Robust translation of γ-secretase modulator pharmacology across preclinical species and human subjectss

Journal of Pharmacology and Experimental Therapeutics

Volumn 358, Issue 1, 2016, Pages 125-137

  Toyn, Jeremy H ^a   Boy, Kenneth M ^b   Raybon, Joseph ^b   Meredith, Jere E ^b   Robertson, Alan S ^b   Guss, Valerie ^b   Hoque, Nina ^b   Sweeney, Francis ^b,c   Zhuo, Xiaoliang ^b   Clarke, Wendy ^b   Snow, Kimberly ^b   Denton, R Rex ^b   Zuev, Dmitry ^d   Thompson, Lorin A ^b   Morrison, John ^b   Grace, James ^b   Berisha, Flora ^e   Furlong, Michael ^f   Wang, Jun Sheng ^g   Lentz, Kimberly A ^b   Padmanabha, Ramesh ^b   Cook, Lynda ^b   Wei, Cong ^c   Drexler, Dieter M ^b   Macor, John E ^b   Albright, Charlie F ^b   Gasior, Maciej ^h   Olson, Richard E ^b   Hong, Quan ⁱ   Soares, Holly D ^b   AbuTarif, Malaz ^b   Ahlijanian, Michael K ^b   more..

^a YALE UNIVERSITY   (United States)

^b BRISTOL MYERS SQUIBB   (United States)

^c PFIZER INC   (United States)

^d Cantor Colburn LLP   (United States)

^e KYOWA HAKKO KOGYO CO LTD   (Japan)

^f FORUM Pharmaceuticals   (United States)

^g GLAXOSMITHKLINE   (United States)

^h TEVA PHARMACEUTICALS   (Israel)

ⁱ EISAI INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

17 (4 CHLORO 2 FLUOROPHENYL) 34 (3 METHYL 1H 1,2,4 TRIAZOL 1 YL) 16,17 DIHYDRO 15H 4 OXA 2,9 DIAZA 1(2,4) CYCLOPENTA[D]PYRIMIDINA 3 (1,3) BENZENACYCLONONAPHAN 6 ENE; 7 (4 FLUOROPHENYL) N2 (3 METHOXY 4 (3 METHYL 1H 1,2,4 TRIAZOL 1 YL)PHENYL) N4 METHYL 6,7 DIHYDRO 5H CYCLOPENTA[D]PYRIMIDINE 2,4 DIAMINE; AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN[1-37]; AMYLOID BETA PROTEIN[1-38]; AMYLOID BETA PROTEIN[1-40]; AMYLOID BETA PROTEIN[1-42]; GAMMA SECRETASE INHIBITOR; PLACEBO; UNCLASSIFIED DRUG; ANILINE DERIVATIVE; BMS-932481; BMS-986133; BRIDGED COMPOUND; NOTCH RECEPTOR; PYRIMIDINE DERIVATIVE; SECRETASE;

ANIMAL EXPERIMENT; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG BRAIN LEVEL; DRUG DISTRIBUTION; DRUG MECHANISM; FEMALE; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN EXPERIMENT; IN VITRO STUDY; IN VIVO STUDY; MALE; MAXIMUM PLASMA CONCENTRATION; MINIMUM PLASMA CONCENTRATION; NONHUMAN; NORMAL HUMAN; PHARMACOLOGICAL PARAMETERS; PRIORITY JOURNAL; PROTEIN CEREBROSPINAL FLUID LEVEL; RAT; RISK ASSESSMENT; ANIMAL; ANTAGONISTS AND INHIBITORS; BRAIN; CELL LINE; CEREBROSPINAL FLUID; CHEMISTRY; DOG; DOSE RESPONSE; DRUG EFFECTS; ENZYMOLOGY; GENETICS; MACACA FASCICULARIS; METABOLISM; PRECLINICAL STUDY; SPECIES DIFFERENCE; SPRAGUE DAWLEY RAT; TISSUE DISTRIBUTION;

AMYLOID BETA-PEPTIDES; AMYLOID PRECURSOR PROTEIN SECRETASES; ANILINE COMPOUNDS; ANIMALS; BRAIN; BRIDGED-RING COMPOUNDS; CELL LINE; DOGS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG EVALUATION, PRECLINICAL; FEMALE; HUMANS; MACACA FASCICULARIS; PYRIMIDINES; RATS, SPRAGUE-DAWLEY; RECEPTORS, NOTCH; SPECIES SPECIFICITY; TISSUE DISTRIBUTION;

EID: 84976486363     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.116.232249     Document Type: Article

References (54)

1. Abramowski D, Wiederhold K-H, Furrer U, Jaton AL, Neuenschwander A, Runser MJ, Danner S, Reichwald J, Ammaturo D, and Staab D, et al. (2008) Dynamics of Abeta turnover and deposition in different b-amyloid precursor protein transgenic mouse models following γ-secretase inhibition. J Pharmacol Exp Ther 327: 411-424.
2. Albright CF, Dockens RC, Meredith JE, Jr, Olson RE, Slemmon R, Lentz KA, Wang JS, Denton RR, Pilcher G, and Rhyne PW, et al. (2013) Pharmacodynamics of selective inhibition of γ-secretase by avagacestat. J Pharmacol Exp Ther 344: 686-695.
3. Barten DM, Guss VL, Corsa JA, Loo A, Hansel SB, Zheng M, Munoz B, Srinivasan K, Wang B, and Robertson BJ, et al. (2005) Dynamics of b-amyloid reductions in brain, cerebrospinal fluid, and plasma of b-amyloid precursor protein transgenic mice treated with a γ-secretase inhibitor. J Pharmacol Exp Ther 312:635-643.
4. Bateman RJ, Wen G, Morris JC, and Holtzman DM (2007) Fluctuations of CSF amyloid-b levels: implications for a diagnostic and therapeutic biomarker. Neurology 68:666-669.
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 Abeta(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, and Harrison T, et al. (2005) Quantitative measurement of changes in amyloidb(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. Borgegard T, Juréus A, Olsson F, Rosqvist S, Sabirsh A, Rotticci D, Paulsen K, Klintenberg R, Yan H, and Waldman M, et al. (2012) First and second generation γ-secretase modulators (GSMs) modulate amyloid-b Aβ peptide production through different mechanisms. J Biol Chem 287:11810-11819.
8. Boy KM, Guernon JM, Macor JE, Thompson LA III, Wu Y-J, and Zhang Y (2014a) Compounds for the Reduction of Beta-Amyloid Production. US 8637523. Assignee: Bristol-Myers Squibb.
9. Boy KM, Guernon JM, Macor JE, Olson RE, Shi J, Thompson LA III, Wu Y-J, Xu L, Zhang Y, and Zuev DS (2014b) Compounds for the Reduction of Beta Amyloid Production. US 8637525 B2. Assignee: Bristol-Myers Squibb.
10. Caldwell JP, Bennett CE, McCracken TM, Mazzola RD, Bara T, Buevich A, Burnett DA, Chu I, Cohen-Williams M, and Josein H, et al. (2010) Iminoheterocycles as γ-secretase modulators. Bioorg Med Chem Lett 20:5380-5384.
11. Crump CJ, Fish BA, Castro SV, Chau DM, Gertsik N, Ahn K, Stiff C, Pozdnyakov N, Bales KR, and Johnson DS, et al. (2011) Piperidine acetic acid based γ-secretase modulators directly bind to Presenilin-1. ACS Chem Neurosci 2:705-710.
12. Duering M, Grimm MOW, Grimm HS, Schröder J, and Hartmann T (2005) Mean age of onset in familial Alzheimer's disease is determined by amyloid beta 42. Neurobiol Aging 26:785-788.
13. Ebke A, Luebbers T, Fukumori A, Shirotani K, Haass C, Baumann K, and Steiner H (2011) Novel γ-secretase enzyme modulators directly target presenilin protein. J Biol Chem 286:37181-37186.
14. Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, and Koo EH, et al. (2003) NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Abeta 42 in vivo. J Clin Invest 112:440-449.
15. Findeis MA (2007) The role of amyloid b peptide 42 in Alzheimer's disease. Pharmacol Ther 116:266-286.
16. Galasko DR, Graff-Radford N, May S, Hendrix S, Cottrell BA, Sagi SA, Mather G, Laughlin M, Zavitz KH, and Swabb E, et al. (2007) Safety, tolerability, pharmacokinetics, and Abeta levels after short-term administration of R-flurbiprofen in healthy elderly individuals. Alzheimer Dis Assoc Disord 21:292-299.
17. Gillman KW, Starrett JE, Jr, Parker MF, Xie K, Bronson JJ, Marcin LR, McElhone KE, Bergstrom CP, Mate RA, and Williams R, et al. (2010) Discovery and evaluation of BMS-708163, a potent, selective, and orally bioavailable γ-secretase inhibitor.ACS Med Chem Lett 1:120-124.
18. Haapasalo A and Kovacs DM (2011) The many substrates of presenilin/γ-secretase. J Alzheimers Dis 25:3-28.
19. Hardy J and Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353-356.
20. Hawkins J, Harrison DC, Ahmed S, Davis RP, Chapman T, Marshall I, Smith B, Mead TL, Medhurst A, and Giblin GM, et al. (2011) Dynamics of Aβ42 reduction in plasma, CSF and brain of rats treated with the γ-secretase modulator, GSM-10h. Neurodegener Dis 8:455-464. .
21. Jumpertz T, Rennhack A, Ness J, Baches S, Pietrzik CU, Bulic B, and Weggen S (2012) Presenilin is the molecular target of acidic γ-secretase modulators in living cells. PLoS One 7:e30484.
22. Karran E (2012) Current status of vaccination therapies in Alzheimer's disease. J Neurochem 123:647-651.
23. Karran E, Mercken M, and De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10:698-712.
24. Kounnas MZ, Danks AM, Cheng S, Tyree C, Ackerman E, Zhang X, Ahn K, Nguyen P, Comer D, and Mao L, et al. (2010) Modulation of γ-secretase reduces b-amyloid deposition in a transgenic mouse model of Alzheimer's disease. Neuron 67:769-780.
25. Kukar T, Prescott S, Eriksen JL, Holloway V, Murphy MP, Koo EH, Golde TE, and Nicolle MM (2007) Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci 8:54.
26. Kumar-Singh S, Theuns J, Van Broeck B, Pirici D, Vennekens K, Corsmit E, Cruts M, Dermaut B, Wang R, and Van Broeckhoven C (2006) Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Hum Mutat 27:686-695.
27. Kuperstein I, Broersen K, Benilova I, Rozenski J, Jonckheere W, Debulpaep M, Vandersteen A, Segers-Nolten I, Van Der Werf K, and Subramaniam V, et al. (2010) Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio. EMBO J 29:3408-3420.
28. Lanz TA, Fici GJ, and Merchant KM (2005) Lack of specific amyloid-b(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.
29. Lanz TA, Wood KM, Richter KEG, Nolan CE, Becker SL, Pozdnyakov N, Martin BA, Du P, Oborski CE, and Wood DE, et al. (2010) Pharmacodynamics and pharmacokinetics of the γ-secretase inhibitor PF-3084014. J Pharmacol Exp Ther 334: 269-277.
30. Li J, Llano DA, Ellis T, Le Blond D, Bhathena A, Jhee SS, Ereshefsky L, Lenz R, and Waring JF (2012a) Effect of human cerebrospinal fluid sampling frequency on amyloid-b levels. Alzheimers Dement 8:295-303.
31. Lu Y, Riddell D, Hajos-Korcsok E, Bales K, Wood KM, Nolan CE, Robshaw AE, Zhang L, Leung L, and Becker SL, et al. (2012) Cerebrospinal fluid amyloid-b Aβ as an effect biomarker for brain Ab lowering verified by quantitative preclinical analyses. J Pharmacol Exp Ther 342:366-375.
32. Lu Y, Zhang L, Nolan CE, Becker SL, Atchison K, Robshaw AE, Pustilnik LR, Osgood SM, Miller EH, and Stepan AF, et al. (2011) Quantitative pharmacokinetic/pharmacodynamic analyses suggest that the 129/SVE mouse is a suitable preclinical pharmacology model for identifying small-molecule γ-secretase inhibitors. J Pharmacol Exp Ther 339:922-934.
33. Martone RL, Zhou H, Atchison K, Comery T, Xu JZ, Huang X, Gong X, Jin M, Kreft A, and Harrison B, et al. (2009) Begacestat (GSI-953): a novel, selective thiophenesulfonamide inhibitor of amyloid precursor protein γ-secretase for the treatment of Alzheimer's disease. J Pharmacol Exp Ther 331:598-608.
34. May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, Monk SA, Mathes BM, Mergott DJ, and Watson BM, et al. (2011) Robust central reduction of amyloid-b in humans with an orally available, non-peptidic b-secretase inhibitor. J Neurosci 31:16507-16516.
35. Mitani Y, Akashiba H, Saita K, Yarimizu J, Uchino H, Okabe M, Asai M, Yamasaki S, Nozawa T, and Ishikawa N, et al. (2014) Pharmacological characterization of the novel γ-secretase modulator AS2715348, a potential therapy for Alzheimer's disease, in rodents and nonhuman primates. Neuropharmacology 79:412-419.
36. Mitani Y, Yarimizu J, Saita K, Uchino H, Akashiba H, Shitaka Y, Ni K, and Matsuoka N (2012) Differential effects between γ-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice. J Neurosci 32:2037-2050.
37. Murray MM, Bernstein SL, Nyugen V, Condron MM, Teplow DB, and Bowers MT (2009) Amyloid b protein: Abeta40 inhibits Abeta42 oligomerization. J Am Chem Soc 131:6316-6317.
38. Nakano-Ito K, Fujikawa Y, Hihara T, Shinjo H, Kotani S, Suganuma A, Aoki T, and Tsukidate K (2014) E2012-induced cataract and its predictive biomarkers. Toxicol Sci 137:249-258.
39. Ohki Y, Higo T, Uemura K, Shimada N, Osawa S, Berezovska O, Yokoshima S, Fukuyama T, Tomita T, and Iwatsubo T (2011) Phenylpiperidine-type γ-secretase modulators target the transmembrane domain 1 of presenilin 1. EMBO J 30: 4815-4824.
40. Okochi M, Tagami S, Yanagida K, Takami M, Kodama TS, Mori K, Nakayama T, Ihara Y, and Takeda M (2013) γ-secretase modulators and presenilin 1 mutants act differently on presenilin/γ-secretase function to cleave Aβ42 and Ab43. Cell Reports 3:42-51.
41. Pozdnyakov N, Murrey HE, Crump CJ, Pettersson M, Ballard TE, Am Ende CW, Ahn K, Li YM, Bales KR, and Johnson DS (2013) γ-Secretase modulator (GSM) photoaffinity probes reveal distinct allosteric binding sites on presenilin. J Biol Chem 288:9710-9720.
42. Prince M, Bryce R, and Ferri C (2011) The benefits of early diagnosis and intervention. Alzheimer's Disease International World Alzheimer Report 2011 pp 1-68, Alzheimer's Disease International, London.
43. Shapiro JS, Stiteler M, Wu G, Price EA, Simon AJ, and Sankaranarayanan S (2012) Cisterna magna cannulated repeated CSF sampling rat model-effects of a gammasecretase inhibitor on Ab levels. J Neurosci Methods 205:36-44.
44. Soares HD, Gasior M, Toyn JH, Wang J-S, Hong Q, Berisha F, Furlong MT, Raybon J, Lentz KA, and Sweeney F, et al. (2016) The gamma secretase modulator, BMS-932481, modulates Aβ peptides in the plasma and CSF of healthy volunteers. J Pharmacol Exp Ther DOI: 10.1124/jpet.116.232256 [published ahead of print].
45. Tai LM, Jacobsen H, Ozmen L, Flohr A, Jakob-Roetne R, Caruso A, and Grimm HP (2012) The dynamics of Ab distribution after γ-secretase inhibitor treatment, as determined by experimental and modelling approaches in a wild type rat. J Pharmacokinet Pharmacodyn 39:227-237.
46. Tate B, McKee TD, Loureiro RMB, Dumin JA, Xia W, Pojasek K, Austin WF, Fuller NO, Hubbs JL, and Shen R, et al. (2012) Modulation of gamma-secretase for the treatment of Alzheimer's disease. Int J Alzheimers Dis 2012:210756.
47. Toyn JH and Ahlijanian MK (2014) Interpreting Alzheimer's disease clinical trials in light of the effects on amyloid-b. Alzheimers Res Ther 6:14.
48. Toyn JH, Thompson LA, Lentz KA, Meredith JE, Jr, Burton CR, Sankaranararyanan S, Guss V, Hall T, Iben LG, and Krause CM, et al. (2014) Identification and preclinical pharmacology of the γ-secretase modulator BMS-869780. Int J Alzheimers Dis 2014:431858.
49. Wan Z, Hall A, Jin Y, Xiang JN, Yang E, Eatherton A, Smith B, Yang G, Yu H, and Wang J, et al. (2011a) Pyridazine-derived γ-secretase modulators. Bioorg Med Chem Lett 21:4016-4019.
50. Wan Z, Hall A, Sang Y, Xiang JN, Yang E, Smith B, Harrison DC, Yang G, Yu H, and Price HS, et al. (2011b) Pyridine-derived γ-secretase modulators. Bioorg Med Chem Lett 21:4832-4835.
51. Watanabe H, Bernier F, and Miyakawa T (2006) A therapeutic agent for Ab related disorders. International patent publication WO2006/112552. Assignee: Eisai Company Ltd., Tokyo.
52. Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, Findlay KA, Smith TE, Murphy MP, and Bulter T, et al. (2001) A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414:212-216.
53. Wimo A and Prince M (2010) The global economic impact of dementia, Alzheimer's Disease International World Alzheimer Report 2010. pp 1-51, Alzheimer's Disease International, London.
54. Yu Y, Logovinsky V, Schuck E, Kaplow J, Chang M-K, Miyagawa T, Wong N, and Ferry J (2014) Safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel γ-secretase modulator, E2212, in healthy human subjects. J Clin Pharmacol 54:528-536.