Discovery of a potent pyrazolopyridine series of γ-secretase modulators

ACS Medicinal Chemistry Letters

Volumn 2, Issue 6, 2011, Pages 471-476

  Qin, Jun ^a   Zhou, Wei ^a   Huang, Xianhai ^a   Dhondi, Pawan ^a   Palani, Anandan ^a   Aslanian, Robert ^a   Zhu, Zhaoning ^a   Greenlee, William ^a   Cohen Williams, Mary ^a   Jones, Nicholas ^a   Hyde, Lynn ^a   Zhang, Lili ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

secretase modulator; Alzheimer's disease; amyloid peptide; Notch

Indexed keywords

AMYLOID BETA PROTEIN[1-42]; GAMMA SECRETASE INHIBITOR; PYRAZOLE DERIVATIVE; PYRIDINE DERIVATIVE;

ARTICLE; CEREBROSPINAL FLUID; DRUG DESIGN; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; IN VITRO STUDY; NONHUMAN; PRIORITY JOURNAL; RAT; STRUCTURE ACTIVITY RELATION;

RATTUS;

EID: 79959223785     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/ml2000438     Document Type: Article

References (35)

1. Shah, R. S.; Lee, H.; Zhu, X.; Perry, G.; Smith, M. A.; Castellani, R. J. Current approaches in the treatment of Alzheimer's disease Biomed. Pharmacother. 2008, 62, 199
2. Williams, M. Progress in Alzheimer's disease drug discovery: An update Curr. Opin. Invest. Drugs 2009, 10, 23
3. Lanctoit, K. L.; Rajaram, R. D.; Herrmann, N. Therapy for Alzheimer's Disease: How Effective Are Current Treatments? Ther. Adv. Neurol. Disorders 2009, 2, 163
4. Hardy, J. A.; Higgins, G. A. Alzheimer's disease: The amyloid cascade hypothesis Science 1992, 256, 184
5. Hardy, J. A.; Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics Science 2002, 297, 353
6. Josien, H. Recent advances in the development of γ-secretase inhibitors Curr. Opin. Drug Discovery Dev. 2002, 5, 513
7. Harrison, T.; Churcher, I.; Beher, D. γ-Secretase as a target for drug intervention in Alzheimer's disease Curr. Opin. Drug Discovery Dev. 2004, 7, 709
8. Wu, W.; Zhang, L. γ-Secretase inhibitors for the treatment of Alzheimer's disease Drug Dev. Res. 2009, 70, 94
9. Hyde, L. A.; Mchugh, N. A.; Chen, J.; Zhang, Q.; Manfra, D.; Nomeir, A. A.; Josien, H.; Bara, T.; Clader, J. W.; Zhang, L.; Parker, E. M. Studies to investigate the in vivo therapeutic window of the gamma-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. 2006, 319, 1133
10. Hyde, L. A.; Zhang, Q.; Mchugh, N. A.; Chen, J.; Del Vecchio, R. A.; Wong, G. T.; Pissarnitski, D.; Clader, J. W.; Higgins, G. A.; Zhang, L.; Parker, E. M. In vivo characterization of a novel γ-secretase inhibitor in CRND8 transgenic mice: Efficacy and side effects. Society for Neuroscience 36th Annual Meeting, Atlanta, October, 2006; Abstract 172.174/FF178.
11. Schor, N. What the halted phase III γ-secretase inhibitor trial may (or may not) be telling us Ann. Neurol. 2011, 69, 237
12. Imbimbo, B.; Panza, F.; Frisardi, V.; Solfrizzi, V.; D'Onofrio, G.; Logroscino, G.; Seripa, D.; Pilotto, A. Therapeutic intervention for Alzheimer's disease with γ-secretase inhibitors: Still a viable option? Expert Opin. Invest. Drugs 2011, 20, 325
13. Pissarnitski, D. Advances in gamma-secretase modulation Curr. Opin. Drug Discovery Dev. 2007, 10, 392
14. Tomita, T. At the frontline of Alzheimer's disease treatment: γ-Secretase inhibitor/modulator mechanism Naunyn-Schmiedeberg's Arch. Pharmacol. 2008, 377, 295
15. Wolfe, M. S. Inhibition and modulation of gamma-secretase for Alzheimer's disease Neurotherapeutics 2008, 5, 391
16. Gasparini, L.; Rusconi, L.; Xu, H.; Del Soldato, P.; Ongini, E. Modulation of beta-amyloid metabolism by non-steroidal anti-inflammatory drugs in neuronal cell cultures J. Neurochem. 2004, 88, 337
17. Leuchtenberger, S.; Kummer, M. P.; Kukar, T.; Czirr, E.; Teusch, N.; Sagi, S. A.; Berdeaux, R.; Pietrzik, C. U.; Ladd, T. B.; Golde, T. E.; Koo, E. H.; Weggen, S. Inhibitors of Rho-kinase modulate amyloid-β (Aβ) secretion but lack selectivity for Aβ42 J. Neurochem. 2006, 96, 355
18. Kukar, T. L.; Ladd, T. B.; Bann, M. A.; Fraering, P. C.; Narlawar, R.; Maharvi, G. M.; Healy, B.; Chapman, R.; Welzel, A. T.; Price, R. W.; Moore, B.; Rangachari, V.; Cusack, B.; Eriksen, J.; Jansen-West, K.; Verbeeck, C.; Yager, D.; Eckman, C.; Ye, W.; Sagi, S.; Cottrell, B. A.; Torpey, J.; Rosenberry, T. L.; Fauq, A.; Wolfe, M. S.; Schmidt, B.; Walsh, D. M.; Koo, E. H.; Golde, T. E. Substrate-targeting gamma-secretase modulators Nature 2008, 453, 925
19. Weggen, S.; Eriksen, J. L.; Das, P.; Sagi, S. A.; Wang, R.; Pietrzik, C. U.; Findlay, K. A.; Smith, T. E.; Murphy, M. P.; Bulter, T.; Kang, D. E.; Marquez-Sterling, N.; Golde, T. E.; Koo, E. H. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity Nature 2001, 414, 212
20. Weggen, S.; Eriksen, J. L.; Sagi, S. A.; Pietrzik, C. U.; Golde, T. E.; Koo, E. H. Aβ42-lowering nonsteroidal anti-inflammatory drugs preserve intramembrane cleavage of the amyloid precursor protein (APP) and ErbB-4 receptor and signaling through the APP intracellular domain J. Biol. Chem. 2003, 278, 30748
21. Weggen, S.; Eriksen, J. L.; Sagi, S. A.; Pietrzik, C. U.; Ozols, V.; Fauq, A.; Golde, T. E.; Koo, E. H. Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity J. Biol. Chem. 2003, 278, 31831
22. Eriksen, J. L.; Sagi, S. A.; Smith, T. E.; Weggen, S.; Das, P.; McLendon, D. C.; Ozols, V. V.; Jessing, K. W.; Zavitz, K. H.; Koo, E. H.; Golde, T. E. NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo J. Clin. Invest. 2003, 112, 440
23. Geerts, H. Drug evaluation: (R)-flurbiprofen-An enantiomer of flurbiprofen for the treatment of Alzheimer's disease Idrugs 2007, 10, 121
24. Hannam, J.; Kulagowski, J.; Madin, A.; Ridgill, M.; Seward, E. Preparation of piperidines and related compounds for treatment of Alzheimer's disease. WO 2006043064, 2006.
25. Cheng, S.; Comer, D.; Mao, L.; Balow, G.; Pleynet, D. Aryl compounds and uses in modulating amyloid β. WO 2004110350, 2004.
26. Bornemann, K.; Trummlitz, G.; Lazer, E.; Miao, C.; Beck, B.; Sams-Dodd, F.; Kugler, D.; Klinder, K.; Dorner-Ciossek, C.; Kostka, M. Preparation of N-phenyl-heterocycle ketone carboxamides and their enols and method of treating diseases and conditions associated with an altered level of amyloid beta peptides. WO 2005110422, 2005.
27. Findeis, M.; Pal, K.; Schroeder, F. Compounds useful for treating neurodegenerative disorders. WO 2006124956, 2006.
28. Kimura, T.; Kawano, K.; Doi, E.; Kitazawa, N.; Shin, K.; Miyagawa, T.; Kaneko, T.; Ito, K.; Takaishi, M.; Sasaki, T.; Hagiwara, H. Preparation of cinnamide, 3-benzylidenepiperidin-2-one, phenylpropynamide compounds as amyloid β production inhibitors. WO 2005115990, 2005.
29. Fischer, C.; Munoz, B.; Rivkin, A. Preparation of 2-[4-(imidazolyl) phenyl]vinylheterocycles which selectively attenuate production of β-amyloid Aβ (1-42). WO 2008097538, 2008.
30. Huang, X.; Aslanian, R.; Zhou, W.; Zhu, X.; Qin, J.; Greenlee, W.; Zhu, Z.; Zhang, L.; Hyde, L.; Chu, I.; Cohen-Williams, M.; Palani, A. The discovery of pyridone and pyridazone heterocycles as γ-secretase modulators ACS Med. Chem. Lett. 2010, 1, 184
31. Oehlrich, D.; Berthelot, D.; Gijsen, H. γ-Secretase modulators as potential disease modifying anti-Alzheimer's drugs J. Med. Chem. 2011, 54, 669
32. Qin, J.; Dhondi, P.; Huang, X.; Mandal, M.; Zhao, Z.; Pissarnitski, D.; Zhou, W.; Aslanian, R.; Zhu, Z.; Greenlee, W.; Clader, J.; Zhang, L.; Cohen-Williams, M.; Jones, N.; Hyde, L.; Palani, A. Discovery of fused 5,6-bicyclic heterocycles as γ-secretase modulators Bioorg. Med. Chem. Lett. 2011, 21, 664
33. We have tested a limited number of compounds in cell lines with different mutations. Our findings suggest that the potency of GSMs studied is affected by PS1 mutation but not by APP mutation, consistent with the mechanism that this type of GSMs binds directly to γ-secretase instead of its substrates.
34. Korfmacher, W. A.; Cox, K. A.; Ng, K. J.; Veals, J.; Hsieh, Y.; Wainhaus, S.; Broske, L.; Prelusky, D.; Nomeir, A.; White, R. E. Cassette-accelerated rapid rat screen: A systematic procedure for the dosing and liquid chromatography/atmospheric pressure ionization tandem mass spectrometric analysis of new chemical entities as part of new drug discovery Rapid Commun. Mass Spectrom. 2001, 15, 335
35. See the Supporting Information for HPLC conditions.