L. J. Van Orden et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1456–1461
1461
13. Dyck, B.; Tamiya, J.; Jovic, F.; Pick, R. R.; Bradbury, M. J.; O’Brien, J.; Wen, J.;
Johns, M.; Madan, A.; Fleck, B. A.; Foster, A. C.; Li, B.; Zhang, M.; Tran, J. A.;
Vickers, T.; Grey, J.; Saunders, J.; Chen, C. J. Med. Chem. 2008, 51, 7265.
14. For a selected review see: Evard, D. A. Annu. Rep. Med. Chem. 2006, 41, 23.
15. Margolis, J. M.; O’Donnell, J. P.; Mankowski, D. C.; Ekins, S.; Obach, R. S. Drug
Metab. Dispos. 2000, 28, 1187.
16. For similar cyclic strategies see: (a) Orjales, A.; Mosquera, R.; Toledo, A.; Pumar,
M. C.; Garcia, N.; Cortizo, L.; Labeaga, L.; Innerarity, A. J. Med. Chem. 2003, 46,
5512; (b) Fish, P. V.; Andrews, M. D.; Fray, M. J.; Stobie, A.; Wakenhut, F.;
Whitlock, G. A. Bioorg. Med. Chem. Lett. 2009, 19, 2829; (c) Fish, P.; Deur, C.;
Gan, X.; Greene, K.; Hoople, D.; Mackenny, M.; Para, K.; Reeves, K.; Ryckmans,
T.; Stiff, C.; Stobie, A.; Wakenhut, F.; Whitlock, G. Bioorg. Med. Chem. Lett. 2008,
17. Yaksh, T. L.; Ozaki, G.; McCumber, D.; Rathbun, M.; Svensson, C.; Malkmus, S.;
Yaksh, M. C. J. Appl. Physiol. 2001, 90, 2386.
18. Kim, S. H.; Chung, J. M. Pain 1992, 50, 355.
19. To determine whether %ee was maintained during the oxidation, the R- and S-
aldehydes were taken on to the next step (phenylmagnesium bromide
addition) and these alcohol products were assessed on chiral, analytical HPLC.
20. Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 973.
22. X-ray crystallography was performed at Avantium. This compound has been
deposited in the CCDC database and can be found with the following
deposition number: CCDC 915348.
23. Tsuruda, P.; Yung, J.; Martin, W. J.; Chang, R.; Mai, N.; Smith, J. A. M. J.
24. As reported in Ref. 23, NET apparent binding pKi values and NET functional
inhibition for a large subset of compounds of this class, were highly correlative.
In a similar fashion, DAT apparent binding pKi correlated well with DAT pIC50
values (unpublished in house data). Because of the relative ease of the DAT
apparent binding assay as compared to the functional assay, the binding assay
was used to test the majority of compounds reported herein.
25. Fish, P.; Wakenhut, F.; Ryckmans, T.; Stobie, A. Bioorg. Med. Chem. Lett. 2009, 19,
26. Knadler, M. P.; Lobo, E.; Chappell, J.; Bergstron, R. Clin. Pharmacokinet. 2011, 50,
281.
27. Pgp efflux ratio for milnacipran can also be found here: Dyck, B.; Tamiya, J.;
Jovic, F.; Pick, R. R.; Bradbury, M. J.; O’Brien, J.; Wen, J.; Johns, M.; Madan, A.;
Fleck, B. A.; Foster, A. C.; Li, B.; Zhang, M.; Tran, J. A.; Vickers, T.; Grey, J.;
Saunders, J.; Chen, C. J. Med. Chem. 2008, 51, 7265.
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