Synthesis and pharmacological characterization of bicyclic triple reuptake inhibitor 3-aryl octahydrocyclopenta[c]pyrrole analogues

Article abstract of DOI:10.1021/jm101312a

The present work expands the chemical space known to offer potent inhibition of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) and discloses novel bicyclic octahydrocyclopenta[c]pyrrole and octahydro-1H-isoindole scaffolds as potent triple reuptake inhibitors (TRIs) for the potential treatment of depression. Optimized compounds 22a (SERT, NET, DAT, IC₅₀ = 20, 109, 430 nM), 23a (SERT, NET, DAT, IC₅₀ = 29, 85, 168 nM), and 26a (SERT, NET, DAT, IC₅₀ = 53, 150, 140 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 10 and 30 mpk PO, and were not generally motor stimulants at doses ranging from 1 to 30 mpk PO. Moderate in vitro cytochrome P450 (CYP) and potassium ion channel Kv11.1 (hERG) inhibition were uncovered as potential liabilities for the chemical series.

Full text of DOI:10.1021/jm101312a

ARTICLE
pubs.acs.org/jmc
Synthesis and Pharmacological Characterization of Bicyclic Triple
Reuptake Inhibitor 3-Aryl Octahydrocyclopenta[c]pyrrole Analogues
Liming Shao,*,† Michael C. Hewitt,†,‡ Scott C. Malcolm,† Fengjiang Wang,† Jianguo Ma,† Una C. Campbell,†
Nancy A. Spicer,† Sharon R. Engel,† Larry W. Hardy,† Zhi-Dong Jiang,† Rudy Schreiber,†,§ Kerry L. Spear,†
||
and Mark A. Varney†,
†Discovery and Early Clinical Research, Sunovion Pharmaceuticals, 84 Waterford Drive, Marlborough Massachusetts 01752,
United States
ABSTRACT: The present work expands the chemical space known to offer
potent inhibition of the serotonin transporter (SERT), norepinephrine
transporter (NET), and dopamine transporter (DAT) and discloses novel
bicyclic octahydrocyclopenta[c]pyrrole and octahydro-1H-isoindole scaffolds
as potent triple reuptake inhibitors (TRIs) for the potential treatment of
depression. Optimized compounds 22a (SERT, NET, DAT, IC50 = 20, 109,
430 nM), 23a (SERT, NET, DAT, IC50 = 29, 85, 168 nM), and 26a (SERT,
NET, DAT, IC50 = 53, 150, 140 nM) were highly brain penetrant, active
in vivo in the mouse tail suspension test at 10 and 30 mpk PO, and were not
generally motor stimulants at doses ranging from 1 to 30 mpk PO. Moderate in
vitro cytochrome P450 (CYP) and potassium ion channel Kv11.1 (hERG)
inhibition were uncovered as potential liabilities for the chemical series.
’ INTRODUCTION
Antidepressants modulate levels of neurotransmitters
(serotonin and norepinephrine) by either inhibiting reuptake
(such as selective serotonin reuptake inhibitors, SSRIs; norepi-
nephrine reuptake inhibitors, NRIs) or blocking metabolism
pathways (monoamine oxidase inhibitors, MAOIs).1 The major
drawbacks to both reuptake inhibitors and MAOIs are slow
onset2 and low patient response rate.
Recent study results showed the linkage between the deficits
Figure 1. Novel DOV-like triple reuptake inhibitors: octahydrocyclo-
in mesocorticolimbic dopaminergic function and anhedonia,
which is a core symptom of depression.3 Clinically, dopamine
reuptake inhibitors (e.g., buproprion) and dopamine agonists
(e.g., pramipexole) are already used to augment the effects of
traditional antidepressants in treatment of refractory patients and
also show improved side effect profiles.4 As a result, there is
considerable interest in designing and developing a triple reup-
take inhibitor (TRI), i.e. a single compound that would simulta-
neously modulate levels of serotonin, norepinephrine, and
dopamine levels for the treatment of major depression disorder
(MDD).5
penta[c]pyrroles (1a) and octahydro-1H-isoindoles (1b).
(vida supra), we expanded the cyclopropyl ring of DOV-216303
to create two novel fused octahydrocyclopenta[c]pyrrole and
octahydro-1H-isoindole scaffolds (Figure 1). Our goal was to
probe the SAR of these novel chiral amines as potential triple
reuptake inhibitors and create novel architectures that possessed
varying degrees of reuptake inhibition at SERT, NET, and DAT.
The synthesis, detailed SAR of the scaffolds, and their inhibition
against SERT, NET, and DAT are detailed below.
DOV Pharmaceuticals previously reported6 on a novel aryl
azabicyclo[3.1.0]hexane scaffold that potently inhibited the three
monoamine transporters and showed antidepressant-like activity
in the rat forced swim and mouse tail suspension tests. In
addition, Breuer et al. (2008) later showed that DOV-216,303
lacked sexual side effects in rat.7
’ RESULTS AND DISCUSSION
Chemistry. Synthetic access to the novel bicyclic aryl amines
1a and 1b was achieved by four different synthetic routes, which
allowed for access to an diverse array of compounds of type 1a
and 1b with a variety of amine substituents and aryl modifications
We previously reported on our work developing TRIs in the
tetralone8 and amino tetralone9 families; our present work
expands the chemical space known to offer potent triple reup-
take inhibition. Starting from the DOV family of compounds
Received: October 12, 2010
Published: July 08, 2011
r
2011 American Chemical Society
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on the bridging carbon of the fused ring systems. The developed
synthetic pathways further allowed access to different chiral
analogues, which were separated by chiral chromatography.
The first route to our novel bicyclic aryl amines utilized
DielsꢀAlder chemistry to construct the six-membered ring
(Scheme 1). Condensation of 3-arylfuran-2,5-diones 2 with
1,3-butadiene gave the desired cis 6ꢀ5 carbon skeleton. Forma-
tion of the imide, hydrogenation, and reduction provided the cis-
octahydro-1H-isoindoles 4.
We also developed an alternate route to the bicyclic amines
that enabled us to synthesize both octahydro-1H-isoindoles and
octahydrocyclopenta[c]pyrroles, using lactone arylation chem-
istry we developed specifically for the scaffold (Scheme 2).10
Palladium catalyzed arylation of lactone 5/6 with commercially
available aryl bromides gave excellent yields of the desired bicylic
aryl lactones, which could be opened by amine nucleophiles
resulting in two alternative pathways: lithium anions of alkyl
amines opened the lactone at the carbonyl to give amido-alcohols
9/10, while potassium phthalimide opened the lactone at carbon
to give phthalimido-acids 11/12. Either precursor could be
elaborated to the desired racemic cis bicyclic aryl amines 13/4
in two steps.
Synthesis of the corresponding trans-octahydro-1H-isoindoles
required a DielsꢀAlder route that is shown in Scheme 3.
HornerꢀWadsworthꢀEmmons reaction of ester 14 with diethyl
cyanomethylphosphonate in toluene provided a 3:1 cis:trans
mixture of alkene 15, which could be equilibrated to 100% trans
after hydrolysis of the ester with aqueous base. Acid chloride 16
was the preferred dienophile for the DielsꢀAlder reaction with
1,3-butadiene. The product acid chloride nitrile was quenched
with methanol to provide an intermediate methyl ester. Both the
methyl ester and nitrile were reduced with LAH to provide amino
alcohol 17. Protection of the primary amine, hydrogenation, and
mesylation provided penultimate compound 18, which could be
cyclized with NaOH after deprotection of the BOC group to
provide racemic trans compound 19.
Preparation of chirally pure cis and trans bicyclic aryl amines
could be accomplished via chiral HPLC of the parent amines,
derivatization (i.e., Boc2O), and chiral separation, or separation
of the amido-alcohol precursors 9/10 (Scheme 4). The route
used depended on the bicyclic scaffold and substitution of the
aryl portion and was determined experimentally. The absolute
configuration was not determined for the single enantiomers but
was assigned arbitrarily, as shown in the schemes.
The last group of analogues we synthesized was the benzyl
substituted amines shown in Scheme 5. Alkylation of imide 28
with 3,4-dichlorobenzyl bromide and reduction gave the desired
racemic N-methyl amines, which could be resolved into consti-
tutive isomers 29 and 30 via chiral HPLC. Demethylation
(chloroethylchloroformate) converted the tertiary amines into
secondary amines 31 and 32.
Inhibition of Serotonin, Norepinephrine, and Dopamine
Reuptake, SAR. The novel compounds described above were
tested for their inhibition of functional uptake of serotonin,
norepinephrine, or dopamine, using recombinant transporters
expressed in HEK-293, MDCK, or CHO-K1 cells (Table 1, see
Experimental Section for details). The first parameter we system-
atically varied was the aromatic substituent in the N-methyl
octahydro-1H-isoindoles (Table 1). We used the racemic com-
pounds to get an initial sense of the potential for triple reuptake
inhibition before investing additional resources in chiral separa-
tion of the individual enantiomers. As Table 1 shows, the
serotonin transporter showed a distinct preference for phenyl
substituents at the 3 and 4-position, with 3,4-di-OCH3 4f,
3-OCH3 4d, and 4-OCH3 phenyl 4e, in addition to 2-naphthyl
4h, all showing reasonably potent inhibition of serotonin reup-
take. Potency against the NE and DA transporter was more
difficult to achieve: the 2-naphthyl compound 4h showed potent
inhibition of both NE and DA, and the 1-naphthyl (4g) and 2,4-
di-Cl (4b) phenyl compounds showed potency at NET and
some potency at DAT. Given the literature data for the DOV
compounds, we knew that a 3,4-dichlorophenyl aromatic would
be a preferred substituent, so we carried out chiral separations of
3,4-dichlorophenyl (4i), 1-naphthyl (4g), and 2-napthyl (4h)
Scheme 1. DielsꢀAlder Route to Racemic cis-Octahydro-
1H-isoindoles with Diverse Substitution Patterns ((()-4aꢀj)
Scheme 2. Lactone Arylation Pathway to cis-Octahydro-1H-isoindole 4 or Octahydrocyclopenta[c]-pyrrole 13 Scaffolds
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Scheme 3. Synthesis of Racemic trans-Octahydro-1H-isoindoles 19
Scheme 4. Chiral Separation Schematic to Prepare Single Enantiomers 20ꢀ27
Scheme 5. Synthesis of Benzyl Compounds 29ꢀ32
compounds and tested their constitutive isomers against SERT,
NET, and DAT. 3,4-Dichlorophenyl enantiomer 23a showed
excellent inhibition against all three transporters and prompted
us to make and separate the N-ethyl analogues (21b, 23b), which
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Table 1. N-Alkyl Octahydro-1H-isoindole Aryl Variationa
a SERT, NET, and DAT reuptake inhibition assays were done with at least n = 2 and five concentrations to generate inhibition curves, from which pIC50
values were determined. The indicated standard deviation (SD) values were determined from replicate independent concentration-dependence studies.
Assay performance was monitored by the use of SERT reference compound fluoxetine (pIC50 = 8.3 ((0.1)), NET reference compound nisoxetine
(pIC50 = 8.1 ((0.1)), and DAT reference compound nomifensine (pIC50 = 7.5 ((0.1)). An IC50 value can be calculated from pIC50 using the following
formula: IC50 (nM) = 10(9-pIC50). b LLE (lipophilic ligand efficiency) = pIC50 ꢀ log P.
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Table 2. Octahydrocyclopenta[c]pyrroles and Octahydro-1H-isoindolesa
a SERT, NET, and DAT reuptake inhibition assays were done with at least n = 2 and five concentrations to generate inhibition curves, from which pIC50
values were determined. The indicated standard deviation (SD) values were determined from replicate independent concentration-dependence studies.
Assay performance was monitored by the use of SERT reference compound fluoxetine (pIC50 = 8.3 ((0.1)), NET reference compound nisoxetine
(pIC50 = 8.1 ((0.1)), and DAT reference compound nomifensine (pIC50 = 7.5 ((0.1)). An IC50 value can be calculated from pIC50 using the following
formula: IC50 (nM) = 10(9-pIC50)). b LLE (lipophilic ligand efficiency = pIC50 ꢀ log P.
showed potent inhibition against all three transporters as well.
The 2-naphthyl enantiomers 21d and 23d showed nice profiles,
although the potency at NET was a bit weaker than in the 3,4-
dichlorophenyl series, and the 1-naphthyl enantiomers 21c and
23c showed a preference for the serotonin transporter over the
dopamine and norepinephrine transporters. For the first series of
compounds, 23a showed the most potential for triple reuptake
inhibition and was also close to the SERT/NET/DAT potency
ratio we were seeking.
Table 2 shows our survey of octahydrocyclopenta[c]pyrroles
and octahydro-1H-isoindoles with aromatic 3,4-dichlorophenyl
and 2-naphthyl substitution, which showed excellent reuptake
inhibition at all three transporters. Racemic 3,4-dichlorophenyl
octahydro-1H-isoindole 4j showed potent inhibition at all three
transporters; resolution into constitutive isomers 27a and 25a
showed that enantiomer 27a was the standout, with potency
against SERT and DAT below 100 nM and NET inhibition
around 200 nM. We also examined if the trans-octahydro-1H-
isoindole compounds showed any potential: neither 19a nor
enantiomer 19b showed potent inhibition and clearly indicated
that a cis ring fusion was necessary to potently inhibit the three
monoamine transporters. In the octahydrocyclopenta[c]pyrrole
series, we did not profile the racemic 3,4-dichlorophenyl and
2-naphthyl compounds but went straight to resolution into
constitutive isomers: the excellent profiles we saw for all four
compounds validated our reasoning. In particular, 3,4-dichlor-
ophenyl amine 26a and 2-naphthyl enantiomer 24b showed
potent reuptake inhibition at all three transporters and became
candidates for additional in vitro ADMET characterization.
In the N-methyl octahydrocyclopenta[c]pyrrole aryl variation,
the 3,4-dichlorophenyl 13a and 2-naphthyl 13f racemic com-
pounds were standouts from a TRI perspective and led us to
separate the racemic compounds into constitutive isomers. All
four enantiomers (20a, 22a, 20b, and 22b) showed potent
inhibition at the three transporters, with a nice variety of ratios
among the four compounds. 2-Naphthyl 20b was among the
most potent SERT inhibitors we profiled (pIC50 = 8.637, IC50
=
2 nM) and maintained the general trends of superior potency for
tertiary amines over second amines at the serotonin transporter
and also of 2-naphthyl > 3,4-dichlorophenyl in absolute trans-
porter potency: the most potent compounds we made were
invariably 2-naphthyl substituted.
One other group of compounds we chose to profile were the
enantiopure
3,4-dichlorobenzyl
octahydro-1H-isoindoles
(Table 4), which showed potent inhibition against SERT and
DAT and dramatically reduced potency against NET compared
with the 3,4-dichlorophenyl counterparts. The tertiary amines
showed increased potency against SERT compared with the
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Table 3. N-Methyl Octahydrocyclopenta[c]pyrroles SARa
a SERT, NET, and DAT reuptake inhibition assays were done with at least n = 2 and five concentrations to generate inhibition curves, from which pIC50
values were determined. The indicated standard deviation (SD) values were determined from replicate independent concentration-dependence studies.
Assay performance was monitored by the use of SERT reference compound fluoxetine (pIC50 = 8.3 ((0.1)), NET reference compound nisoxetine
(pIC50 = 8.1 ((0.1)), and DAT reference compound nomifensine (pIC50 = 7.5 ((0.1)). An IC50 value can be calculated from pIC50 using the following
formula: IC50 (nM) = 10(9-pIC50). b LLE (lipophilic ligand efficiency = pIC50 ꢀ log P.
secondary amines in the benzyl series, keeping with the trends we
observed with the phenyl analogues shown above.
lead when the lead had a LE in the “ideal” range (i.e., 0.3).14 For
all the reasons stated above, we chose to also consider the LLE of
our novel compounds when evaluating their potency
(Table 1ꢀ4) and comment on it briefly below. Our LLE
considerations were complicated slightly by the fact that we were
trying to optimize potency at three different transporters simul-
taneously; in general, we saw the best LLE at SERT (range 3ꢀ4),
while LLE at NET and DAT were closer to 2ꢀ3 for the majority
of our compounds. In the octahydro-1H-isoindole series, di-
chlorophenyl N-methyl analogue 23a showed a nice LLE of 3.42
at SERT, while 2-naphthyl N-CH3 analogues 21d and 23d were
at SERT LLEs of 3.99 and 3.73, respectively. Racemic octahydro-
1H-isoindole methoxy phenyl substituted compounds 4e, 4d,
and 4f were also standouts in SERT LLE, with values of 3.58,
3.64, and 4.23 but no appreciable potency/LLE at NET and
DAT. In the octahydrocyclopenta[c]pyrrole series, the LLE
values were generally higher due to the lower log Ps of the
compounds compared to their octahydro-1H-isoindole counter-
parts and also maintained the general trend of better LLEs at
SERT vs NET and DAT. Some standouts in the dichlorophenyl
octahydro-1H-isoindole series were 22a, with LLE at SERT of
4.3 and 3.51 at NET and 26a, with LLE at SERT of 3.71, 3.37 at
Ligand Efficiency. Ligand efficiency11 (LE) considerations
during the lead optimization process are a current topic of great
interest to medicinal chemists and were also factored into our
thinking in the evaluation of our novel TRIs. LE refers to the
potency of a compound normalized for its molecular weight
(MW) and is used to try to avoid unnecessary increases in MW as
a lever to increase potency. LE can be defined a number of ways,
but in general is pKi, pKd, or pIC50/no. of heavy atoms. Another
useful metric that can be easily calculated is the lipophilic ligand
efficiency12, which is defined as LLE = pKi or pIC50 ꢀ ClogP or
(ClogP7.4). LLE normalizes potency for lipophicity and attempts
to tease our potency that is due to specific interactions between a
ligand and a protein and potency that is simply due to entropy
driven hydrophobic effects (burying lipophicity in a cavity of the
protein to avoid water). Increases in MW and lipophilicity will
increase unwanted off-target interactions and lead to, among
other things, poor solubility, permeability, and oral
bioavailability.13 A review from 2010 also showed a nice correla-
tion between LE for leads and approved drugs and showed that
most approved drugs were not that different from their respective
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Table 4. Benzyl Substituted Bicyclic Aminesa
a SERT, NET, and DAT reuptake inhibition assays were done with at least n = 2 and five concentrations to generate inhibition curves, from which pIC50
values were determined. The indicated standard deviation (SD) values were determined from replicate independent concentration-dependence studies.
Assay performance was monitored by the use of SERT reference compound fluoxetine (pIC50 = 8.3 ((0.1)), NET reference compound nisoxetine
(pIC50 = 8.1 ((0.1)), and DAT reference compound nomifensine (pIC50 = 7.5 ((0.1)). An IC50 value can be calculated from pIC50 using the following
formula: IC50 (nM) = 10(9-pIC50). b LLE (lipophilic ligand efficiency = pIC50 ꢀ log P.
NET, and 3.31 at DAT. One surprise in the SAR was the excellent
LLE for 2-naphthyl octahydrocyclopenta[c]pyrrole 20b (N-
CH3), with SERT LLE of 4.92 and for 2-naphthyl 24b (N-H),
with SERT LLE of 3.82, NET LLE of 3.8, and DAT LLE of 3.42.
In Vitro ADME: Microsomal Stability, CYP, and hERG
Inhibition. Table 5 details the in vitro microsomal stability,
CYP, and hERG inhibition data for a selection of our potent
TRIs. In the 3,4-dichlorophenyl series, microsomal stability was
best for the secondary amines and worse, albeit respectable, for
both 23a (N-CH3) and 23b (N-Et) compounds. Although N-
ethyl compound 23b showed potent CYP2D6 inhibition and 24a
showed potent CYP1A1 inhibition, the 3,4-dichlorophenyl com-
pounds in general in both octahydrocyclopenta[c]pyrrole and
octahydro-1H-isoindole scaffolds showed minimal CYP inhibi-
tion profiles. hERG inhibition was present at low potency for
several of the dichlorophenyl compounds, but none showed
inhibition below 1 μM. There was no clear distinction in stability,
CYP inhibition, or hERG inhibition for either the
octahydrocyclopenta[c]pyrrole and octahydro-1H-isoindoles
dichlorophenyl compounds secondary amines (compare 26a
to 27a): both compounds showed excellent stability and
moderate CYP and hERG inhibition profiles. The standout in
the dichlorophenyl series from an ADME perspective was
secondary amine 26a; for tertiary amines both 23a and 22a
showed good profiles, albeit with decreased stability compared
to secondary amine 26a. The 2-naphthyl compounds 21d and
23d showed significantly decreased microsomal stability com-
pared to the 3,4-dichlorophenyl counterparts for both N-H and
N-Me and were not profiled extensively for that reason. Finally,
the 3,4-dichlorobenzyl compounds 30 (N-CH3) and 32 (N-H)
showed excellent stability in both human and mouse liver
microsomes but also significant (IC50 < 50 nM) inhibition of
CYP2D6.
(octahydro-1H-isoindoles, N-Me), 22a (octahydrocyclopenta[c]
pyrrole, N-Me), and 26a (octahydrocyclopenta[c]pyrrole, N-H)
were selected for profiling in the mouse tail suspension test
(TST).15 The assay is not a model of depression but is sensitive
to the effects of several classes of antidepressants, including
tricyclics, SSRIs, and SNRIs. The HCl salt of 26a was prepared
and dosed 3, 10, and 30 mg/kg PO in male mice in the TST. A
60 min pretreatment time was used based on exposure work prior
to the assay, which showed maximal brain levels 60 min after PO
dosing. 26a dose dependently reduced in immobility, which was
statistically significant compared to vehicle at 10 and 30 mg/kg
doses (Figure 2a). The positive control, desipramine, also
showed a statistically significant reduction in immobility at
100 mg/kg PO dosing. Terminal brain and plasma samples taken
from the test animals showed that the brain to plasma (B/P) ratio
was close to 30 at the 30 mg/kg dose, and approximately 50 μM
of 26a was present in the brain (Table 6). Given the high degree
of protein binding measured for compound 26a (96% protein
binding using mouse plasma protein), there was an estimated
2 μM of free compound 26a in brain, which exceeded the IC50s at
all three transporters. The effects of compound 26a (Figure 2b)
in the TST was 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 10 or
30 mg/kg dose, as the 5 min time point was significant because
that is the amount of time the compounds were evaluated in
the TST.
3,4-Dichlorophenyl N-methyl amines 23a (Figure 3a) and 22a
(Figure 4a) also showed dose-dependent reductions in immo-
bility, which were statistically significant compared to vehicle at
10 and 30 mg/kg doses. In both experiments, the positive
control, desipramine, also showed a statistically significant
reduction in immobility at 100 mg/kg PO. The effects of 23a
and 22a (Figure 3b and 4b) in the TST were also not due to a
general locomotor activation effect; the compounds did not
In Vivo Pharmacology. On the basis of ADMET, efficiency,
and potency considerations, dichlorophenyl compounds 23a
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Figure 2. (a) Compound 26a in the mouse TST at 3, 10, and 30 mg/kg PO. (b) Compound 26a in mouse locomotor activity assay at 5 min time point,
at 3, 10, and 30 mg/kg PO. * p < 0.05, one-way ANOVA, Dunnett's post test.
Figure 3. (a) Compound 23a in the mouse TST at 3, 10, and 30 mg/kg PO. (b) Compound 23a in mouse locomotor activity assay at 5 min time point,
at 3, 10, and 30 mg/kg PO. * p < 0.01, one-way ANOVA, Dunnett's post test.
Figure 4. (a) Compound 22a in the mouse TST at 3, 10, and 30 mg/kg PO. (b) Compound 22a in mouse locomotor activity assay at 5 min time point,
at 3, 10, and 30 mg/kg PO. * p < 0.05, one-way ANOVA, Dunnett's post test.
significantly increase spontaneous locomotor activity in vivo in
the first 5 min at the 30 mg/kg dose. Terminal whole brain
levels from test animals (Table 6) for 23a showed significant
amounts of both 23a and its metabolite 27a and a B/P ratio
close to 5. Terminal brain levels from test animals for 22a
showed a significant amount of metabolite 26a and a B/P ratio
close to 20.
’ CONCLUSIONS
The present work expanded the chemical space known to offer
potent inhibition of the serotonin, norepinephrine, and dopa-
mine transporters and disclosed novel octahydrocyclopenta-
[c]pyrrole and octahydro-1H-isoindole scaffolds as TRIs for
the treatment of depression. We showed the synthesis and in
vitro characterization of a wide range of aromatic amines in this
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Table 5. In Vitro Microsomal Stability, CYP, and hERG Inhibition of Selected Bicyclic Aminesa
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Table 5. Continued
a NT = not tested.
new scaffold and probed the SAR around the serotonin, norepi-
nephrine, and dopamine transporters. 3,4-Dichlorophenyl and
2-naphthyl emerged as preferred aromatic substituents for devel-
oping potency at the three transporters, and 3,4-dichlorophenyl
showed greater potential from an ADME perspective. In vivo
profiling of three 3,4-dichlorophenyl amines in the TST confirmed
our hypothesis and showed that this scaffold holds potential for
the development of novel antidepressants. Future publications
will disclose our efforts to expand upon the favorable profile of
3a-(3,4-dichlorophenyl)octahydrocyclopenta[c]pyrrole, a new TRI
for the potential treatment of major depressive disorder.
’ EXPERIMENTAL SECTION
Chemistry. General Statement. Reagents were commercial grade
and were used as received unless otherwise noted. Reactions were run
with anhydrous solvents under an atmosphere of nitrogen unless
otherwise noted. Flash column chromatography was done using an
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Table 6. Whole Brain and Plasma Levels of Compounds 23a,
26a, and 22a from TST Animals
with 3 N HCl, and evaporated. The crude brown oil was separated on
silica gel to give the title compound (578 mg, 44%) as pale-brown oil.
GC-MS Rt = 12.48 min, m/z = 270 (M+). The purity was 98% by LCMS
analysis. 1H NMR (CDCl3, δ): 7.49 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 8.4
Hz, 1H), 7.24 (dd, J = 2.3, 8.4 Hz, 1H), 4.50 (dd, J = 7.3, 9.6 Hz, 1H),
4.14 (dd, J = 2.2, 9.6 Hz, 1H), 3.1 (m, 1H), 2.60 (ddd, J = 3.0, 6.4, 12.5
Hz, 1H), 2.2ꢀ1.6 (m, 5H). 13C NMR (CDCl3): 179.7, 140.6, 132.8,
131.5, 130.6, 128.3, 125.8, 72.7, 59.4, 46.2, 40.3, 34.4, 25.8.
dose
plasma levels
(ng/mL)
brain levels
(ng/g)
compd
(mg/kg), PO
23a
3
14
(114)
50
294
(440)
1054
(27a metabolite)
10
30
cis-7a-(3,4-Dichlorophenyl)octahydroisoindol-1-one (8). A mixture
of the dichlorophenyl lactone 6 (580 mg, 2.049 mmol), potassium
phthalimide (758 mg, 2 equiv), and DMF (4 mL) was stirred in a 150 °C
bath for 24 h. Evaporation gave the crude acid. The crude material from
above was diluted with 5 M KOH (10 mL) and heated in a 110 °C bath
for 24 h. Extraction with ethyl acetate followed by evaporation gave the
crude lactam. Separation on silica gel gave the pure lactam (67.5 mg,
12%) as colorless oil. GC-MS Rt = 13.77 min, m/z = 283 (M ꢀ 1). The
(417)
181
(1228)
69
(1878)
4203
(6193)
1747
26a
3
10
30
3
214
569
2
5950
14050
34
22a
1
purity was 98% by LCMS analysis. H NMR (CDCl3/DMSO-d6, δ):
(26a metabolite)
(69)
7
(1531)
113
7.37 (d, J = 2.3 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 7.14 (dd, J = 2.3, 8.5 Hz,
1H), 4.02 (s, 1H), 3.07 (dd, J = 5.8, 9.9 Hz, 1H), 2.83 (dd, J = 3.6, 9.9 Hz,
1H), 2.6 (m, 1H), 1.9 (m, 1H), 1.7 (m, 1H), 1.6ꢀ1.2 (m, 6H). 13C NMR
(CDCl3/DMSO-d6, δ): 179.3, 142.5, 132.2, 130.6, 130.1, 128.8, 126.2,
51.6, 44.2, 40.3, 32.6, 26.9, 22.7, 22.6.
10
30
(211)
30
(4762)
507
(537)
(11433)
For Aryl = 2-naphthyl (24b/26b, Table 2; 20b/22b, Table 3),
2-bromonaphthalene was used instead of dichlorophenylbromide. For
Ar = 3,4-di-F Ph (13b, Table 3), 4-OCH3 Ph (13c, Table 3), 3-OCH3 Ph
(13d, Table 3), ans 3,5-di-Cl Ph (13e, Table 3), the appropriate aryl
bromide was employed instead of dichlorophenylbromide.
ISCO purification system on silica gel columns. The structures of all new
compounds were consistent with their 1H, 13C NMR, and mass spectra
and were judged to be >95% pure by LCMS. Chiral chromatography was
done using the designated Chiral Technologies Chiracel 20 μm analy-
tical (0.46 cm ID ꢁ 25 cm L) column, a flow rate of 1 mL/min with the
designated solvent, with detection by UV at 220 and 254 nM. LCMS was
performed on an Agilent 1100 series system connected to a Micromass
Platform LC. GC-MS was performed on a Hewlett-Packard 6890 series
GC system with an HP1 column (30 m, 0.15 μ film thickness) coupled
to a Hewlett-Packard 5973 series mass selective detector. Accurate mass
measurements were carried out on a Waters Q-TOF micro system.
General procedures are described below for synthesis of the novel
bicyclic compounds with Ar = 3,4-dichlorophenyl. For Ar = Ph (4a,
Table 1), 2,4-di-Cl-Ph (4b, Table 1), 3,4-di-F-Ph (4c, Table 1), 3-OCH3
(4d, Table 1), 4-OCH3 (4e, Table 1), 3,4-di-OCH3 (4f, Table 1),
1-naphthyl (4g, Table 1), and 2-naphthyl (4h, Table 1), the arylation
procedure described below for Ar = 3,4-di-Cl Ph was used, substituting
in the appropriate aryl bromide.
cis-3a-(3,4-Dichlorophenyl)octahydro-1H-isoindole (4j). The lac-
tam cis-7a-(3,4-dichlorophenyl)octahydro-1H-isoindol-1-one (65 mg,
0.2287 mmol) was diluted in THF (2 mL) and borane (0.7 mL, 1 M in
THF, 3 equiv) and heated in the microwave for 15 min (max temp =
100 °C). After cooling, the mixture was stirred with 6 N HCl for 30 min
and washed with MTBE. The aqueous layer was basified with KOH and
extracted with MTBE. The organic phase was evaporated and filtered
(aminopropyl cartridge) to give 4j (15.5 mg, 24%) as a colorless oil.
HRMS [M + H]+: calculated for C14H18Cl2N 270.0811, found
270.0795. LCMS Rt = 7.60 min, m/z = 270 (M + 1). The purity was
98% by LCMS analysis. 1H NMR (CDCl3, δ): 7.43 (d, J = 2.3 Hz, 1H),
7.37 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 2.3, 8.5 Hz, 1H), 3.1 (m, 2H), 2.9
(m, 1H), 2.6 (m, 2H), 2.0ꢀ1.2 (m, 8H). 13C NMR (CDCl3, δ): 146.7,
132.3, 130.1, 129.7, 128.9, 126.2, 59.9, 49.6, 47.9, 41.0, 32.8, 24.2,
22.0, 21.4.
cis-1-(3,4-Dichlorophenyl)-2-(hydroxymethyl)-N-methylcyclopen-
tanecarboxamide (9). To a solution of methylamine (1.5 mL, 2 M in
THF, 2 equiv) at ꢀ78 °C was added n-BuLi (1.2 mL, 2.5 M in hexanes, 2
equiv) dropwise. After 5 min, a solution of the lactone 7 (413 mg, 1.529
mmol) in THF (3 mL) was added in one portion. The mixture was
stirred at low temperature for 5 min and at ambient temperature for 2 h.
The solution was quenched with NH4Cl, extracted with MTBE, and
evaporated. The residue was purified on silica to give the title compound
as pale-yellow oil (351.0 mg, 76%). GC-MS Rt = 12.4 min, m/z = 283
(M ꢀ H2O). The purity was 98% by LCMS analysis. 1H NMR (CDCl3,
δ): 7.51 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.25 (dd, J = 2.3, 8.5
Hz, 1H), 3.8 (bs, 1H), 3.7 (m, 2H), 3.5 (s, 1H), 2.73 (d, J = 4.8 Hz, 3H),
2.7ꢀ2.4 (m, 2H), 2.1ꢀ1.5 (m, 4H). 13C NMR (CDCl3, δ): 175.7, 144.4,
132.5, 131.0, 130.4, 129.1, 126.8, 63.9, 61.3, 50.0, 37.9, 27.8, 26.7, 22.1.
cis-2-(3,4-Dichlorophenyl)-2-((methylamino)methyl)cyclopentyl)-
methanol. To a solution of 9 (110 mg, 0.442 mmol) in THF (1.3 mL)
was added boraneꢀTHF (1.3 mL). After 2 min, the solution was heated
in the microwave for 30 min (max temp = 100 °C). After cooling, the
reaction was quenched cautiously with a few drops of methanol followed
by 3 N HCl (4 mL) and stirred for 30 min. The solution was washed with
50%MTBE/hexanes, chilled, basified with KOH, and extracted with
MTBE. After evaporation, the compound was filtered through an
aminopropyl cartridge to give the amine (315.9 mg, 95% yield) as a
1
pale-yellow oil. LCMS Rt = 5.98 min, m/z = 288 (M + 1). H NMR
(CDCl3, δ): 7.6 (m, 1H), 7.4 (m, 2H), 6.8 (bs, 1H), 3.7 (m, 2H), 2.8 (m,
3H), 2.32 (s, 3H), 2.1ꢀ1.2 (m, 6H). 13C NMR (CDCl3, δ): 147.3,
132.5, 130.2, 130.1, 129.3, 126.9, 63.7, 58.3, 52.9, 47.1, 41.6, 36.0,
28.6, 22.1.
The amino alcohol was separated on a ChiralTech AD column using
2:3:95:0.1 MeOH/EtOH/Hex/DEA. The faster moving enantiomer
eluted at 6.5 min and the slower moving enantiomer eluted at 8.5 min.
The purity was 98% and 96%, respectively, by HPLC analysis.
cis-3a-(3,4-Dichlorophenyl)-2-methyloctahydrocyclopenta[c]pyrrole
(20a). The aminol cis-2-(3,4-dichlorophenyl)-2-((methylamino)methyl)-
cyclopentyl)methanol (47.3 mg, 0.164 mmol) was dissolved in 1 mL of
DCM and allowed to react with mesyl chloride (19 μL, 1.5 equiv) in the
presence of diisopropylethylamine (86 μL, 3 equiv) for 2 h. The mixture
cis-6a-(3,4-Dichlorophenyl)hexahydrocyclopenta[c]furan-1-one
(7). To a solution of lactone 5 (630 mg, 5 mmol), palladium dba (145
mg, 5 mol %), and toluene (6 mL), which was stirring under nitrogen in a
sealed vial, was added tri-t-butylphosphine (250 uL, 5 mol %), lithium
HMDS (6 mL, 1.2 equiv), and dichlorophenylbromide (1.69 g, 1.5
equiv). The solution was heated in the microwave for 15 min (max temp =
140 °C). After cooling, the mixture was diluted with hexane, washed
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Journal of Medicinal Chemistry
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was quenched with aqueous potassium carbonate and extracted with
MTBE. The crude residue after evaporation was passed through an
aminopropyl column to afford 20a (43.5 mg, 99%) as a clear oil. HRMS
[M + H]+: calculated for C14H18Cl2N 270.0811, found 270.0809. LCMS
Rt = 8.56 min m/z = 270 (M + 1). The purity was >99% by LCMS analysis.
1H NMR (CDCl3, δ): 7.41 (d, J = 2.3 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H),
7.17 (dd, J = 2.3, 8.4 Hz, 1H), 2.87 (t, J = 8.4 Hz, 1H), 2.7 (m, 1H), 2.6 (m,
2H), 2.3 (m, 1H), 2.32 (s, 3H), 2.0ꢀ1.5 (m, 6H). 13C NMR (CDCl3, δ):
150.4, 131.9, 129.9, 128.2, 125.7, 70.4, 64.6, 58.3, 50.2, 42.0, 41.0, 33.6, 25.8.
Enantiomer 22a was prepared as above in 100% yield. HRMS [M +
H]+: calculated for C14H18Cl2N 270.0811, found 270.0820. The purity
was 97% by LCMS analysis.
cis-3a-(3,4-Dichlorophenyl)-2-ethyloctahydro-1H-isoindole (21b).
Compound 21b was prepared as above with starting material cis-
2-(3,4-dichlorophenyl)-2-((ethylamino)methyl)cyclohexyl)methanol
in 53% yield. LCMS Rt = 7.87 min, m/z = 298 (M + 1). The purity was
>99% by LCMS analysis. 1H NMR (CDCl3, δ): 7.47 (d, J = 2.2 Hz, 1H),
7.40 (d, J = 8.5 Hz, 1H), 7.18 (dd, J = 2.4, 8.5 Hz, 1H), 3.0 (m, 2H), 2.85
(t, J = 9.0 Hz, 1H), 2.7ꢀ2.5 (m, 4H), 2.0 (m, 2H), 1.8ꢀ1.4 (m, 6H), 1.11
(t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, δ): 147.7, 132.1, 129.9, 129.5,
128.9, 126.2, 68.1, 56.7, 51.0, 46.9, 39.9, 34.6, 24.6, 21.9, 21.1, 14.0.
cis-3a-(3,4-Dichlorophenyl)-2-methyloctahydro-1H-isoindole
(23a). Compound 23a was prepared as above with starting material cis-
2-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclohexyl)methanol
in 75% yield. HRMS [M + H]+: calculated for C15H20Cl2N 284.0967,
found 284.0973. LCMS Rt = 8.20 min, m/z = 284 (M + 1). The purity
was 99% by LCMS analysis. 1H NMR (CDCl3, δ): 7.43 (d, J = 2.3 Hz,
1H), 7.37 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 2.3, 8.5 Hz, 1H), 2.9 (m, 2H),
2.78 (t, J = 9.2 Hz, 1H), 2.7ꢀ2.6 (m, 2H), 2.42 (s, 3H), 2.0ꢀ1.8 (m,
2H), 1.8ꢀ1.6 (m, 2H), 1.6ꢀ1.4 (m, 3H), 1.2ꢀ1.0 (m, 1H). 13C NMR
(CDCl3, δ): 146.9, 132.2, 130.1, 129.8, 128.8, 126.1, 69.8, 58.8, 47.7,
43.3, 40.5, 34.3, 24.6, 21.7, 20.9.
cis-3a-(3,4-Dichlorophenyl)octahydrocyclopenta[c]pyrrole (24a).
Methyl amine 20a (20 mg) was dissolved in 1-chloroethyl chloroformate
(250 μL) and heated to 80 °C for 15 h. The reaction was cooled and
evaporated. The residue was dissolved in methanol and heated at 80 °C
for an additional 3 h. After evaporation, the residue was diluted in DCM,
washed with K2CO3, and filtered (aminopropyl cartridge). The product
(50% conversion) was then separated from unreacted starting material
by chromatography (Chiracel AD; 95:5:0.1 IPA/Hex/DEA). HRMS
[M + H]+: calculated for C13H16Cl2N 256.0654, found 256.0666.
LCMS Rt = 7.14 min m/z = 256 (M + 1). The purity was 97% by
LCMS analysis. 1H NMR (CDCl3, δ): 7.3 (m, 2H), 7.12 (dd, J = 2.3, 8.4
Hz, 1H), 3.3 (m, 1H), 3.00 (s, 2H), 2.7 (m, 2H), 2.0ꢀ1.9 (m, 3H),
1.8ꢀ1.5 (m, 2H), 1.5 (m, 1H). 13C NMR (CDCl3, δ): 150.2, 132.1,
130.0, 129.4, 128.1, 125.7, 62.2, 60.0, 56.1, 50.7, 40.5, 33.7, 25.8.
In Vitro ADMET. In vitro microsomal stability, hERG inhibition,
and CYP inhibition assays were performed at Cyprotex, Macclesfield,
UK, using their standard assay protocols, as described below.
CYP-450 Inhibition. The five cytochrome P450 isoforms of interest
(CYP1A, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) were investi-
gated. Isoform-specific substrates were incubated individually with hu-
man liver microsomes and a range of test compound concentrations
(typically 0.1ꢀ25 μM). At the end of the incubation, the formation of
metabolite was monitored by LC-MS/MS (or fluorescence in the case of
CYP1A using ethoxyresorufin as substrate) at each of the test compound
concentrations. A decrease in the formation of the metabolites com-
pared to vehicle control was used to calculate an IC50 value (test
compound concentration which produced 50% inhibition).
The disappearance of test compound was monitored over a 45 min time
period. The in peak area ratio (compound peak area/internal standard
peak area) was plotted against time and the gradient of the line
determined. Using this information and the formula below, half-life in
minutes could be calculated.
elimination rate constant ðkÞ ¼ ð ꢀ gradientÞ
half-life ðt1=2Þ ðminÞ ¼ 0:693=k
hERG Inhibition. The hERG inhibition assay used a high throughput
single cell planar patch clamp approach (Ionworks HT System from
Molecular Devices). Chinese hamster ovary cells transfected with the
hERG gene (CHO-hERG) were dispensed into the PatchPlate. Am-
photericin was used as a perforating agent to gain electrical access to the
cells. The hERG tail current was measured prior to the addition of the
test compound by perforated patch clamping. Following addition of the
test compound (typically 0.008, 0.04, 0.2, 1, 5, and 25 μM, n = 4 cells per
concentration, final DMSO concentration = 0.25%), a second recording
of the hERG current was performed. Postcompound hERG currents
were expressed as a percentage of precompound hERG currents (%
control current) and plotted against concentration for each compound.
Where concentration dependent inhibition was observed, the Hill
equation was used to fit a sigmoidal line to the data and an IC50
(concentration at which 50% inhibition was observed) was determined.
In Vitro Pharmacology. The novel compounds described above
were tested for their inhibition of functional uptake of 5-HT,16 NE,17 or
DA,18 using recombinant transporters expressed in HEK-293, MDCK,
or CHO-K1 cells as described in the literature. Compounds were tested
initially at 10 μM in duplicate, and if g50% inhibition of uptake was
observed, they were tested further at 10 different concentrations in
duplicate in order to obtain full inhibition curves. IC50 values
(concentration inhibiting control activity by 50%) were then determined
by nonlinear regression analysis of the inhibition curves. Replicate
studies done independently on a set of compounds allowed the
determination of values for minimum significant ratios (MSR). MSR
is a statistical measure for how many-fold different IC50 values for two
compounds (determined only once) must be for those two IC50 values
to be considered significantly different with 95% confidence limits.19
From replicate studies of the effects of 13 reuptake inhibitors assayed
with the human transporters at MDS Pharma on two separate occasions,
MSR values were 2, 2, and 3, respectively, for SERT, NET, and DAT.
Similar analysis of the assays performed internally at Sunovion provides
MSR values of 4, 3, and 2, respectively, for SERT, NET, and DAT. These
correspond to average SD values (on pIC50s) of 0.2ꢀ0.3.
In Vivo Pharmacology. Mouse Tail Suspension Test. The meth-
od, which detects antidepressant activity, follows that described by Stꢀeru
et al.15 Rodents, suspended by the tail, rapidly become immobile.
Antidepressants decrease the duration of immobility. The behavior of
the animal was recorded automatically for 5 min using a computerized
device (Med-Associates Inc.) similar to that developed by Stꢀeru et al.20
-
Tenꢀtwelve mice were tested in each group. The test was performed
blind. The dosing solution was test compound dissolved in 5% transcu-
tol (2-(2-ethoxyethoxy)ethanol) in saline. Compounds were typically
evaluated at 3 doses (1ꢀ30 mg/kg), administered orally one time:
30ꢀ120 min before the test, and compared with a vehicle control group.
Desipramine (100 mg/kg), administered under the same experimental
conditions, was used as the positive reference substance.
Data were analyzed by one way analysis of variance (ANOVA)
followed by posthoc comparisons where appropriate. An effect was
considered significant if p < 0.05.
Human and Mouse Liver Microsomes. The microsomes (0.5 mg/
mL) were incubated with 3 μM test compound at 37 °C in the presence
of the cofactor, NADPH, which initiated the reaction. The reaction was
terminated by the addition of methanol containing internal standard.
Following centrifugation, the supernatant was analyzed by LC-MS/MS.
Locomotor Activity. To ensure effects of the compounds on im-
mobility time were not related to a general stimulant effect on baseline
motor activity, locomotor activity was assessed using photocell
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Journal of Medicinal Chemistry
ARTICLE
monitored cages (Med-Associates Inc.). Each test chamber was
equipped with infrared photocell beams to measure movement of the
animals. Horizontal and vertical activities were measured.
Rats or mice were pretreated with vehicle or test compounds and
placed back in home cage, following which they were individually placed
in locomotor cages and activity was monitored in 5 min intervals for up
to 60 min.
Data were analyzed by one way analysis of variance (ANOVA)
followed by posthoc comparisons where appropriate. An effect was
considered significant if p < 0.05.
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’ AUTHOR INFORMATION
Corresponding Author
*Phone: (508) 357-7468. Fax: (508) 490-5454. E-mail: Liming.
shao@sunovion.com; lshao@fas.harvard.edu.
Present Addresses
‡Constellation Pharmaceuticals, 215 First Street, Suite 200,
Cambridge Massachusetts 02142, United States
§Evotec, Schnacokenburgallee 114, Hamburg 22525, Germany
Cortex Pharmaceuticals, 15231 Barranca Parkway, Irvine
California 92618, United States
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’ ABBREVIATIONS USED
SERT, serotonin transporter; NET, norepinephrine transporter;
DAT, dopamine transporter; TRI, triple reuptake inhibitor;
hERG, potassium ion channel Kv11.1; CYP, cytochrome
P450; HLM, human liver microsomes; RLM, rat liver micro-
somes; TST, tail suspension tests; MAOIs, monoamine oxidase
inhibitors; SSRIs, selective serotonin reuptake inhibitors; SNRIs,
dual serotonin and norepinephrine reuptake inhibitors; 5-HT,
serotonin; NE, norepinephrine; DA, dopamine; B/P ratio, brain/
plasma ratio; LE, ligand efficiency; LLE, lipophilic ligand effi-
ciency; MW, molecular weight
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