTEIN CEREBROSPINAL FLUID LEVEL; T LYMPHOCYTE; THYMOCYTE;

AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; B-LYMPHOCYTES; BRAIN; CELL LINE; DOSE-RESPONSE RELATIONSHIP, DRUG; ENZYME INHIBITORS; ESCHERICHIA COLI; FEMALE; GUINEA PIGS; HUMANS; LYMPHOCYTE COUNT; MALE; MICE; MICE, INBRED STRAINS; MOLECULAR STRUCTURE; SPECTROMETRY, MASS, MATRIX-ASSISTED LASER DESORPTION-IONIZATION; SPLEEN; TETRAHYDRONAPHTHALENES; TISSUE DISTRIBUTION; TRANSFECTION; VALINE;

EID: 77953732993     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.110.167379     Document Type: Article

References (37)

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 β-amyloid concentrations in vivo by the γ-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. Bateman RJ, Siemers ER, Mawuenyega KG, Wen G, Browning KR, Sigurdson WC, Yarasheski KE, Friedrich SW, Demattos RB, May PC, et al. (2009) A γ-secretase inhibitor decreases amyloid-β production in the central nervous system. Ann Neurol 66:48-54.
4. 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-ox o-6,7-dihydro-5H-dibenzo[b,d]azepin- 7-yl]-L-alaninamide]. J Pharmacol Exp Ther 313:902-908.
5. Best JD, Smith DW, Reilly MA, O'Donnell R, Lewis HD, Ellis S, Wilkie N, Rosahl TW, Laroque PA, Boussiquet-Leroux C, et al. (2007) 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. J Pharmacol Exp Ther 320:552-558.
6. Brodney MA, Becker AG, Brockhurst B, Bronk B, Brown TM, Coffman K, Finley JE, Hicks C, Lanz TA, Lau L, et al. (2009) Discovery of PF-3084014: a novel γ-secretase inhibitor for the treatment of Alzheimer's disease, in Proceedings of the American Chemical Society National Meeting; 2009, Aug. 16-20; Washington, DC; Abstract MEDI-233, American Chemical Society, Washington, DC.
7. Burton CR, Meredith JE, Barten DM, Goldstein ME, Krause CM, Kieras CJ, Sisk L, Iben LG, Polson C, Thompson MW, et al. (2008) The amyloid-β rise and γ-secretase inhibitor potency depend on the level of substrate expression. J Biol Chem 283: 22992-23003.
8. Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, and Wong PC (2001) BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nat Neurosci 4:233-234.
9. Du P, Wood KM, Rosner MH, Cunningham D, Tate B, and Geoghegan KF (2007) Dominance of amyloid precursor protein sequence over host cell secretases in determining β-amyloid profiles studies of interspecies variation and drug action by internally standardized immunoprecipitation/mass spectrometry. J Pharmacol Exp Ther 320:1144-1152.
10. El Mouedden M, Vandermeeren M, Meert T, and Mercken M (2006) Reduction of Aβ levels in the Sprague Dawley rat after oral administration of the functional γ-secretase inhibitor, DAPT: a novel non-transgenic model for Aβ production inhibitors. Curr Pharm Des 12:671-676.
11. Glenner GG and Wong CW (1984) Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120:885-890. (Pubitemid 14104991)
12. Hall A, Elliott RL, Giblin GM, Hussain I, Musgrave J, Naylor A, Sasse R, and Smith B (2010) Piperidine-derived γ-secretase modulators. Bioorg Med Chem Lett 20: 1306-1311.
13. Henley DB, May PC, Dean RA, and Siemers ER (2009) Development of semagacestat (LY450139), a functional γ-secretase inhibitor, for the treatment of Alzheimer's disease. Expert Opin Pharmacother 10:1657-1664.
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 274:99-102.
15. Hyde LA, McHugh NA, Chen J, Zhang Q, Manfra D, Nomeir AA, Josien H, Bara T, Clader JW, Zhang L, et al. (2006) Studies to investigate the in vivo therapeutic window of 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 (LY411,575) in the CRND8 mouse. J Pharmacol Exp Ther 319:1133-1143.
16. Johnstone EM, Chaney MO, Norris FH, Pascual R, and Little SP (1991) Conservation of the sequence of the Alzheimer's disease amyloid peptide in dog, polar bear and five other mammals by cross-species polymerase chain reaction analysis. Brain Res Mol Brain Res 10:299-305.
17. Konishi J, Kawaguchi KS, Vo H, Haruki N, Gonzalez A, Carbone DP, and Dang TP (2007) γ-Secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers. Cancer Res 67:8051-8057.
18. 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.
19. Lanz TA, Hosley JD, Adams WJ, and Merchant KM (2004) Studies of Aβ 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.
20. Lanz TA, Karmilowicz MJ, Wood KM, Pozdnyakov N, Du P, Piotrowski MA, Brown TM, Nolan CE, Richter KE, Finley JE, et al. (2006) Concentration-dependent modulation of amyloid-β in vivo and in vitro using the γ-secretase inhibitor, LY-450139. J Pharmacol Exp Ther 319:924-933.
21. Lanz TA, Salatto CT, Semproni AR, Marconi M, Brown TM, Richter KE, Schmidt K, Nelson FR, and Schachter JB (2008) Peripheral elevation of IGF-1 fails to alter Aβ clearance in multiple in vivo models. Biochem Pharmacol 75:1093-1103.
22. Lanz TA and Schachter JB (2006) Demonstration of a common artifact in immunosorbent assays of brain extracts: development of a solid-phase extraction protocol to enable measurement of amyloid-β from wild-type rodent brain. J Neurosci Methods 157:71-81.
23. Li YM, Lai MT, Xu M, Huang Q, DiMuzio-Mower J, Sardana MK, Shi XP, Yin KC, Shafer JA, and Gardell SJ (2000) Presenilin 1 is linked with γ-secretase activity in the detergent solubilized state. Proc Natl Acad Sci USA 97:6138-6143.
24. Martone RL, Zhou H, Atchison K, Comery T, Xu JZ, Huang X, Gong X, Jin M, Kreft A, Harrison B, et al. (2009) Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein γ-secretase for the treatment of Alzheimer's disease. J Pharmacol Exp Ther 331:598-608.
25. Plentz R, Park JS, Rhim AD, Abravanel D, Hezel AF, Sharma SV, Gurumurthy S, Deshpande V, Kenific C, Settleman J, et al. (2009) Inhibition of γ-secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma. Gastroenterology 136:1741-1749.
26. Portelius E, Zhang B, Gustavsson MK, Brinkmalm G, Westman-Brinkmalm A, Zetterberg H, Lee VM, Trojanowski JQ, and Blennow K (2009) Effects of γ-secretase inhibition on the amyloid β isoform pattern in a mouse model of Alzheimer's disease. Neurodegener Dis 6:258-262.
27. Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Dolios G, Hirotani N, Horikoshi Y, Kametani 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.
28. Rao SS, O'Neil J, Liberator CD, Hardwick JS, Dai X, Zhang T, Tyminski E, Yuan J, Kohl NE, Richon VM, et al. (2009) Inhibition of NOTCH signaling by γ-secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells. Cancer Res 69:3060-3068.
29. Siemers E, Skinner M, Dean RA, Gonzales C, Satterwhite J, Farlow M, Ness D, and May PC (2005) Safety, tolerability, and changes in amyloid β concentrations after administration of a γ-secretase inhibitor in volunteers. Clin Neuropharmacol 28:126-132.
30. Siemers ER, Dean RA, Friedrich S, Ferguson-Sells L, Gonzales C, Farlow MR, and May PC (2007) Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-β after inhibition of γ-secretase. Clin Neuropharmacol 30:317-325.
31. Stanton ML, Joy MS, and Frye RF (2010) Validation and application of a liquid chromatography-tandem mass spectrometric method for quantification of the drug transport probe fexofenadine in human plasma using 96-well filter plates. J Chromatogr B Analyt Technol Biomed Life Sci 878:497-501.
32. Takahashi Y, Hayashi I, Tominari Y, Rikimaru K, Morohashi Y, Kan T, Natsugari H, Fukuyama T, Tomita T, and Iwatsubo T (2003) Sulindac sulfide is a noncompetitive γ-secretase inhibitor that preferentially reduces Aβ42 generation. J Biol Chem 278:18664-18670.
33. Watters JW, Cheng C, Majumder PK, Wang R, Yalavarthi S, Meeske C, Kong L, Sun W, Lin J, Heyer J, et al. (2009) De novo discovery of a γ-secretase inhibitor response signature using a novel in vivo breast tumor model. Cancer Res 69:8949-8957.
34. Willuweit A, Velden J, Godemann R, Manook A, Jetzek F, Tintrup H, Kauselmann G, Zevnik B, Henriksen G, Drzezga A, et al. (2009) Early-onset and robust amyloid pathology in a new homozygous mouse model of Alzheimer's disease. PLoS One 4:e7931.
35. 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.
36. Yagishita S, Morishima-Kawashima M, Tanimura Y, Ishiura S, and Ihara Y (2006) DAPT-induced intracellular accumulations of longer amyloid β-proteins: further implications for the mechanism of intramembrane cleavage by γ-secretase. Biochemistry 45:3952-3960.
37. Yohrling GJ, Felsenstein KM, Conway KA, Zupa-Fernandez A, Brenneman DE, and Arnold HM (2007) A comparative analysis of brain and plasma Aβ levels in eight common non-transgenic mouse strains: validation of a specific immunoassay for total rodent Aβ. Curr Alzheimer Res 4:297-303.