Orally bioavailable and brain-penetrant pyridazine and pyridine-derived γ-secretase modulators reduced amyloidogenic Aβ peptides in vivo

Neuropharmacology

Volumn 70, Issue , 2013, Pages 278-286

  Huang, Yunhong ^a,d   Li, Ting ^a,e   Eatherton, Andrew ^b   Mitchell, William L ^b,f   Rong, Na ^a,g   Ye, Liang ^a,h   Yang, Xiu Juan ^a   Jin, Shiyi ^a   Ding, Yu ^a   Zhang, Jinqiang ^a   Li, Yi ^a   Wu, Yiwen ^a   Jin, Yun ^a   Sang, Yingxia ^a   Cheng, Ziqiang ^a   Browne, Edward R ^c   Harrison, David C ^b,i   Hussain, Ishrut ^b,j   Wan, Zehong ^a   Hall, Adrian ^b,k   Lau, Lit Fui ^a   Matsuoka, Yasuji ^a,c   more..

^a GLAXOSMITHKLINE   (China)

^b GLAXOSMITHKLINE   (United Kingdom)

^c GlaxoSmithKline   (Singapore)

^d Center for Human Genetics   (Belgium)

^e ARIZONA STATE UNIVERSITY   (United States)

^f EVOTEC UK LTD   (United Kingdom)

^g Henan Xingyang High School   (China)

^h Cadence Beijing R and D Center   (China)

ⁱ Takeda Cambridge Ltd   (United Kingdom)

^j MERCK SERONO S A   (Switzerland)

^k EISAI CO LTD   (Japan)

more..

Author keywords

Secretase; Secretase modulator; Alzheimer's disease; Amyloid

Indexed keywords

AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN[1-40]; AMYLOID BETA PROTEIN[1-42]; GAMMA SECRETASE MODULATOR C; GAMMA SECRETASE MODULATOR D; NOTCH RECEPTOR; PYRIDAZINE DERIVATIVE; PYRIDINE DERIVATIVE; SEMAGACESTAT; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; BLOOD BRAIN BARRIER; BRAIN LEVEL; BRAIN NERVE CELL; BRAIN TISSUE; CONTROLLED STUDY; DOSE RESPONSE; DOSE TIME EFFECT RELATION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG BRAIN LEVEL; DRUG CLEARANCE; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; DRUG PENETRATION; DRUG STRUCTURE; IN VIVO STUDY; MALE; MAXIMUM PLASMA CONCENTRATION; NEUROPATHOLOGY; NONHUMAN; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; PROTEIN FUNCTION; PROTEIN SYNTHESIS INHIBITION; RAT; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; THYMUS; TIME TO MAXIMUM PLASMA CONCENTRATION; TREATMENT DURATION;

ADMINISTRATION, ORAL; AMYLOID BETA-PEPTIDES; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; BIOLOGICAL AVAILABILITY; BRAIN; DOSE-RESPONSE RELATIONSHIP, DRUG; MALE; NEURONS; PRIMARY CELL CULTURE; PYRIDAZINES; PYRIDINES; RATS; RECEPTORS, NOTCH; THYMOCYTES;

EID: 84876965841     PISSN: 00283908     EISSN: 18737064     Source Type: Journal    
DOI: 10.1016/j.neuropharm.2013.02.003     Document Type: Article

References (46)

1. Alzheimer's Association Alzheimer's disease facts and figures Alzheimer's Demen. J. Alzheimer's Assoc. 8 2012 131 168
2. R.J. Bateman, E.R. Siemers, K.G. Mawuenyega, G. Wen, K.R. Browning, W.C. Sigurdson, K.E. Yarasheski, S.W. Friedrich, R.B. Demattos, P.C. May, S.M. Paul, and D.M. Holtzman A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system Ann. Neurol. 66 2009 48 54
3. C.R. Burton, J.E. Meredith, D.M. Barten, M.E. Goldstein, C.M. Krause, C.J. Kieras, L. Sisk, L.G. Iben, C. Polson, M.W. Thompson, X.A. Lin, J. Corsa, T. Fiedler, M. Pierdomenico, Y. Cao, A.H. Roach, J.L. Cantone, M.J. Ford, D.M. Drexler, R.E. Olson, M.G. Yang, C.P. Bergstrom, K.E. McElhone, J.J. Bronson, J.E. Macor, Y. Blat, R.H. Grafstrom, A.M. Stern, D.A. Seiffert, R. Zaczek, C.F. Albright, and J.H. Toyn The amyloid-beta rise and gamma-secretase inhibitor potency depend on the level of substrate expression J. Biol. Chem. 283 2008 22992 23003
4. E. Czirr, B.A. Cottrell, S. Leuchtenberger, T. Kukar, T.B. Ladd, H. Esselmann, S. Paul, R. Schubenel, J.W. Torpey, C.U. Pietrzik, T.E. Golde, J. Wiltfang, K. Baumann, E.H. Koo, and S. Weggen Independent generation of Abeta42 and Abeta38 peptide species by gamma-secretase J. Biol. Chem. 283 2008 17049 17054
5. R. Deane, and B.V. Zlokovic Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease Curr. Alzheimer Res. 4 2007 191 197
6. H.F. Dovey, V. John, J.P. Anderson, L.Z. Chen, A.P. de Saint, L.Y. Fang, S.B. Freedman, B. Folmer, E. Goldbach, E.J. Holsztynska, K.L. Hu, K.L. Johnson-Wood, S.L. Kennedy, D. Kholodenko, J.E. Knops, L.H. Latimer, M. Lee, Z. Liao, I.M. Lieberburg, R.N. Motter, L.C. Mutter, J. Nietz, K.P. Quinn, K.L. Sacchi, P.A. Seubert, G.M. Shopp, E.D. Thorsett, J.S. Tung, J. Wu, S. Yang, C.T. Yin, D.B. Schenk, P.C. May, L.D. Altstiel, M.H. Bender, L.N. Boggs, T.C. Britton, J.C. Clemens, D.L. Czilli, D.K. Eckman-McGinty, J.J. Droste, K.S. Fuson, B.D. Gitter, P.A. Hyslop, E.M. Johnstone, W.Y. Li, S.P. Little, T.E. Mabry, F.D. Miller, and J.E. Audia Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain J. Neurochem. 76 2001 173 181
7. Eisai Inc A Randomized, Double-blind, Placebo-controlled, Sequential Ascending, Single-dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of E2212 in Healthy Subjects 2010 http://clinicaltrials.gov/ct2/results?term=NCT01221259 (accessed 21.12.12.)
8. EnVivo Pharmaceuticals EnVivo Announces Initiation of Gamma Secretase Modulator Clinical Program in Alzheimer's Disease 2011 http://www.envivopharma. com/news-item.php?id=33 (accessed 21.12.12.)
9. J.L. Eriksen, S.A. Sagi, T.E. Smith, S. Weggen, P. Das, D.C. McLendon, V.V. Ozols, K.W. Jessing, K.H. Zavitz, E.H. Koo, and T.E. Golde NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo J. Clin. Invest. 112 2003 440 449
10. A.M. Fagan, M.A. Mintun, R.H. Mach, S.Y. Lee, C.S. Dence, A.R. Shah, G.N. LaRossa, M.L. Spinner, W.E. Klunk, C.A. Mathis, S.T. DeKosky, J.C. Morris, and D.M. Holtzman Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans Ann. Neurol. 59 2006 512 519
11. A.S. Fleisher, R. Raman, E.R. Siemers, L. Becerra, C.M. Clark, R.A. Dean, M.R. Farlow, J.E. Galvin, E.R. Peskind, J.F. Quinn, A. Sherzai, B.B. Sowell, P.S. Aisen, and L.J. Thal Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease Arch. Neurol. 65 2008 1031 1038
12. B.D. Gitter, D.L. Czilli, W. Li, D.K. Dieckman, M.H. Bender, J.S. Nissen, T.E. Mabry, T. Yin, L.N. Boggs, D.B. McClure, S.P. Little, E.M. Johnstone, J.E. Audia, P.C. May, and P.A. Hyslop P4-339 stereoselective inhibition of amyloid beta peptide secretion by LY450139, a novel functional gamma secretase inhibitor Neurobiol. Aging 25 2004 S571
13. L. Gravitz Drugs: a tangled web of targets Nature 475 2011 S9 S11
14. R.C. Green, L.S. Schneider, D.A. Amato, A.P. Beelen, G. Wilcock, E.A. Swabb, and K.H. Zavitz Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial J. Am. Med. Assoc. 302 2009 2557 2564
15. A. Haapasalo, and D.M. Kovacs The many substrates of presenilin/gamma- secretase J. Alzheimers Dis. 25 2011 3 28
16. A. Hall, R.L. Elliott, G.M. Giblin, I. Hussain, J. Musgrave, A. Naylor, R. Sasse, and B. Smith Piperidine-derived gamma-secretase modulators Bioorg. Med. Chem. Lett. 20 2010 1306 1311
17. T. Hashimoto E2012: a novel gamma-secretase modulator-pharmacology part Alzheimer's Demen. 6 2010 2
18. J. Hawkins, D.C. Harrison, S. Ahmed, R.P. Davis, T. Chapman, I. Marshall, B. Smith, T.L. Mead, A. Medhurst, G.M. Giblin, A. Hall, M.I. Gonzalez, J. Richardson, and I. Hussain Dynamics of Abeta42 reduction in plasma, CSF and brain of rats treated with the gamma-secretase modulator, GSM-10h Neurodegener. Dis. 8 2011 455 464
19. P.A. Hyslop, P.C. May, J.E. Audia, D.O. Calligaro, C.L. McMillian, C.O. Garner, J.W. Cramer, B.D. Gitter, W.J. Porter, and J.S. Nissen Reduction in a-beta(1-40) and A-beta(1-42) in CSF and plasma in the beagle dog following acute oral dosing of the gamma secretase inhibitor, LY450139 Neurobiol. Aging 25 2004 S147
20. B.P. Imbimbo, L. Giardino, S. Sivilia, A. Giuliani, M. Gusciglio, V. Pietrini, G.E. Del, A. D'Arrigo, A. Leon, G. Villetti, and L. Calza CHF5074, a novel gamma-secretase modulator, restores hippocampal neurogenesis potential and reverses contextual memory deficit in a transgenic mouse model of Alzheimer's disease J. Alzheimers Dis. 20 2010 159 173
21. N. Iwata, S. Tsubuki, Y. Takaki, K. Shirotani, B. Lu, N.P. Gerard, C. Gerard, E. Hama, H.J. Lee, and T.C. Saido Metabolic regulation of brain Abeta by neprilysin Science 292 2001 1550 1552
22. W.T. Kimberly, M.J. LaVoie, B.L. Ostaszewski, W. Ye, M.S. Wolfe, and D.J. Selkoe Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2 Proc. Natl. Acad. Sci. U S A 100 2003 6382 6387
23. M.Z. Kounnas, A.M. Danks, S. Cheng, C. Tyree, E. Ackerman, X. Zhang, K. Ahn, P. Nguyen, D. Comer, L. Mao, C. Yu, D. Pleynet, P.J. Digregorio, G. Velicelebi, K.A. Stauderman, W.T. Comer, W.,C. Mobley, Y.M. Li, S.S. Sisodia, R.E. Tanzi, and S.L. Wagner Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease Neuron 67 2010 769 780
24. T. Kukar, S. Prescott, J.L. Eriksen, V. Holloway, M.P. Murphy, E.H. Koo, T.E. Golde, and M.M. Nicolle Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice BMC. Neurosci. 8 2007 54
25. T.A. Lanz, M.J. Karmilowicz, K.M. Wood, N. Pozdnyakov, P. Du, M.A. Piotrowski, T.M. Brown, C.E. Nolan, K.E. Richter, J.E. Finley, Q. Fei, C.F. Ebbinghaus, Y.L. Chen, D.K. Spracklin, B. Tate, K.F. Geoghegan, L.F. Lau, D.D. Auperin, and J.B. Schachter Concentration-dependent modulation of amyloid-beta in vivo and in vitro using the gamma-secretase inhibitor, LY-450139 J. Pharmacol. Exp. Ther. 319 2006 924 933
26. T. Li, Y. Huang, S. Jin, L. Ye, N. Rong, X. Yang, Y. Ding, Z. Cheng, J. Zhang, Z. Wan, D.C. Harrison, I. Hussain, A. Hall, D.H. Lee, L.F. Lau, and Y. Matsuoka gamma-secretase modulators do not induce Abeta-rebound and accumulation of beta-C-terminal fragment J. Neurochem. 121 2012 277 286
27. T. Li, H. Wen, C. Brayton, F.M. Laird, G. Ma, S. Peng, L. Placanica, T.C. Wu, B.J. Crain, D.L. Price, C.G. Eberhart, and P.C. Wong Moderate reduction of gamma-secretase attenuates amyloid burden and limits mechanism-based liabilities J. Neurosci. 27 2007 10849 10859
28. Y. Lu, L. Zhang, C.E. Nolan, S.L. Becker, K. Atchison, A.E. Robshaw, L.R. Pustilnik, S.M. Osgood, E.H. Miller, A.F. Stepan, C. Subramanyam, I. Efremov, A.J. Hallgren, and D. Riddell Quantitative pharmacokinetic/pharmacodynamic analyses suggest that the 129/SVE mouse is a suitable preclinical pharmacology model for identifying small-molecule gamma-secretase inhibitors J. Pharmacol. Exp. Ther. 339 2011 922 934
29. R.L. Martone, H. Zhou, K. Atchison, T. Comery, J.Z. Xu, X. Huang, X. Gong, M. Jin, A. Kreft, B. Harrison, S.C. Mayer, S. Aschmies, C. Gonzales, M.M. Zaleska, D.R. Riddell, E. Wagner, P. Lu, S.C. Sun, J. Sonnenberg-Reines, A. Oganesian, K. Adkins, M.W. Leach, D.W. Clarke, D. Huryn, M. Abou-Gharbia, R. Magolda, J. Bard, G. Frick, S. Raje, S.B. Forlow, C. Balliet, M.E. Burczynski, P.H. Reinhart, H.I. Wan, M.N. Pangalos, and J.S. Jacobsen Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease J. Pharmacol. Exp. Ther. 331 2009 598 608
30. Y. Mitani, J. Yarimizu, K. Saita, H. Uchino, H. Akashiba, Y. Shitaka, K. Ni, and N. Matsuoka Differential effects between gamma-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice J. Neurosci. 32 2012 2037 2050
31. J. Morales-Corraliza, M.J. Mazzella, J.D. Berger, N.S. Diaz, J.H. Choi, E. Levy, Y. Matsuoka, E. Planel, and P.M. Mathews In vivo turnover of tau and APP metabolites in the brains of wild-type and Tg2576 mice: greater stability of sAPP in the beta-amyloid depositing mice PLoS. One 4 2009 e7134
32. F. Panza, V. Frisardi, B.P. Imbimbo, C. Capurso, G. Logroscino, D. Sancarlo, D. Seripa, G. Vendemiale, A. Pilotto, and V. Solfrizzi REVIEW: gamma-secretase inhibitors for the treatment of Alzheimer's disease: the current state CNS. Neurosci. Ther. 16 2010 272 284
33. I. Peretto, and P.E. La Gamma-secretase modulation and its promise for Alzheimer's disease: a medicinal chemistry perspective Curr. Top. Med. Chem. 8 2008 38 46
34. D.L. Price, and S.S. Sisodia Mutant genes in familial Alzheimer's disease and transgenic models Annu. Rev. Neurosci. 21 1998 479 505
35. W.Q. Qiu, D.M. Walsh, Z. Ye, K. Vekrellis, J. Zhang, M.B. Podlisny, M.R. Rosner, A. Safavi, L.B. Hersh, and D.J. Selkoe Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation J. Biol. Chem. 273 1998 32730 32738
36. C.A. Saura, S.Y. Choi, V. Beglopoulos, S. Malkani, D. Zhang, B.S. Shankaranarayana Rao, S. Chattarji, R.J. Kelleher III, E.R. Kandel, K. Duff, A. Kirkwood, and J. Shen Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration Neuron 42 2004 23 36
37. E.R. Siemers, R.A. Dean, S. Friedrich, L. Ferguson-Sells, C. Gonzales, M.R. Farlow, and P.C. May Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase Clin. Neuropharmacol. 30 2007 317 325
38. E.R. Siemers, J.F. Quinn, J. Kaye, M.R. Farlow, A. Porsteinsson, P. Tariot, P. Zoulnouni, J.E. Galvin, D.M. Holtzman, D.S. Knopman, J. Satterwhite, C. Gonzales, R.A. Dean, and P.C. May Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease Neurology 66 2006 602 604
39. B.Z. Stanger, R. Datar, L.C. Murtaugh, and D.A. Melton Direct regulation of intestinal fate by Notch Proc. Natl. Acad. Sci. U S A 102 2005 12443 12448
40. M.G. Stanton, J. Hubbs, D. Sloman, C. Hamblett, P. Andrade, M. Angagaw, G. Bi, R.M. Black, J. Crispino, J.C. Cruz, E. Fan, G. Farris, B.L. Hughes, C.M. Kenific, R.E. Middleton, G. Nikov, P. Sajonz, S. Shah, N. Shomer, A.A. Szewczak, F. Tanga, M.T. Tudge, M. Shearman, and B. Munoz Fluorinated piperidine acetic acids as gamma-secretase modulators Bioorg. Med. Chem. Lett. 20 2010 755 758
41. N. Suzuki, T.T. Cheung, X.D. Cai, A. Odaka, L. Otvos Jr., C. Eckman, T.E. Golde, and S.G. Younkin An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants Science 264 1994 1336 1340
42. L.M. Tai, H. Jacobsen, L. Ozmen, A. Flohr, R. Jakob-Roetne, A. Caruso, and H.P. Grimm The dynamics of Abeta distribution after gamma-secretase inhibitor treatment, as determined by experimental and modelling approaches in a wild type rat J. Pharmacokinet. Pharmacodyn. 39 2012 227 237
43. Z. Wan, A. Hall, Y. Jin, J.N. Xiang, E. Yang, A. Eatherton, B. Smith, G. Yang, H. Yu, J. Wang, L. Ye, L.F. Lau, T. Yang, W. Mitchell, W. Cai, X. Zhang, Y. Sang, Y. Wang, Z. Tong, Z. Cheng, I. Hussain, J.D. Elliott, and Y. Matsuoka Pyridazine-derived gamma-secretase modulators Bioorg. Med. Chem. Lett. 21 2011 4016 4019
44. Z. Wan, A. Hall, Y. Sang, J.N. Xiang, E. Yang, B. Smith, D.C. Harrison, G. Yang, H. Yu, H.S. Price, J. Wang, J. Hawkins, L.F. Lau, M.R. Johnson, T. Li, W. Zhao, W.L. Mitchell, X. Su, X. Zhang, Y. Zhou, Y. Jin, Z. Tong, Z. Cheng, I. Hussain, J.D. Elliott, and Y. Matsuoka Pyridine-derived gamma-secretase modulators Bioorg. Med. Chem. Lett. 21 2011 4832 4835
45. S. Weggen, J.L. Eriksen, P. Das, S.A. Sagi, R. Wang, C.U. Pietrzik, K.A. Findlay, T.E. Smith, M.P. Murphy, T. Bulter, D.E. Kang, N. Marquez-Sterling, T.E. Golde, and E.H. Koo A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity Nature 414 2001 212 216
46. G.T. Wong, D. Manfra, F.M. Poulet, Q. Zhang, H. Josien, T. Bara, L. Engstrom, M. Pinzon-Ortiz, J.S. Fine, H.,J. Lee, L. Zhang, G.A. Higgins, and E.M. Parker Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation J. Biol. Chem. 279 2004 12876 12882