C. C. McComas et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4929–4931
4931
Table 2
Characterization of compounds 14, 18, 19, and 20 at the human norepinephrine, serotonin, and dopamine transporters
a
b
c
Compound
X
Y
Z
hNET IC50 (nM)
hSERT IC50 (nM)
hSERT IC50/hNET IC50
hDAT % inhib @ 1 lM
7
H
H
F
F
H
F
H
H
F
H
F
H
H
H
Cl
Cl
F
H
F
F
F
F
47
175
14
19
7
327
7
44%
3%
7%
0%
10%
0%
0%
3%
20%
26%
1%
14a
14b
14c
14d
14e
14f
18a
19a
19b
20a
20b
>3000
2550
>3000
290
>17
182
>157
41
F
H
6
7
330
55
H
1350
1950
>3000
>3000
1150
1750
192
<0.65
>115
>56
<0.38
<0.58
>3000
26
53
>3000
>3000
0%
a
Inhibition of norepinephrine uptake in MDCK-Net6 cells, stably transfected with human NET. Desipramine (IC50 = 3.9 0.5 nM) was used as standard.
Inhibition of serotonin uptake in JAR cells, stably transfected with human SERT. Fluoxetine (IC50 = 10.3 1.7 nM) was used as a standard.
Unitless value as a ratio in which higher numbers represent relatively greater NET selectivity.
b
c
loss of hNET activity observed previously and even displayed a
modest selectivity for hSERT. Although not anticipated to be active
at DAT, these compounds were evaluated for their dopamine trans-
porter binding activity and showed very weak affinity for the DA
transporter. In general compounds 14 and 19 were potent NRIs
and showed excellent selectivity against the 5-HT and DA
trasporters.
References and notes
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In summary, a medicinal chemistry program focused on the de-
sign of potent and selective NRIs successfully identified a new class
of
a 1-(3-amino-1-phenylpropyl)indolin-2-ones that represent
some of the most selective hNET ligands reported to date. Com-
pounds 14d, 14e, and 14f in particular, showed excellent potency
at the hNET and remarkable selectivity over hSERT and hDAT.
Additionally, compounds 14d, 14e, and 14f have low TPSA (ꢀ32)
and are therefore anticipated to cross the blood-brain barrier effi-
ciently.12 These compounds will be further profiled in in vivo mod-
els of neurological disorders and dysfunction thought to be
associated with NE deficiency. The synthesis and characterization
of additional compounds is ongoing in an effort to identify potent
and selective NRIs that may have utility in treating various neuro-
logical disorders.
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Acknowledgments
The authors thank the members of the Discovery Analytical
Chemistry group at Wyeth, especially Diane Andraka, Scott Brec-
ker, Rebecca Dooley, Dr. Christopher Petucci, and Dr. Oliver McCon-
nell for compound analysis. We also thank Dr. Ron Magolda and Dr.
Magid Abou-Gharbia for their encouragement and support.
12. Hitchcock, S. A.; Pennington, L. D. J. Med. Chem. 2006, 49, 7559.