L. Shao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1438–1441
1441
Figure 3. (a) Compound 1 in the mouse TST at 3, 10, and 30 mpk po. DES = desipramine 100 mpk po. (b) Compound 1 in mouse locomotor activity assay at 5-min time point,
at 3, 10, and 30 min.
Figure 4. (a) Compound 42 in the mouse TST at 3, 10, and 30 mpk po. DES = desipramine 100 mpk po. (b) Compound 42 in mouse locomotor activity assay at 5 min time
point, at 3, 10, and 30 min.
predictive of antidepressant activity in humans. Our future efforts
will be targeted at fine tuning the potency and metabolic stability
of the scaffold, with an emphasis on increasing potency at SERT
Table 3
Whole brain and plasma levels of compounds 1 and 42 from TST animals
Compd
Dose (mg/kg), po
Plasma levels (ng/ml)
Brain levels (ng/g)
and NET and finding the optimal potency at DAT.
1
3
10
30
3
11
50
227
8
546
2166
7464
123
References and notes
42
1. El Mansari, M.; Guiard, B. P.; Chernoloz, O.; Ghanbari, R.; Katz, N.; Blier, P. CNS
Neuorosci. Ther. 2010, 16, (epub ahead of print).
2. Millan, M. Pharmacol. Ther. 2006, 110, 135.
10
30
21
120
306
2175
3. Blier, P.; Ward, H. E.; Trembley, P.; Laberge, L.; Herbert, C.; Bergeron, H. Am. J.
Psychiatry 2010, 167, 281.
4. Kapur, S.; Mann, J. J. Biol. Psychiatry 1992, 32, 1.
prior to the assay which showed maximal brain levels 30 min after
po dosing. Compound 1 (Fig. 3a) and 42 (Fig. 4a) showed a dose-
dependent reduction in immobility, which was statistically signif-
icant at the 30 mpk dose; the positive control desipramine also
showed a reduction in immobility. Both compounds showed brain
concentrations at the 30 mpk dose that were significantly higher
than their IC50’s (Table 3). The effect of compound 1 (Fig. 3b) and
42 (Fig. 4b) in the TST were also not due to a general locomotor
activation effect; the compounds did not significantly increase
spontaneous locomotor activity in vivo in the first 5 min at the
30 mpk dose—the 5-min time point was significant because that
is the amount of time the compounds were evaluated in the TST.
Our initial lead optimization efforts directed toward a novel tri-
ple reuptake inhibitor for depression achieved the goal of develop-
ing a novel cyclohexane alkyl amine chemotype. Exemplified by
dichlorophenyl methylamine 1 and 2-naphthyl methylamine 42,
we developed compounds with good potency for all three mono-
amine transporters, excellent in vitro metabolic stability, brain
penetration and, most importantly, efficacy in an in vivo model
5. (a) Lucas, M. C.; Weikert, R. J.; Carter, D. S.; Cai, H.-Y.; Greenhouse, R.; Iyer, P. S.;
Lin, C. J.; Lee, E. K.; Madera, A. M.; Moore, A.; Ozboya, K.; Schoenfeld, R. C.;
Steiner, S.; Zhai, Y.; Lynch, S. M. Bioorg. Med. Chem. Lett. 2010, 20, 5559; (b) Lee,
K.-H.; Park, C.-E.; Min, K.-H.; Shin, Y.-J.; Chung, C.-M.; Kim, H.-H.; Yoon, H.-J.;
Kim, W.; Ryu, E.-J.; Shin, Y.-J.; Nam, H.-S.; Cho, J.-W.; Lee, H.-Y. Bioorg. Med.
Chem. Lett. 2010, 20, 5567.
6. Skolnick, P.; Popik, P.; Janowsky, A.; Beer, B.; Lippa, A. S. Eur. J. Pharmacol. 2003,
461, 99.
7. (a) Beer, B.; Stark, J.; Krieter, P.; Czobor, P.; Beer, G.; Lippa, A.; Skolnick, P. J. Clin.
Pharmacol. 2004, 44, 1360; (b) Skolnick, P.; Popik, P.; Janowsky, A.; Beer, B.;
Lippa, A. S. Life Sci. 2003, 73, 3175.
8. DOV Pharmaceutical Press Release September 27, 2005.
9. Calderon, S. N.; Izenwasser, S.; Heller, B.; Gutkind, J. S.; Mattson, M. V.; Su, T.-P.;
Newman, A. H. J. Med. Chem. 1994, 37, 2285.
10. Eschweiler–Clarke reductive alkylation of amines. In Name Reactions for
Functional Group Transformations, John Wiley & Sons, Inc.: Hoboken, N. J.,
2007; pp 86–111.
11. De Luca, S.; Giacomelli, G.; Porcheddu, A.; Salaris, M. Synlett 2004, 2570.
12. Gu, H.; Wall, S.; Rudnick, G. J. Biol. Chem. 1994, 269, 7124.
13. Galli, A.; DeFelice, L. J.; Duke, B. J.; Moore, K. R.; Blakely, R. D. J. Exp. Biol. 1995,
198, 2197.
14. Pristupa, Z. B.; Wilson, J. M.; Hoffman, B. J.; Kish, S. J.; Niznik, H. B. Mol.
Pharmacol. 1994, 45, 125.
15. Steru, L.; Chermat, R.; Thierry, B.; Simon, P. Psychopharmacology 1985, 85, 367.