Conformationally restricted homotryptamines. Part 5: 3-(trans-2-aminomethylcyclopentyl)indoles as potent selective serotonin reuptake inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.06.026

A series of racemic 3-(trans-2-aminomethylcyclopentyl)indoles was synthesized and found to have potent binding to the human serotonin transporter (hSERT). The most active analog was synthesized stereospecifically and the active enantiomer was shown to hav

Full text of DOI:10.1016/j.bmcl.2009.06.026

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4031–4033
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Conformationally restricted homotryptamines. Part 5: 3-(trans-2-
aminomethylcyclopentyl)indoles as potent selective serotonin
reuptake inhibitors
*
Derek J. Denhart , Jeffrey A. Deskus, Jonathan L. Ditta, Qi Gao, H. Dalton King, Edward S. Kozlowski,
Zhaoxing Meng, Melissa A. LaPaglia, Gail K. Mattson, Thaddeus F. Molski, Matthew T. Taber,
Nicholas J. Lodge, Ronald J. Mattson, John E. Macor
Bristol-Myers SquibbPharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-7660, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 February 2009
Revised 5 June 2009
Accepted 8 June 2009
Available online 13 June 2009
A series of racemic 3-(trans-2-aminomethylcyclopentyl)indoles was synthesized and found to have
potent binding to the human serotonin transporter (hSERT). The most active analog was synthesized ste-
reospecifically and the active enantiomer was shown to have high affinity binding to hSERT.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indoles
Homotryptamines
SSRI
Serotonin
Serotonin (5-hydroxytryptamine or 5-HT) is an important neu-
rotransmitter and alterations in its signaling are implicated in
affective disorders. The selective serotonin reuptake inhibitors
(SSRIs) block the serotonin transporter (SERT) and prevent reup-
take into presynpatic neuron.1
The SSRIs are widely used antidepressants, and are relatively
safe despite some recognized issues.2 Some recent SSRI research
has sought to discover compounds with more rapid onset of action
as well as discovering compounds that increase the number of pa-
tients who respond to treatment. Among other approaches, some
investigations have attempted to combine SERT inhibition with
5-HT1A, 5-HT1B, or NK1 antagonism.3
The conformational restriction of ligands or inhibitors is a well-
precedented way to improve binding and selectivity of these
agents. We have previously reported SERT binding results with
homotryptamines 14 and conformationally-restricted homotrypta-
mine analogs 25 and 36 (Fig. 1).
The synthesis of the racemic cis and trans 3-(2-aminomethyl-
cyclopentyl)indoles is shown in Scheme 1 5-cyanoindole 4 is con-
verted into iodoindole 5 and then subjected to a Stille coupling
with 6 to provide olefin 7.7 Tosyl removal and hydrogenation pro-
vided racemic cis compound 8. Base equilibration followed by
functional group conversion produced racemic trans aldehyde 9
NH2
N
HO
NC
N
H
N
H
serotonin
1
N
In this report we discuss methods to vary the ring size from the
cyclopropyl in 3 to cyclopentyl and the effect this modification has
on SERT binding and the physical properties of the 3-cyclopenty-
lindole derivatives. The 5-cyanoindole core (Fig. 1, X = CN) was
maintained based on SAR from the indole cyclopropane series dis-
covered previously.6
N
NC
NC
N
H
N
H
3
2
* Corresponding author. Tel.: +1 203 677 7117.
E-mail address: derek.denhart@bms.com (D.J. Denhart).
Figure 1. Previously reported indole SERT ligands.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.06.026

4032
D. J. Denhart et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4031–4033
I
NC
c,d
NC
a,b
a,b,c
CO2Et
CHO
NC
N
H
N
Ts
67%
5
4
7
N
Ts
7
CO2Et
g, h, i
CO2Et
NC
NC
NMe2
e, f
NC
d,e
NC
N
H
N
Ts
8
N
N
H
Ts
12
11
R
N
CHO
Scheme 2. Synthesis of cis cyclopentane 10. Reagents and conditions: (a) H2, Pd/C;
(b) LiAlH4, ꢀ40 °C; (c) (COCl)2, DMSO, then ROH, then Et3N; (d) Me2N, NaBH(OAc)3;
(e) NaOH, EtOH.
R'
NC
j
NC
N
N
H
H
10
9
Table 2
hSERT binding affinities of stereoisomers of 10b and 12a
a
Compound
cis/trans
SERT IC50 (nM)
10b
trans
trans
trans
cis
cis
cis
0.32 0.04
0.13
58
2.6 0.34
130 16
1.2 0.21
TfO
CO2Et
(+)-10b
(-)-10b
12
(+)-12
(-)-12
6
Scheme 1. Synthesis of trans racemic cyclopentanes. Reagents and conditions: (a)
I2. KOH; (b) TsCl, DIPEA (67%); (c) (Bu3Sn)2, Pd(OAc)2, PPh3 (82%); (d) 6, Pd2dba3,
Ph3As (73%); (e) NaOH, H2O (94%); (f) H2, Pd/C, (89%); (g) LiOH, H2O, EtOH, reflux;
(h) MeONHMe–HCl, EDCI, Et3N (41%); (i) LAH, ꢀ38 °C (68%); (j) R-NH-R0,
NaBH(OAc)3.
a
Where indicated with SEM, n >= 3 for the reported IC50 values. Otherwise,
n = 2.
which was then reductively aminated to provide a variety of
amines 10.
Table 3
Binding affinities (IC50 in nM) versus selected receptors for 2, 3, and (+)-10b
The data for the racemic trans compounds are shown in Table 1.
This series provided several highly potent SERT8 inhibitors, most
notably the dimethylamine 10b. The data show a clear preference
for small alkyl groups, exemplified by the potent binding of 10a–c
contrasted with the drop in activity for the diethylamine 10f. These
SAR trends are similar to what was observed for the previously re-
ported 3-cyclopropylindole series.6
Compound
SERT
DAT
NET
390
9200
7900
2
3
0.72
0.36
0.13
290
4200
690
(+)-10b
To test the effects of bond orientation about the cyclopentane
ring, we desired to test the enantiomers of both trans and cis cyclo-
pentane dimethylamines. The racemic trans 10b could be sepa-
rated into (1S,2S) (+)-10b and (1R,2R) (ꢀ)-10b using chiral HPLC.
Alternatively, larger amounts of these trans enantiomers could be
synthesized by an asymmetric Michael addition as previously re-
ported.9 The synthesis of racemic cis compounds is shown in
Scheme 2. The previously synthesized 7 was hydrogenated and
subjected to careful ester reduction followed by Swern oxidation10
to provide racemic cis aldehyde 11. Reductive amination followed
by tosyl removal gave desired racemic cis amine 12. This racemic
mixture was separated into (+)-12 and (ꢀ)-12 using chiral HPLC.
As can be seen from the data in Table 2, the most potent com-
pound was the trans-(1S,2S) enantiomer (+)-10b with a hSERT
binding IC50 of 0.13 nM. The cis compounds (+)-12 and (ꢀ)-12 were
several fold less active than the trans analogs. The most active cis
enantiomer was the (1R,2S) (+)-12 with an IC50 of 1.2 nM. The
absolute configurations of active enantiomers were as expected
based on the indole cyclopropane series reported previously.2
In Table 3 can be seen data on the binding potency of (+)-10b
and the previously reported compounds 2 and 3 to the major bio-
genic amine transporters SERT, DAT (dopamine) and NET (norepi-
nephrine).11 The cyclo pentyl compound (+)-10b is the most
potent at binding to SERT, with the cyclohexene compound 2 being
the least potent (although still subnanomolar in IC50). Both com-
pounds 2 and 3 show binding to DAT which is at least 5000 fold
weaker than its binding to SERT, and binding to NET which is at
least 25,000 fold weaker than SERT. Compound 2 is significantly
less selective than 3 and (+)-10b.
In vivo microdialysis studies with (+)-10b are shown in Figure 2.12
Compound (+)-10b given orally caused a robust increase in extracel-
lular serotonin concentrations in the frontal cortex of awake, freely
moving rats. The maximal response was achieved at 1 mg/kg (po),
and this increased serotonin levels to greater than 300% of baseline.
This effect was similar to that produced by the SSRI paroxetine given
at 5 mg/kg.
In conclusion, the 3-(2-aminomethylcyclopentyl)indole series
provided a compound (+)-10b which was a picomolar potent and
selective inhibitor of the hSERT transporter. Future studies are
ongoing to fully appreciate the therapeutic potential of such a
compound.
Table 1
Binding affinities of racemic trans compounds 10a–ga
a
Compound
R
R’
SERT IC50 (nM)
10a
10b
10c
10d
10e
10f
Me
Me
Me
Me
Et
H
Me
Et
CH2Ph
H
7.0 1.1
0.32 0.04
10 0.50
85 12
170
Et
Et
240
22 4.2
ꢀ
10g
—ðCH2Þ4
a
Where indicated with SEM, n >= 3 for the reported IC50 values. Otherwise,
n = 2.

D. J. Denhart et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4031–4033
4033
(+)-10b (3 mg/kg po)
(+)-10b (1 mg/kg po)
(+)-10b (0.3 mg/kg)
450
400
350
300
250
200
150
100
50
Vehicle (water, 1 ml/kg po)
Paroxetine (5 mg/kg po)
0
0
20
40
60
80 100 120 140 160 180 200 220 240 260 280 300
Time (min)
Figure 2. Dose-reponse curves for compound (+)-10b given po.
7. Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1994, 35, 2405.
References and notes
8. The SERT binding affinities were determined using membrane homogenates
from HEK-293 cells that stably expressed human serotonin transporters (HEK-
hSERT cells). Membrane homogenates were incubated with 2 nM
[3H]citalopram (specific activity = 85 Ci/mmol) and increasing concentrations
1. Spinks, D.; Spinks, G. Curr. Med. Chem. 2002, 9, 799.
2. Ananth, J. Psychother. Psychosom. 1998, 67, 61.
3. (a) Rocco, V. P.; Spinazze, P. G.; Kohn, T. J.; Honigschmidt, N. A.; Nelson, D. L.;
Wainscott, D. B.; Ahmad, L. J.; Shaw, J.; Threlkeld, P. G.; Wong, D. T.; Takeguchi,
K. Bioorg. Med. Chem. Lett. 2004, 14, 2653; (b) Oficialdegui, A. M.; Martinez, J.;
Perez, S.; Hears, B.; Irurzun, M.; Palop, J. A.; Tordera, R.; Lasheras, B.; del Rio, J.;
Monge, A. Farmaco 2000, 55, 345; (c) Evrard, D. A.; Zhou, P.; Yi, S.; Zhow, D.;
Smith, D.; Sullivan, K. M.; Hornby, G. A.; Scheckter, L. E.; Andree, T. H.;
Mewshaw, R. E. Bioorg. Med. Chem. Lett. 2005, 15, 911; (d) Ryckmans, T.;
Balancon, L.; Berton, O.; Genicot, C.; Lamberty, Y.; Lallemand, B.; Pasau, P.; Pirol,
N.; Quere, L.; Talaga, P. Bioorg. Med. Chem. Lett. 2002, 12, 261; (e) Ryckmans, T.;
Berton, O.; Grimee, R.; Kogej, T.; Lamberty, Y.; Pasau, P.; Talaga, P.; Genicot, C.
Bioorg. Med. Chem. Lett. 2002, 12, 3195.
4. (a) Schmitz, W. D.; Denhart, D. J.; Brenner, A. B.; Ditta, J. L.; Mattson, R. J.; Mattson,
G. K.; Molski, T. F.; Macor, J. E. Bioorg. Med. Chem. Lett. 2005, 15, 1619; (b) Denhart,
D. J.; Mattson, R. J.; Ditta, J. L.; Macor, J. E. Tetrahedrom Lett. 2004, 45, 3803.
5. Deskus, J. A.; Epperson, J. R.; Sloan, C. P.; Cipollina, J. A.; Dextraze, P.; Qian-
Cutrone, J.; Gao, Q.; Ma, B.; Beno, B. R.; Mattson, G. K.; Molski, T. F.; Krause, R. G.;
Taber, M. T.; Lodge, N. J.; Mattson, R. J. Bioorg. Med. Chem. Lett. 2007, 17, 3099.
6. Mattson, R. J.; Catt, J. D.; Denhart, D. J.; Deskus, J. A.; Ditta, J. L.; Higgins, M. A.;
Marcin, L. R.; Sloan, C. P.; Beno, B. R.; Gao, Q.; Cunningham, M. A.; Mattson, G.
K.; Molski, T. F.; Taber, M. T.; Lodge, N. J. J. Med. Chem. 2005, 48, 6023.
of test compounds for 1 h at 25 °C in a total volume of 250 lL. Amount of
radioligand bound in the presence and absence of a competitor was analyzed
by plotting (-)log drug concentration versus the amount of radioligand
specifically bound. Non-specific binding was defined with 10 lM fluoxetine.
The midpoint of the displacement curve (IC50 in nM) signified the potency.
9. King, H. D.; Meng, Z.; Denhart, D.; Mattson, R.; Kimura, R.; Wu, D.; Gao, Q.;
Macor, J. E. Org. Lett. 2005, 7, 3437.
10. Omura, K.; Swern, D. Tetrahedron Lett. 1978, 34, 1651.
11. SERT, DAT, and NET binding affinities were determined using membrane
homogenates from stably transfected HEK-293 cell lines expressing the human
form of the transporters. Membrane homogenates were incubated with 125I
labeled ligands. RTI-55 (Perkin–Elmer) was used for SERT (260 pM) and DAT
(125 pM). A custom labeled 125I Nisoxetine (Perkin Elmer) was used for NET
(300 pM). The reactions were carried out in a 384-well format and harvested in
384-well filter plates. The IC50 data was determined from a 20-point curve.
Non-specific binding was defined using 10
lM fluoxetine for SERT, 100 lM
Desipramine for NET, and 10 M GBR-12935 for DAT.
l
12. Taber, M. T.; Wright, R. N.; Molski, T. F.; Clarke, W. J.; Brassil, P. J.; Denhart, D. J.;
Mattson, R. J.; Lodge, N. J. Pharmacol., Biochem. Behav. 2005, 80, 521.