ACS Medicinal Chemistry Letters
Letter
(9) Yan, R.; Vassar, R. Targeting the β secretase BACE1 for
Alzheimer’s disease therapy. Lancet Neurol. 2014, 13, 319.
Taken together, we believe that compound 26 can be considered
for further preclinical evaluations for testing the amyloid cascade
hypothesis.
(10) Oehlrich, D.; Prokopcova, H.; Gijsen, H. J. M. The evolution of
amidine-based brain penetrant BACE1 inhibitors. Bioorg. Med. Chem.
Lett. 2014, 24, 2033−45.
(11) Audia, J. E.; Mergott, D. J.; Dustin, J.; Sheehan, S. M.; Watson, B.
M. Aminodihydrothiazine derivatives as BACE inhibitors for the
treatment of Alzheimer’s diseases. WO-2009/134617.
ASSOCIATED CONTENT
* Supporting Information
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S
The Supporting Information is available free of charge on the
(12) May, P. C.; Dean, R. A.; Lowe, S. L.; Martenyi, F.; Sheehan, S. M.;
Boggs, L. N.; Monk, S. A.; Mathes, B. M.; Mergott, D. J.; Watson, B. M.;
Stout, S. L.; Timm, D. E.; LaBell, E. S.; Gonzales, C. R.; Nakano, M.;
Jhee, S. S.; Yen, M.; Ereshefsky, L.; Lindstrom, T. D.; Calligaro, D. O.;
Cocke, P. J.; Hall, D. G.; Friedrich, S.; Citron, M.; Audia, J. E. Robust
central reduction of amyloid-β in humans with an orally available, non-
peptidic β-secretase inhibitor. J. Neurosci. 2011, 31, 16507−16516.
(13) Zhu, Y.; Huang, S.; Wan, J.; Yan, L.; Pan, Y.; Wu, A. Two novel
diastereoselective three-component reactions of alkenes or 3,4-dihydro-
(2H)-pyran with urea/thiourea-aldehyde mixtures: [4 + 2] cyclo-
addition vsbBiginelli-type reaction. Org. Lett. 2006, 8, 2599−2602.
(14) After this work was near completion, Lilly disclosed LY2811376
in ref 12 by the end of 2011. This paper suggests that the purpose of the
quaternary methyl group is to exacerbate the desired topology and
enhance chemical stability, but no details were provided.
Synthetic methods and characterization data for com-
pounds 6−28 and methods for in vitro, in vivo, and
pharmacokinetic assays (PDF)
AUTHOR INFORMATION
Corresponding Author
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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(15) Structure coordinates have been deposited with the RSCB Protein
Data Bank (PDB ID 5ENM).
We thank Dr. Nicholas Meanwell for critically reviewing this
manuscript. We also thank Rudy Krause, Alan Xu Lin, and Tracey
Hall for various biological evaluations, and A. Arumugam, K.
Mahammed, Murali Botlagunta, P. N. Arunachalam, Arun Kumar
Gupta, and Richard Rampulla for scaling up intermediate 15.
(16) For an example of applying hydrogen-bond interactions involving
3,5-dimethylisoxazole in drug discovery, see: Hewings, D. S.; Wang, M.;
Philpott, M.; Fedorov, O.; Uttarkar, S.; Panagis Filippakopoulos, P.;
Picaud, S.; Vuppusetty, C.; Marsden, B.; Knapp, S.; Conway, S. J.;
Heightman, T. D. 3,5-Dimethylisoxazoles act as acetyl-lysine-mimetic
bromodomain ligands. J. Med. Chem. 2011, 54, 6761−70.
(17) Guernon, J.; Marcin, L.; Higgins, M.; Yang, F.; Shi, J.; Snyder, L.;
Thompson, L. A.; Wu, Y.-J. Synthesis of β-disubstituted β-amino
isoxazolyl ketones by addition of ketimines with isoxazolyl methyl
ketone enolates. Tetrahedron Lett. 2014, 55, 2134−2137.
(18) The crystal structure of 16 has been deposited in the Cambridge
Crystallographic Data Centre (CCDC #: 1436245).
(19) Edwards, P. D.; Albert, J. S.; Sylvester, M.; Aharony, D.; Andisik,
D.; Callaghan, O.; Campbell, J. B.; Carr, R. A.; Chessari, G.; Congreve,
M.; Frederickson, M.; Folmer, R.H. A.; Geschwindner, S.; Koether, G.;
Kolmodin, K.; Krumrine, J.; Mauger, R. C.; Murray, C. W.; Olsson, L.;
Patel, S.; Spear, N.; Tian, G. Application of fragment-based lead
generation to the discovery of novel, cyclic amidine β-secretase
inhibitors with nanomolar potency, cellular activity, and high ligand
efficiency. J. Med. Chem. 2007, 50, 5912−5925.
(20) Structure coordinates have been deposited with the RSCB Protein
Data Bank (PDB ID 5ENK).
(21) May, P. C.; Willis, B. A.; Lowe, S. L.; Dean, R. A.; Monk, S. A.;
Cocke, P. J.; Audia, J. E.; Boggs, L. N.; Borders, A. R.; Brier, R. A.;
Calligaro, D. O.; Day, T. A.; Ereshefsky, L.; Erickson, J. A.; Gevorkyan,
H.; Gonzales, C. R.; James, D. E.; Jhee, S. S.; Komjathy, S. F.; Li, L.;
ABBREVIATIONS USED
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TFA, trifluoroacetic acid; TEA, triethylamine; DMF, N,N-
dimethylformamide; HATU, 1-[bis(dimethylamino)-
methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexa-
fluorophosphate; rt, room temperature; Metstab, metabolic
stability; CYP, cytochrome P450 enzymes; po, oral admin-
istration; PK/PD, pharmacokinetic/pharmacodynamic
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