Synthesis and SAR of 4-aminocyclopentapyrrolidines as orally active N-type calcium channel inhibitors for inflammatory and neuropathic pain

Article abstract of DOI:10.1016/j.bmcl.2013.06.074

A novel series of N-type calcium channel inhibitors have been discovered. Optimization of potency and HT-ADME properties provides 4- aminocyclopentapyrrolidines with analgesic efficacy after oral dosing.

Full text of DOI:10.1016/j.bmcl.2013.06.074

Bioorganic & Medicinal Chemistry Letters 23 (2013) 4857–4861
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR of 4-aminocyclopentapyrrolidines as orally active
N-type calcium channel inhibitors for inflammatory and neuropathic
pain
⇑
Xenia Beebe , Clinton M. Yeung, Daria Darczak, Shashank Shekhar, Timothy A. Vortherms, Loan Miller,
Ivan Milicic, Andrew M. Swensen, Chang Z. Zhu, Patricia Banfor, Jill M. Wetter, Kennan C. Marsh,
Michael F. Jarvis, Victoria E. Scott, Michael R. Schrimpf, Chih-Hung Lee
Neuroscience Research, AbbVie, 1 N. Waukegan Road, North Chicago, IL 60064, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of N-type calcium channel inhibitors have been discovered. Optimization of potency and
HT-ADME properties provides 4-aminocyclopentapyrrolidines with analgesic efficacy after oral dosing.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 14 May 2013
Accepted 27 June 2013
Available online 4 July 2013
Keywords:
N-type calcium channels
SAR
Enantiomeric synthesis
Microsomal stability
Analgesia
Voltage-gated calcium channels are divided broadly into high
voltage-activated (HVA) and low voltage-activated (LVA) channels
based on the relative voltages they require for activation. The L-
(Cav1.1–Cav1.4), N-(Cav2.2), P/Q-(Cav2.1), and R-type (Cav2.3) cal-
cium channels require a larger depolarization for activation,
whereas T-type (Cav3.1–Cav3.3) calcium channels activate in re-
sponse to more moderate depolarizations.1 Inhibition of N-type
voltage gated calcium channels represents an attractive approach
for the treatment of pain. Ziconotide2 (Prialt™), a synthetic peptide
with Cav2.2 potency. The HT-ADME data allowed for optimization
of pharmacokinetic properties to provide compounds for oral dos-
ing in efficacy studies. Select compounds were then tested in pre-
clinical models of inflammatory, osteoarthritic, and neuropathic
pain. Select compounds were also tested in the rat aorta ring relax-
ation assay to measure activity at L-type calcium channels which
when inhibited can contribute to cardiovascular responses8.
In an effort to improve the oral bioavailbility of this class of
compounds while maintaining good potency and PK properties,
we explored the SAR of benzyl, sulfonamide, and aryl substituents
on the ring nitrogen, in conjunction with changes to the amide
group. We also explored the other synthetically accessible
version of
x-conotoxin MVIIA derived from the piscivorous marine
snail (Conus magus), is currently used to treat intractable pain for
patients for whom opiates are no longer efficacious. Ziconotide is
a potent and selective blocker of neuronal N-type calcium chan-
nels; however its use is limited due to intrathecal administration.
The discovery of small molecule blockers of N-type calcium chan-
nels with oral analgesic efficacy would be a valuable alternative for
the treatment of pain. Recent progress in this area is very encour-
aging.3–6
O
N
S
CF3
H
We recently reported7 a potent and selective N-type calcium
channel blocker 1 (Fig. 1) with efficacy in animal pain models when
delivered intraperitoneal (i.p.). Herein we describe the discovery of
orally efficacious N-type calcium channel blockers using a set of
in vitro high throughput-ADME (HT-ADME) data in conjunction
4
S
6a
3a
N
H
R
1
Cav2.2 IC50= 0.46 µM
L-type IC50 >30µM
⇑
Corresponding author. Tel.: +1 847 937 8291; fax: +1 847 937 9195.
E-mail address: xenia.b.searle@abbvie.com (X. Beebe).
Figure 1. Cav2.2 inhibitor with analgesic activity when dosed i.p.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.06.074

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X. Beebe et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4857–4861
diastereomers of the 4-aminotetrahydropyrrolidine core. Synthesis
of the (3aS,4R,6aR)-diastereomer of 4-aminocyclopentapyrrolidine
is outlined in Scheme 1. Resolved sulfinylimine 27 was deprotected
to give the chiral ketone 3. The ketone was then stereoselectively
reduced to the alcohol 4 using sodium borohydride at low temper-
ature, favoring hydride delivery from the less hindered convex face
of the bicycle by approximately >20:1. The alcohol 4 was converted
to the amine 6 by mesylation, azide inversion, and Staudinger
reduction. The amine was then acylated with bis-cyclcohexyl ace-
tic acid to give the diastereomeric bis-cyclohexyl compound 7.
Leucine derived amides 10–12 were then synthesized as out-
lined in Scheme 2. The appropriately Boc-protected leucine deriv-
ative was coupled to the amine 6 and then deprotected under
acidic conditions. The primary amine of compound 10 was then
sulfonylated to give compound 12.
N-sulfonamide derivatives were then synthesized as outlined in
Scheme 3. (3aR,6aS)-Ketone 139 was converted to (3aS,4R,6aR)-
amine 14 using the same azide inversion sequence outlined in
Scheme 1. Appropriately protected leucine was then coupled to
the amine to give amides 15 and 16 and the N-benzyl group was
removed using catalytic hydrogenation with Degussa’s catalyst.
The resulting pyrrolidines 17 and 18 were then sulfonamidated
using benzene sulfonylchlorides and then the Boc group removed
under acidic conditions to give compounds 22–24. The primary
amine 22 was bis-methylated using formaldehyde in a reductive
alkylation to give N,N-dimethyl derivative 25.
N-sulfonamide derivatives with the opposite stereochemistry
were then synthesized as outlined in Scheme 4. (3aS,6aR)-Ketone
269 was converted to (3aR,4S,6aS)-amine 27 using the same azide
inversion sequence outlined in Scheme 1. The common intermedi-
ate p-trifluoromethylbenzene sulfonamide 28 was synthesized by
using the protection/deprotection steps outlined in Scheme 4.
The (3aR,4S,6aS)-enantiomeric amine 28 was used to vary the ami-
no acid portion of the molecule by coupling with the appropriate
amino acid and then deprotection of the Boc group to give the de-
sired sulfonamide analogs 30–36. The amino acid could then be
alkylated with acetone or ethyl iodide to give compounds 37 and
38.
N-Aryl 4-aminocyclopentapyrrolidine analogs were synthesized
as described in Scheme 5. Starting with (3aR,4S,6aS)-amine 27,
acylation with Boc-N-methyl leucine gives compound 39. Subse-
quent debenzylation, palladium catalyzed N-arylation with aryl
bromides and final deprotection of the Boc group provides novel
analogs 40, 41 and 42 with our most effective trifluoromethyl
groups. Palladium catalyzed N-arylation with aryl bromides in
the presence of a mild base such as potassium phosphate tribasic
and tert-amyl alcohol as solvent enabled chemoselective cross cou-
pling of a secondary amine in the presence of an unprotected
amide.
In order to discover more potent N-type calcium channel block-
ers while maintaining drug-like properties, HT-ADME in vitro data
were incorporated in the SAR evaluation of the new analogs as
shown in Table 1. Starting with compound 1, by changing the rel-
ative stereochemistry of at C3 from (S) to (R) (compound 7), we ob-
served decreasing dofetilide binding (Ki = 0.69 and 9.52 lM,
respectively). In order to impart more favorable physicochemical
properties on our 4-aminocyclopentylpyrrolidine analogs, we
changed our bis-cyclohexyl amide to a less lipophilic group and
added a basic nitrogen by using L
-leucine.10,11 This gave rise to
compound 11 with greatly improved solubility and microsomal
stability and comparable potency to compound 7. The methanesul-
fonamide derivative 12 showed an improvement in solubility, but
did not improve the potency or microsomal stability. However,
changing the N-benzyl group into a benzene sulfonamide in com-
pound 22 gave a more potent N-type calcium channel blocker with
acceptable human liver microsomal stability and solubility. The N-
Me leucine derivative 23 had improved potency and microsomal
stability with a decrease in solubility. Moving the trifluoromethyl
group from the meta-position in compound 23 to the para-position
in compound 24 decreased both potency and solubility but not
metabolic stability. The opposite(3aR,4S,6aS)-enantiomer 30 gave
increased microsomal stability without significantly decreasing
potency or solubility.
Potency gains were then made by varying the amino acid por-
tion of the molecule on the most metabolically stable (3aR,4-
S,6aS)-enantiomer of the 4-aminocyclopentapyrrolidine core.
When the amino acid was shortened by one methyl group from
leucine for compound 30 to norvaline for compound 31 the solubil-
ity and microsomal stability increased while the potency de-
creased. When the steric bulk of the amino acid is decreased to
the norleucine analog 32 the potency and microsomal stability re-
mained the same, but the solubility decreased from 77 to 38
lM.
Adding steric bulk and lipophilicity as in the neopentylglycine
compound 35 had no effect on the potency and solubility but the
human microsomal stability decreased. Primary amines with bulky
alkyl group amino acids such as tert-leucine (compound 33) had
excellent solubility but weaker potency with no real decrease in
microsomal stability. For the neopentylglycine analogs, the
N-methyl analog 35 had comparable potency and solubility com-
pared with the amino analog 34 and lower metabolic stabilities
O
S
O
OH
H
N
CF3
CF3
H
CF3
H
a
b
c,d
N
N
N
H
H
H
2
3
4
O
NH2
H
N3
CF3
CF3
H
NH
e
f
CF3
H
N
N
H
H
N
H
5
6
7
Scheme 1. Synthesis of (3aS,4R,6aR) chiral 4-aminocyclopentyl pyrrolidine via azide inversion. Reagents and conditions: (a) HCl, H2O, THF, rt, 2 h; (b) NaBH4, MeOH, À78 °C
to rt, 16 h; (c) Et3N, MsCl, CH2Cl2, 25 °C, 30 min; (d) NaN3, DMA 90 °C 16 h; (e) PPh3, H2O, THF, 80 °C, 1 h; (f) EDC, HOBt, CH2Cl2, rt, 16 h.

X. Beebe et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4857–4861
4859
O
S
R
N
O
H
H
O
O
N
R
O
Boc
HN
NH
NH
NH
H
CF3
H
CF3
H
CF3
a, AA
b
c
6
N
N
H
N
H
12
AA = N-Boc-LeuOH 8
AA = Boc-N-MeLeuOH 9
R = H 10
R = CH3 11
Scheme 2. Synthesis of leucine analogs. Reagents and conditions: (a) EDC, HOBt, CH2Cl2, rt, 16 h; (b) 4 N HCl/dioxane, rt, 1 h; (c) Et3N, MsCl, CH2Cl2, 1 h.
Boc
O
N
R
NH2
H
AA
H
O
NH
H
NH
H
H
e, AA
f
a-d
N
N
H
H
NH
N
H
13
14
R = H 17
R = CH3 18
AA = N-Boc-LeuOH 15
AA = Boc-N-MeLeuOH 16
Boc
N
O
O
H
O
H
N
R
N
R
NH
NH
NH
ArSO2Cl
g
i
h
H
H
H
CF3
Ar
N
N
N
Ar
H
S
S
H
S
O
O
O
O
O
O
25
19
R = H; Ar = m-CF3Ph
R = CH3; Ar = m-CF3Ph
R = CH3; Ar = p-CF3Ph 21
22
R = H; Ar = m-CF3Ph
R = CH3; Ar = m-CF3Ph
20
23
R = CH3; Ar = p-CF3Ph 24
Scheme 3. Synthesis of (3aS,4R,6aR)-enantiomeric N-sulfonamide analogs. Reagents and conditions: (a) NaBH4, MeOH, À78 °C to rt, 16 h; (b) Et3N, MsCl, CH2Cl2, 25 °C,
30 min; (c) NaN3, DMA 90 °C 16 h; (d) PPh3, H2O, THF, 80 °C, 1 h; (e) EDC, HOBt, CH2Cl2, rt, 16 h; (f) 20% Pd(OH)2/carbon, EtOH, 30 psi H2, rt, 4h; (g) Et3N, rt 3 h; (h) 4 N HCl/
dioxane, rt, 1 h; (i) H2CO, PS-CNBH3, HOAc, CH2Cl2, rt, 16 h.
NH2
H
O
NH2
H
a-d
e-h
H
i, AA
CF3
Boc-N-MeLeuOH
N
AA =
N
N
H
H
H
S
Boc-N-Me-NorValOH
Boc-N-Me-NorLeuOH
N-Boc-neopentylGlyOH
N-Boc-tert-LeuOH
O O
26
27
28
Boc-N-Me-neopentylGlyOH
Boc-N-Me-PheOH
R1
N
H
N
H
N
O
O
O
R1
R1
Boc
NH
H
NH
H
NH
H
R
R
R
h
j,
CF3
CF3
CF3
N
N
N
H
H
H
S
O O
S
S
O O
O O
29
R = CH2C(CH3)3 R1 = CH(CH ) 37
R = CH2C(CH3)3 R1 = CH CH3 328
30
R = CH2CH(CH3)2
R1 = CH3
R = CH2CH2CH3
R1 = CH3 31
2
2
32
33
R = CH2CH2CH2CH3 R1 = CH3
R = CH2C(CH3)3
R = CH(CH3)3
R = CH2C(CH3)3
R = CH2Ph
R1 = H
R1 = H 34
35
36
R1 = CH3
R1 = CH3
Scheme 4. Synthesis of (3aR,4S,6aS)-enantiomeric p-trifluoromethyl benzene sulfonamide analogs. Reagents and conditions: (a) NaBH4, MeOH, À78 °C to rt, 16 h; (b) Et3N,
MsCl, CH2Cl2, 25 °C, 30 min; (c) NaN3, DMA 90 °C 16 h; (d) PPh3, H2O, THF, 80 °C, 1 h; (e) Et3N, Boc2O, CH2Cl2; (f) 20% Pd(OH)2/carbon, EtOH, 30 psi H2, rt, 4 h; (g) p-CF3–
benzenesulfonyl chloride, Et3N, rt, 3 h; (h) 4 N HCl/dioxane, rt, 1 h; (i) EDC, HOBt, CH2Cl2, rt, 16 h; (j) acetone, PS-CNBH3, HOAc, CH2Cl2, rt, 16 h or EtI, Et3N, THF, 65 °C, 3 days.

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X. Beebe et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4857–4861
O
HN
O
NH
N
Boc
NH2
H
NH
b-d
a
H
H
N
N
H
H
N
27
39
H
R
R = m-CF3 40
41
42
R = p-CF3
R = p-OCF3
Scheme 5. Synthesis of (3aR,4S,6aS)-enantiomeric N-aryl analogs. Reagents and conditions: (a) Boc-N-MeLeuOH, EDC, HOBt, CH2Cl2, rt, 16 h; (b) 20% Pd(OH)2/carbon, EtOH,
30 psi H2, rt, 4 h; (c) ArBr, Pd2(dba)3, X-PHOS, K3PO4, tert-amylalcohol, 80 °C, 16 h; (d) 4 N HCl/dioxane, rt, 1 h.
Table 1
compared with the amino (compound 22) and N,N-dimethylamino
(compound 25) analogs. Also, the increase in microsomal stability
N-type calcium channel activity of 4-aminocyclopentapyrrolidine analogs
for compound 24 is accompanied by an increase in oral bioavail-
ability. For the opposite enantiomer 30, doubling the microsomal
stability was accompanied by an increase in oral bioavailability.
Compound 37 represents a compromise between solubility, po-
tency and oral bioavailability. Rat phamacokinetics of the N-aryl
compounds was remarkably different from the sulfonamide ana-
logs. As shown in Table 2, compound 41 had a marked increase
in half life, high volume of distribution, high clearance and high
oral bioavailability. Further analysis showed a brain/plasma ratio
Compd
N-type FLIPR
% Rem @ 30 min
CLND
a
IC50
(
lM)
pIC50 SEMa
RLM
HLM
Sol. (lM)
1
7
0.46
1.87
1.89
2.84
1.06
0.52
0.77
0.45
0.75
0.96
0.75
1.51
0.87
0.79
0.86
0.39
0.49
1.19
1.24
5.15
6.33 0.06
5.73 0.08
5.72 0.04
5.55 0.05
5.98 0.05
6.20 0.02
6.07 0.05
6.34 0.05
6.07 0.04
6.02 0.12
6.13 0.08
5.82 0.03
6.03 0.10
6.08 0.05
6.06 0.03
6.41 0.13
6.24 0.02
5.93 0.05
5.91 0.11
5.29 0.11
0.1
0.5
<3
<3
67
80
44
75
27
79
77
97
38
94
68
76
nt
2.6
1.2
11
12
22
23
24
25
30
31
32
33
34
35
36
37
38
40
41
42
60.7
42.1
10.3
26.5
47.3
1.0
19.4
23.6
45.0
25.5
50.5
0.1
of 16.5/1 at 30 min after an i.p. dose of 3 lmol/kg. In comparison,
the brain/plasma ratio of compound 37 was 0.9/1 at 60 min after
oral dosing.
69.9
83.4
66.4
77.1
79.4
66.5
26.2
64.3
89.2
81
54.4
74.6
51.1
75.6
41.8
33.6
26.8
79.6
22.8
73
Compound 37 was tested in manual electrophysiology using
whole cell patch-clamp recordings of rat N-type calcium channels
overexpressed in HEK293 cells (Fig. 2). Cells were held depolarized
to partially inactivate the channels and allow for inhibition of mul-
tiple channel states to be detected. Under these conditions, com-
pound 37 inhibited N-type calcium channels with an IC50 value
of 340 nM. Under more hyperpolarized conditions, where channels
are biased towards the closed-state, compound 37 was 30Â less
potent, consistent with state-dependent block of N-type calcium
channels. Similarly, manual electrophysiology with compound 41
21
20
56
33
31
>85
66
>85
>85
a
All values are means SEM of at least three separate experiments.
showed an IC50 value of 1.0
lM under depolarized conditions, with
in human liver microsomes. Alkylation of the neopentylglycine
analog 34 with either acetone or ethyl iodide gave compounds
37 and 38 as shown in Scheme 4. The isopropyl amine analog 37
had similar potency to the ethyl amino analog 38 but improved
stability in human liver microsomes. The phenyl alanine analog
36 had similar potency to compound 34 but poorer microsmal sta-
bility. The N-aryl compounds 40–41 were less potent in the N-type
calcium channel FLIPR assay than the sulfonamide analogs (Table 1)
but exhibited excellent microsomal stability and solubility.
a shift to 4.4
l
M under more hyperpolarized conditions.12
To determine analgesic activity of an orally bioavailable N-type
calcium channel inhibitor, compound 37 was tested against pre-
clinical pain models. Compound 37 showed efficacy in the capsai-
cin secondary mechanical hyperalgesia pain model13 with an ED50
of 13 mg/kg. Compound 37 was also efficacious in the MIA-OA
(monoiodoaceate induced osteoarthritis) pain model7 with an
ED50 of 8 mg/kg. When tested in the chronic constriction injury
(CCI)-induced neuropathic pain model for neuropathic pain,14
Increases in microsomal stability were consistent with the rat
PK as shown in Table 2. The N-methyl amino acid derivatives, rep-
resented by compound 23 were considered to have the best PK
110
100
90
80
70
60
50
40
30
20
10
0
▼resting
Table 2
IC50=10.4 µM
n=3 cells
Rat PK for selected calcium channel blockers
Compd
t1/2 (h)
Vss (L/kg)
CLp (L/h/kg)
%F
Oral AUC
(ng h/mL)
inactivated
IC50 = 340 nM
n = 4 cells
22a
23a
24b
25a
30b
37a
41b
0.5
2.0
2.1
1.4
3.3
15.0
9.2
5.6
5.2
13.2
7.1
34.1
3.6
2.2
3.4
2.8
2.0
1.3
0
0
405
221
35
422
240
799
10.5
21.0
0.8
50.0
46.7
83.0
-8
-7
-6
-5
-4
-3
2.7
15.4
log [Compound 37] (M)
26.5
a
5
5
l
l
mol/kg IV dose and 30
mol/kg IV dose and oral dose.
lmol/kg oral dose.
Figure 2. Inhibition of N-type calcium channel current by compound 37 assessed
by manual electrophysiology.
b

X. Beebe et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4857–4861
4861
compound 37 showed efficacy with an ED50 of 32 mg/kg. Com-
References and notes
pound 41 showed efficacy in the MIA-OA model with an ED50 of
3 mg/kg. When tested in the CCI model of neuropathic pain, com-
pound 41 had an ED50 of 10 mg/kg.12
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In cardiovascular safety studies, compound 37 showed a dose
dependent decrease in mean arterial pressure in the anesthetized
rat cardiovascular model15 starting at a plasma concentration of
1.57
pound 37 had an IC50 value of 2.6
l
g/mL. In the rat aorta ring tissue relaxation assay7, com-
lM. This assay is a measure of
L-type calcium channel activity in native vascular tissue and the
cardiovascular effects observed in rats may be due to interaction
of compound 37 with L-type calcium channels.
In conclusion, we have discovered N-type calcium channel
inhibitors with efficacy in inflammatory and neuropathic preclini-
cal pain models with a therapeutic window for cardiovascular
safety. This was achieved by optimizing for in vitro ADME param-
eters of microsomal stability and solubility along with potency at
the biological target.
Disclosures
X.B., C.M.Y., D.D., S.S., T.A.V., L.M., I.M., A.M.S., C.Z.Z., P.B., J.M.W.,
K.C.M., M.F.J., V.E.S., M.S.R. and C.-H.L. are employees of AbbVie and
may hold AbbVie stock. The research described herein is solely
funded by AbbVie. AbbVie contributed to the study design, re-
search and interpretation of data.
Acknowledgments
14. Bennett, G. J.; Xie, Y. K. Pain 1988, 33, 87.
15. Liu, G.; Zhao, H.; Liu, B.; Xin, Z.; Liu, M.; Serby, M. D.; Lubbers, N. L.; Widomski,
D. L.; Polakowski, J. S.; Beno, D. W. A., et al Bioorg. Med. Chem. Lett. 2007, 17,
495.
The authors would like to thank the AbbVie HT-ADME group for
microsomal stability and solubility data and the AbbVie structural
chemistry group for 1H NMR and MS on all compounds.