Abstract
Novel tricyclic sulfones as γ-secretase inhibitors have been reported by this laboratory for the treatment of Alzheimer’s disease. Compounds in this series have comparable or better in vitro activities and in vivo efficacies than sulfonamide analogues reported previously by this laboratory. Based on the previously reported tricyclic sulfone scaffold, additional SAR studies of C ring were carried out. Various C-ring structures including cyclohexane, pyran, and piperidine were tolerated. Additionally, the 7- and 8- positions of the C-ring were identified as the best sites to introduce substituent for modulating the pharmacokinetic properties of compounds from this series.
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References
Hardy JA, selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science, 2002, 297: 353–356
Selkoe DJ. The molecular pathology of Alzheimer’s disease. Neuron, 1991, 6: 487–498
Hardy JA, Higgins GA. Alzheimer’s disease: The amyloid cascade hypothesis. Science, 1992, 256: 184–185
Wu W, Zhang L. γ-Secretase inhibitors for the treatment of Alzheimer’s disease. Drug Develop Res, 2009, 70: 94–100
Nguyen J, Yamani A, Kiso Y. Views on amyloid hypothesis and secretase inhibitors for treating Alzheimer’s disease: Progress and problems. Curr Pharmaceut Des, 2006, 12: 4295–4312
Harrison T, Churcher I, Beher D. γ-Secreatase as a target for drug intervention in Alzheimer’s disease. Curr Opin Drug Discov, 2004, 7: 709–719
Neitzel ML, Aubele DL, Marugg JL, Jagodzinski JJ, Konradi AW, Pleiss MA, Szoke B, Zmolek W, Goldbach E, Quinn KP, Sauer JM, Brigham EF, Wallace W, Bova MP, Hemphill S, Basi G. Amino-caprolactam γ-secretase inhibitors showing potential for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett, 2011, 3715–3720
Brodney MA, Auperin DD, Becker SL, Bronk BS, Brown TM, Coffman KJ, Finley JE, Hicks CD, Karmilowicz MJ, Lanz TA, Liston D, Liu X, Martin BA, Nelson RB, Nolan CE, Oborski CE, Parker CP, Richter KE, Pozdnyakov N, Sahagan BG, Schachter JB, Sokolowski SA, Tate B, Van Deusen JW, Wood DE, Wood KM. Diamide amino-imidazoles: A novel series of γ-secretase inhibitors for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett, 2011, 2631–2638
Hamblett CL, Shah S, Heidebrecht R, Jr Munoz B. γ-Secretase inhibition: an overview of development of inhibitors for the treatment of Alzheimer’s disease. Meth Princ Med Chem, 2010, 45: 353–390
Nguyen J-T, Yamani A, Kiso Y. Views on amyloid hypothesis and secretase inhibitors for treating Alzheimer’s disease: Progress and problems. Curr Phar Des, 2006, 12: 4295–4312
Xu R, Cole D, Asberom T, Bara T, Bennett C, Burnett D, Clader J, Domalski M, Greenlee W, Hyde L, Josien H, Li H, McBriar M, McKittrick B, Pissarnitski D, Qiang L, Rajagopalan M, Sasikumar T, Su J, Tang H, Wu W, Zhang L, Zhao Z. Design and synthesis of tricyclic sulfones as γ-secretase inhibitors with greatly reduced Notch toxicity. Bioorg Med Chem Lett, 2010, 2591–2596
Su J, Tang H, McKittrick BA, Xu R, Clader JW, Greenlee WJ, Hyde L, Zhang L.. Synthesis and SAR study of tricyclic sulfones as γ-secretase inhibitors: C-6 and C-8 positions. Bioorg Med Chem Lett, 2010, 3447-3451
Li H, Xu R, Cole D, Clader JW, Greenlee WJ, Nomeir AA, Song L, Zhang L. Design, synthesis, and structure-activity relationship studies of N-arylsulfonyl morpholines as γ-secretase inhibitors. Bioorg Med Chem Lett, 2010, 20: 6606–6609.
Sasikumar TK, Qiang L, Burnett DA, Cole D, Xu R, Li H, Greenlee WJ, Clader J, Zhang L, Hyde L. Tricyclic sulfones as orally active γ-secretase inhibitors: Synthesis and structure-activity relationship studies. Bioorg Med Chem Lettt, 2010, 12: 3632–3635
Josien H, Bara T, Rajagopalan M, Asberom T, Clader JW, Favreau L, Greenlee WJ, Hyde LA, Nomeir AA, Parker EM, Pissarnitski DA, Song L, Wong GT, Zhang L, Zhang Q, Zhao Z. Small conformationally restricted piperidine N-arylsulfonamides as orally active γ-secretase inhibitors. Bioorg Med Chem Lett, 2007, 17: 5330–5335
McBriar MD, Clader JW, Chu I, Del Vecchio RA, Favreau L, Greenlee WJ, Hyde LA, Nomeir AA, Parker EM, Pissarnitski DA, Song L, Zhang L, Zhao Z. Discovery of amide and het-eroaryl isosteres as carbamate replacements in a series of orally active γ-secretase inhibitors. Bioorg Med Chem Lett, 2008, 18: 215–219
Li H, Asberom T, Bara TA, Clader JW, Greenlee WJ, Josien HB, McBriar MD, Nomeir A, Pissarnitski DA, Rajagopalan M, Xu R, Zhao Z, Song L, Zhang L. Discovery of 2,4,6-trisubstituted N-arylsulfonyl piperidines as γ-secretase inhibitors. Bioorg Med Chem Lett, 2007, 17: 6290–6294
Asberom T, Zhao Z, Bara TA, Clader JW, Greenlee WJ, Hyde LA, Josien HB, Li W, McPhail AT, Nomeir AA, Parker EM, Rajagopalan M, Song L, Wong GT, Zhang L, Zhang Q, Pissarnitski DA. Discovery of γ-secretase inhibitors efficacious in a transgenic animal model of Alzheimer’s disease. Bioorg Med Chem Lett, 2007, 17: 511–516
Unpublished internal data
Zhang L, Song L, Terracina G, Liu Y, Pramanik B, Parker E. Biochemical characterization of the γ-secretase activity that produces γ-amyloid peptides. Biochemistry, 2001, 40: 5049–5055
Hyde LA, McHugh NA, Chen J, Zhang Q, Manfra D, Nomeir AA, Josien H, Bara T, Clader JW, Zhang L, Parker EM, Higgins GA. 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 Pharm Exp Therap, 2006, 319: 1133–1143
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Dedicated to Prof. Ronald Breslow on the occasion of his 80th birthday
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Xu, R., Cole, D., Asberom, T. et al. SAR of tricyclic sulfones as γ-secretase inhibitors. Sci. China Chem. 54, 1688–1701 (2011). https://doi.org/10.1007/s11426-011-4388-6
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DOI: https://doi.org/10.1007/s11426-011-4388-6