A novel series of [3.2.1] azabicyclic biaryl ethers as α3β4 and α6/4β4 nicotinic receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2010.06.142

We report the synthesis of a series of [3.2.1]azabicyclic biaryl ethers as selective agonists of α3- and α6-containing nicotinic receptors. In particular, compound 17a from this series is a potent α3β4 and α6/4β4 receptor agonist in terms of both binding and functional activity. Compound 17a also shows potent in vivo activity in CNS-mediated animal models that are sensitive to antipsychotic drugs. Compound 17a may thus be a useful tool for studying the role of α3β4 and α6/4β4 nicotinic receptors in CNS pharmacology.

Full text of DOI:10.1016/j.bmcl.2010.06.142

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4749–4752
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A novel series of [3.2.1] azabicyclic biaryl ethers as a3b4
and
a6/4b4 nicotinic receptor agonists
*
John A. Lowe III , Shari L. DeNinno, Jotham W. Coe, Lei Zhang, Scot Mente, Raymond S. Hurst,
Robert J. Mather, Karen M. Ward, Alka Shrikhande, Hans Rollema, David E. Johnson, Weldon Horner,
Roxanne Gorczyca, F. David Tingley III, Rouba Kozak, Mark J. Majchrzak, Theresa Tritto, Jen Sadlier,
Chris L. Shaffer, Brenda Ellerbrock, Sarah M. Osgood, Mary C. MacDougall, Laura L. McDowell
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the synthesis of a series of [3.2.1]azabicyclic biaryl ethers as selective agonists of
a
3- and
3b4 and
6/4b4 receptor agonist in terms of both binding and functional activity. Compound 17a also shows
Received 23 April 2010
Revised 28 June 2010
Accepted 29 June 2010
Available online 19 July 2010
a6-containing nicotinic receptors. In particular, compound 17a from this series is a potent a
a
potent in vivo activity in CNS-mediated animal models that are sensitive to antipsychotic drugs.
Compound 17a may thus be a useful tool for studying the role of
a3b4 and a6/4b4 nicotinic receptors
in CNS pharmacology.
Keywords:
Nicotinic
Receptor
Agonist
Ó 2010 Elsevier Ltd. All rights reserved.
Alpha-6
Alpha-3
Schizophrenia
Nicotinic acetylcholine receptors (nAChRs) are located in both
the central and peripheral nervous systems and serve a wide vari-
ety of physiological functions.1 Assigning any particular physiolog-
ical response to activity at a specific nicotinic receptor, however, is
challenging because of the complexity of the nAChR. The nAChR is
a pentameric structure, and in the central nervous system (CNS) is
The starting point for our medicinal chemistry studies was the
structure of varenicline, 1, which, in addition to its potent activity
at the
the 3b4 and
template present in 1 seemed like a potential starting point for
exploring 3b4 and 6/4b4 nicotinic receptor SAR. In addition, the
a
4b2 nicotinic receptor, we found to have weak affinity for
a
a
6/4b4 nicotine receptors (see Table 1).2 The [3.2.1]
a
a
comprised of various combinations of
a
(2–10) and b(2–4) sub-
[3.2.1] template precursor compound 2 (see below) was readily
available from our earlier SAR studies in this area. At the time we be-
units.2 We have previously described our work on the smoking-
cessation drug varenicline, (6,7,8,9-tetrahydro-6,10-methano-6H-
pyrazino[2,3-h][3]benzazepine), 1, (Fig. 1), a potent and selective
gan the studies described herein, there were few literature reports
examining
a
3
nicotinic receptor SAR,6 and no literature reports
*
*
partial agonist at the
a
4b2 nicotinic receptor.3 This compound al-
that we were aware of describing
*
cent report of a6b2 selective compounds is the first in this area.
a6 nicotinic receptor SAR. A re-
7
lowed us to investigate the pharmacology of the
a4b2 nicotinic
receptor, which is the major nicotinic receptor subtype present
In addition, high-throughput screening of our in-house compound
in the CNS. In addition, we have reported the activity of positive
collection for activity at 6/4b4 nAChRs failed to identify viable hits.
a
effectors of
to these studies, we became interested in the biology of other nic-
otinic receptor subtypes present in the CNS, in particular, the 3,
5, and
6 subunit-containing nAChRs.2,5 Hence we began an
a
7 nAChRs, also present in the CNS.4 As a follow-up
So we initiated our work by exploring various derivatives of 2, in
particular extending the ‘fused’ type structure of 1 to a ‘pendant’
type of structure in which a linker would join the [3.2.1]azabicyclic
template to an aromatic group. After exploring numerous combina-
tions of linkers and aromatic groups, we discovered that an ether
a
a
a
investigation into finding selective ligands for these receptors to
characterize their CNS pharmacology.
N
HN
1, Varenicline
* Corresponding author. Address: 28 Coveside Lane, Stonington, CT 06378, United
States. Tel.: +1 860 535 4283.
N
E-mail address: jal3rd@gmail.com (J.A. Lowe).
Figure 1. Structure of varenicline, 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.142

4750
J. A. Lowe et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4749–4752
Table 1
In vitro activity of compounds 7–24
c
Compound
Binding Kia
EC50
Alpha-1
Alpha-3
Alpha-4
Alpha-6
Alpha-7
Alpha-3
Alpha-6
7
7a
7b
8
9
NT
1020
NT
NT
NT
1.3 0.33 (n = 5)
>1307 194.6 (n = 4)
>832 (n = 1)
3.8 0.505 (n = 5)
2.15 0.617 (n = 3)
78.5 27.5 (n = 3)
1.77 0.782 (n = 4)
9.01 2.21 (n = 4)
3.15 1.00 (n = 5)
0.425 0.159 (n = 3)
0.177 0.040 (n = 5)
7.16 2.25 (n = 3)
1.33 (n = 1)
NT
3300
NT
NT
NT
>15,000
1580
>13,500
>15,000
NT
>13,500
NT
>15,000
7590
4750
4780
>15,000
9870
57 (61.5%)
<100 (45%)
NT
102 (32.5%)
53 (35%)
NT
1.21 0.306 (n = 3)
16.9 8.43 (n = 3)
0.882 0.376 (n = 4)
94.1 92.2 (n = 4)
2.1 0.62 (n = 5)
0.186 0.06 (n = 3)
0.748 0.557 (n = 5)
2.02 0.72 (n = 3)
0.856 (n = 1)
2.17 0.365 (n = 4)
0.957 0.186 (n = 4)
1.48 0.553 (n = 4)
0.382 0.662 (n = 3)
0.243 116 (n = 3)
0.158 0.04 (n = 6)
1.33 0.268 (n = 4)
0.149 0.07 (n = 4)
0.126 0.12 (n = 3)
9.53 2.01 (n = 3)
3.79 1.03 (n = 3)
496 134 (n = 3)
74.7 6.19 (n = 18)
394 17.5 (n = 67)
>614 270.53 (n = 3)
477 202 (n = 4)
>309 205 (n = 2)
>419 190 (n = 4)
255 41.8 (n = 4)
252 57.9 (n = 6)
149 27.4 (n = 3)
1860 (n = 1)
>1503 637.5 (n = 2)
>1040 (n = 1)
>575 147 (n = 3)
250 52.8 (n = 3)
>424 225 (n = 3)
336 22 (n = 6)
2905 835 (n = 2)
>604 78 (n = 3)
745 74.8 (n = 5)
>615.5 150.5 (n = 2)
>962.5 407.5 (n = 2)
NA
<100 (46%)
32.7 (49%)
16.3 (11%)
2.59 (82%)
2.99 (117%)
34.4 (118%)
197 (52%)
316 (65%)
33.6 (84.5%)
33.9 (97%)
112 (80.5%)
2.99 (117%)
3.06 (116%)
2.92 (120%)
1.09 (122%)
0.16 (108%)
252 (57%)
36.8 (100%)
NA
126 (23%)
>30,000 (<20%)
28.9 (91%)
5.00 (75%)
4.30 (230%)
279 (70%)
NT
625 (45%)
248 (61%)
265 (107%)
64.4 (48%)
4.30 (230%)
3.15 (148%)
3.27 (182%)
2.27 (182%)
0.37 (160%)
98.5 (51%)
35.4 (59.5%)
NA
10
11
11a
11b
12
13
14
15
16
17
17a
17b
18
19
20
21
24
1
>15,300
5000
1680
8320
NT
>16,900
4430
>15,000
>15,000
>13,500
11,700
>15,000
>15,000
4240
530
10.1 2.6 (n = 4)
2.05 0.754 (n = 4)
5.83 2.12 (n = 4)
5.21 1.43 (n = 3)
0.241 0.038 (n = 4)
0.168 0.030 (n = 6)
3.73 1.17 (n = 4)
0.313 0.194 (n = 4)
0.202 0.129 (n = 4)
17.1 3.32 (n = 3)
12.5 ( 5.61 (n = 3)
1130 563 (n = 3)
89 7.34 (n = 18)
168 8.75 (n = 67)
14,600
>15,000
>15,000
NT
>15,000
NT
8200
1480
0.295 0.02 (n = 18)
9.46 0.557 (n = 66)
125 18b
2110 852b
Nicotine
NT—not tested; NA—not active.
a
Binding Ki values given in nM units, s.e.m, and number of determinations, n, in parentheses, for the a1bcd, a3b4, a4b2, a6/4b4, and a7 receptors respectively (see text).
The numbers in italics indicate that one or more of the individual determinations did not give a Ki value since the required inhibition of binding could not be reached at the
maximum concentration used in the assay. These values reflect only the determinations for which a Ki value could be determined, and are therefore underestimates of the
actual binding potency.
b
Values from Ref. 12.
c
EC50 values for efficacy given in nM units, with the % efficacy in parentheses, results for a single determination.
CH3
OH
OH
OH
BOC anhydride
O
Et3N, THF, H 2O
r. t.
N
Pd(OH)2
EtOH
reflux
N
N
H
O
2
4
91%
3
100%
X
X
N
N
Br
O
B
CH3
CH3
O
O
OH
O
Br
CH3
CH3
O
O
N
O
N
Pd(PPh3)4
Na2CO3
i-PrO2C-N=N-CO2i-Pr
THF, reflux
O
EtOH/toluene
reflux
5
6
89%
100%
X
N
7, X = H
14, X = 4-NH2
15, X = 5-NH2
16, X = 4-NHSO2Me
17, X = 5-NHSO2Me
17a, X = 5-NHSO2Me (3R, 4S, 6R)
17b, X = 5-NHSO2Me (3S, 4R, 6S)
18, X = 5-NHSO2Et
19, X = 5-NHSO2i-Pr
20, X = 5-NHCOMe
21, X = 5-CONH2
7a, X = H (3R, 4S, 6R)
7b, X = H (3S, 4R, 6S)
8, X = 4-OMe
HCl
O
EtOAc
9, X = 5-OMe
10, X = 4-OH
N
80-100%
H
11, X = 5-OH
11a, X = 5-OH (3R, 4S, 6R)
11b, X = 5-OH (3S, 4R, 6S)
12, X = 4-F
.HCl
7-21
13, X = 5-F
Scheme 1. Preparation of [3.2.1] azabicyclic compounds.
linker and an ortho-substituted phenyl ring offered the best combi-
nation for potent 3b4 and 6/4b4 agonist activity. As we describe
below, this effort led to the discovery of a highly potent and
selective agonist of 3b4 and 6/4b4 nAChRs, 17a.
a
a
a
a

J. A. Lowe et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4749–4752
4751
The synthesis of the compounds described in this work is sum-
marized in Schemes 1 and 2. In Scheme 1, the known [3.2.1]azabi-
cyclic intermediate 2, readily prepared from acetoxynorbornene as
previously described,8 was converted to the free amine 3 and then
re-protected as the t-butyl carbamate, 4. The following two steps,
Mitsunobu displacement9 with 2-bromophenol to afford 5 and
Suzuki coupling10 with an aryl boronic acid to afford intermediate
6 followed the literature precedent. The known flexibility of these
two extensively studied reactions and their adaptability to library
chemistry affords a wide range of potential derivatives for SAR fol-
low-up. Standard acid-catalyzed removal of the t-BOC group com-
pleted the synthesis, affording the target compounds 7–21. In cases
with a free OH group in the final product, a benzyl protecting group
was used and was removed using palladium-mediated 1-methyl-
1,4-cyclohexadiene reduction. Addition of the appropriate sulfon-
amide or acetamide function followed by deblocking completed
the synthesis of compounds 16–20.
Since the endo alcohol 2 is the readily available stereoisomer
starting from a mixture of acetoxynorbornene isomers, inversion
of the stereochemistry in the Mitsunobu reaction gave exclusively
the exo isomer of the aryl ether product 5. X-ray structure determi-
nation of crystalline 5a, the 1R,6S,5R enantiomer of 5, established
this stereochemistry unambiguously (see Supplementary data for
details).11 In order to prepare the corresponding endo isomer,
nucleophilic aromatic displacement using 2-fluoro bromobenzene
afforded the desired intermediate 22 as shown in Scheme 2. The
remainder of the synthesis followed Scheme 1.
tuted phenyl ring containing a 3-pyridyl ring affords potent bind-
ing activity with modest functional agonism as shown in
compound 7. The 3-substituted pyridine ring is reminiscent of
the structure of nicotine, but attempts to overlap nicotine with
compound 7 in molecular modeling studies were unrewarding.
Given that the functional agonism of compound 7 is partial, unlike
nicotine, this is not surprising. Finally, the endo isomer of com-
pound 7, compound 24, afforded only weak activity in vitro.
In an effort to increase functional agonism, we next explored
substitution on the pyridine ring. In the course of this effort, we
serendipitously discovered that H-bond donating substituents at
the 5-position of the pyridine ring have a marked effect on
in vitro activity at nicotinic receptors, especially in terms of func-
tional agonism. For example, compound 11 shows potent and
nearly full functional agonist activity at both a3b4 and a6/4b4 nic-
otinic receptors, in contrast to close-in analogues 8–10. This trend
continues with compounds 12–15. In addition, as these com-
pounds demonstrate, a H-bond acceptor function is clearly not able
to reproduce the activity afforded by a H-bond donor. Compound
17 in particular demonstrates that the strength of the H-bond do-
nor is important, as it is much more potent as a functional
a3b4
and 6/4b4 agonist than compound 15, and very similar to com-
a
pound 11, its most similar compound in terms of H-bond donating
ability (as an indication, calculated pKa values for 11 = 8.08 and for
17 = 6.94). A small series of sulfonamides showed that this func-
tionality is well tolerated, and compound 19 in particular demon-
strated the most potent functional
a3b4 and a6/4b4 agonism in
Table 1 summarizes the in vitro SAR results for compounds
7–21 and 24, and includes both binding and functional activity at
nAChRs (see Supplementary data for detailed protocol for the
assays). Binding displacement assays using tritiated epibatidine
this series. Finally, we examined two isosteres for the H-bond
donating OH group, the N-acetyl and carboxamido groups, com-
pounds 20 and 21. These compounds proved surprisingly active,
although far less active than compound 17, and so may actually
be serving as modestly effective isosteres in this case.
followed established literature protocols.12 The
a6/4b4 nAChR
data, however, requires additional comment. This receptor is an
artificial construct, using the extracellular, ligand-binding, domain
Table 2 summarizes the physical properties and in vitro ADME
properties of selected compounds in this series. While the physical
properties for these compounds are generally in the drug-able
range, the requirement for a H-bond donor to achieve very potent
binding and functional activity limits permeability. For example,
compound 7 shows good permeability across MDCK cell mem-
branes (MDCK AB Papp corrected = 30.3, with a value over 10 indi-
cating generally good membrane permeability) and low liability for
Pgp-mediated efflux (MDR ratio of 1.75 where a value below 2
indicates limited MDR liability and good brain penetration). Intro-
duction of the H-bond donor functionality, however, markedly
of the
a6 receptor and the transmembrane and intracellular
domains of the
a
4 receptor, expressed with the b4 subunit, as de-
scribed previously.13 Positive controls nicotine and varenicline are
included for comparative purposes. Results of functional testing,
using a FLIPR (Fluorimetric Imaging Plate Reader) protocol, are
given for the
a3b4 and a6/4b4 nicotinic receptors only, because
functional activity at the other nicotinic receptors was negligible.
Examining the SAR results in Table 1 shows that combining an
ether linker from the [3.2.1] azabicyclic system to an ortho-substi-
Br
O
OH
Br
F
NaH
+
NMP, 100 oC
N
N
58%
2
22
N
N
CH3
B(OH)2
N
O
O
Pd(OH)2
EtOH
reflux
Pd(PPh3)4
Na2CO3
EtOH/toluene
reflux
N
N
H
100%
72%
23
24
Scheme 2. Preparation of endo diastereomer 24.

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J. A. Lowe et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4749–4752
Table 2
Physical properties of selected compounds
Compound
Mol wt
PSA
cLog P
hMic ER
MDCK Papp AB, corr
MDR ratio
Dofetilide Ki (nM)
7
7a
9
281
281
311
297
297
297
299
299
374
374
388
402
34.1
34.1
43.4
54.4
54.4
54.4
34.1
34.1
88.7
88.7
88.7
88.7
2.28
2.28
2.69
2.57
2.57
2.57
2.5
0.5
NA
NA
0.35
<0.27
0.59
0.47
0.7
30.3
28.7
24.4
4.05
3.36
2.66
13.3
10
1.17
0.84
0.44
0.56
1.75
1.65
1.76
5.84
5.02
3.5
1.26
1.29
4.38
4.65
0.93
1.49
2160
NA
NA
1580
NA
NA
1780
NA
NA
NA
NA
11
11a
11b
12
13
17a
17b
18
19
2.5
1.72
1.72
2.24
2.55
NA
<0.30
<0.27
<0.27
NA
Mol wt—molecular weight, PSA—polar surface area, cLog P—calculated lipophilicity, hMic ER—extraction ratio for clearance of compound from human microsomes in vitro,
MDCK Papp AB, corr—corrected apparent permeability in MDCK cells, given in units of 10À6 cm/s, MDR ratio—ratio of the ratio of permeability in the BA direction over the AB
direction in MDCK cells transfected with the human MDR gene versus the parent cell line, Dofetilide Ki, nM—binding affinity in nM units for the human ERG-encoded
potassium channel, as determined by displacement of radiolabeled dofetilide.
reduces cell membrane permeability and increases MDR liability.
For example, introduction of a 5-OH substituent, in compound
11, affords a corrected MDCK AB Papp value of 4.05 and an MDR
ratio of 5.84. For the sulfonamide compound 17a, the values are
1.17 and 4.38. Given the necessity of the H-bond donor substituent
are sensitive to antipsychotic agents, MIS and PPI. Given its potent
a
a
3b4 and
4b2 receptors as well as its potent in vivo activity, 17a may comple-
4b2 and 7 nicotinic receptor ligands as a useful
a6/4b4 agonist activity without significant activity at
ment selective
a
a
tool for investigating nicotinic receptor pharmacology.
for potent in vitro functional a3b4 and a6/4b4 agonism, the reduc-
tion of brain penetration it affords limits the developability of this
class of compounds for CNS applications. However, although its
CNS penetration is limited, it is nonetheless adequate for it to be
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.06.142.
used as a reagent for investigating central
tinic receptors, as described below.
a3b4 and a6/4b4 nico-
In vivo testing was carried out in the prepulse inhibition (PPI)
and mescaline-induced scratching (MIS) assays. PPI is a measure
of sensorimotor gating, a form of information filtering that is defi-
cient in patients with schizophrenia.14 The MIS reflex is an induc-
ible behavior that is sensitive to antipsychotic agents.15 Both
models are intended to develop pre-clinical evidence of potential
therapeutic benefit in schizophrenia, and known antipsychotic
drugs work in both assays. But for compounds with an untested
mechanism of action in schizophrenia, these models suggest only
that the compound acts in the CNS, but do not suggest what recep-
tors may be involved in the response.
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profile of 17a, the results suggest that these in vivo activities are
not mediated by either
In conclusion, compound 17a represents an opportunity for the
study of the pharmacology of 3-containing and 6-containing
a4b2 or a7 receptors.
a
a
nAChRs. It shows potent activity in binding and functional assays
for both these receptors, with little additional in vitro activity. 17a
was evaluated against a panel of 70 other receptors and in vitro
targets, and showed no significant activity at 1.0
lM. In vivo, 17a
shows potent activity in two CNS-mediated animal models that