Synthesis and structure-activity relationship of novel pyridyl ethers for the nicotinic acetylcholine receptor

Article abstract of DOI:10.1016/S0960-894X(00)00168-2

The preparation of novel pyridyl ethers as ligands for the nicotinic acetylcholine receptor (nAChR) is described. Variations of the ring size of the azacycle and substitution on the pyridine had dramatic effects on receptor binding affinity with IC₅₀S at the α₄β₂ nAChR ranging from 22 to >10,000 nM. The most potent molecule was (R)-2-chloro-3-(4-cyanophenyl)-5-((3-pyrrolidinyl)oxy)pyridine 27f with an IC₅₀ of 22 nM. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00168-2

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1063±1066
Synthesis and Structure±Activity Relationship of Novel Pyridyl
Ethers for the Nicotinic Acetylcholine Receptor
Jung Lee,* Coralie B. Davis, Ralph A. Rivero, Allen B. Reitz and Richard P. Shank
R.W. Johnson Pharmaceutical Research Institute, Welsh & McKean Road, Spring House, Pennsylvania PA 19477, USA
Received 13 December 1999; accepted 7 March 2000
AbstractÐThe preparation of novel pyridyl ethers as ligands for the nicotinic acetylcholine receptor (nAChR) is described. Varia-
tions of the ring size of the azacycle and substitution on the pyridine had dramatic e€ects on receptor binding anity with IC50s at
the a4b2 nAChR ranging from 22 to >10,000 nM. The most potent molecule was (R)-2-chloro-3-(4-cyanophenyl)-5-((3-pyrrolidi-
nyl)oxy)pyridine 27f with an IC50 of 22 nM. # 2000 Elsevier Science Ltd. All rights reserved.
The discovery of compounds that can safely treat both
acute and chronic pain without the side e€ect of drug
dependency would be an important advance in pain
management. The discovery of epibatidine 1, a nAChR
modulator, suggested that it might be possible to obtain
an analgesic compound that is devoid of opioid-related
side e€ects.1 But the narrow therapeutic index of epiba-
tidine prohibited further development of the compound
as an analgesic.2 The discovery of ABT-594 fueled fur-
ther investigation of the therapeutic potential of ligands
that bind to the nAChR.3 ABT-594 was shown to be
at least 20 times more potent than morphine as an
analgesic.3a Furthermore, the initial ®ndings suggested
that the compound did not elicit the drug dependency
associated with morphine. To this end, we now report
the discovery of novel pyridyl ethers as potent ligands
for the a4b2 nAChR subtype.
the pyridyl group as a part of the novel ligands. The
only criteria left on the molecule was to place nitrogen
in an optimal distance from the 3 position of the pyridine.
Numerous models have been suggested in the literature
regarding the location and angle of the nitrogen in
respect to the pyridine.4 As part of our structure±activity
program, we identi®ed the pyridyl ethers 3 as potent
ligands that bound to the a4b2 nAChR subtype.
Chemistry
The nitrogen of 3-pyrrolidinol 4a5 was ®rst protected
with a Boc group as shown in Scheme 1. The Boc-pro-
tected pyrrolidinol 5 (n=1) was then coupled with 3-
hydroxypyridine under Mitsunobu conditions.6 The
pyridyl ether 6 (n=1) was then treated with a solution
of tri¯uoroacetic acid (TFA) and methylene chloride
(1:1) to obtain 3-((3-pyrrolidinyl)oxy)pyridine (7). 3-((4-
Piperidinyl)oxy)pyridine (8) was obtained from 4-piper-
idinol5 by a similar route as described above. N-Methyl,
-ethyl, -isopropyl analogues 3 (n=2, R=CH3, CH2CH3,
CH(CH3)2) were prepared from N-methyl, -ethyl, -iso-
propyl-3-pyrrolidinols5 as shown in Scheme 1 without
the Boc-protecting group. The chiral 3-pyrrolidinols5
were used to prepare the corresponding enantiomers as
shown in Scheme 1.
Our program focused on using natural product ligands
such as epibatidine 1 and nicotine 2 as starting points
for analogue design as shown in Figure 1. We retained
Figure 1. Ligands for nAChR.
The azetidine analogue was prepared as shown in
Scheme 2. The hydrogenation of 1-(diphenylmethyl)-3-
hydroxyazetidine5 under H2, Pd/C and protection of the
reduced nitrogen with a Boc group resulted in the Boc-
*Corresponding author. Tel.: +1-215-628-5228; fax: +1-215-628-
3297; e-mail: jlee@prius.jnj.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00168-2

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J. Lee et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1063±1066
sence of DIEA and DMF. Mitsunobu coupling between
the resin bound pyrrolidinol 23 and either 3-bromo-
5-hydroxypyridine or 2-chloro-3-bromo-5-hydroxy-
pyridine provided the resin bound core structure 24.
Suzuki coupling between 24 and arylboronic acids, fol-
lowed by cleavage of the coupled products from the
resin provided the desired compounds 27.
Results and Discussion
To elucidate the structure±activity relationship of the
pyridyl ethers, the ring size of the azacycle of the pyridyl
ethers was initially examined. The binding anities of
these initial compounds are shown in Table 1. As shown
in Table 1, both 5- and 6-membered pyridyl ethers 7 and
8 showed a similar binding anity toward the a4b2
nAChR subtype (209 and 205 nM, respectively). The
azetidine analogue 11 did not show any binding anity
toward the receptor subtype. Then substitution at the
nitrogen of the pyrrolidine was examined. The N-methyl
analogue 3a showed more than a 2-fold increase in the
binding anity compared with des-methyl analogue 7,
with an IC50 of 92 nM. Substitution with either N-ethyl
or -isopropyl groups (3b,c) resulted in the loss of the
binding activity.
Scheme 1. (a) Boc2O, DIEA, Dioxane:H2O (1:1); (b) 3-Hydroxy-
pyridine, PPh3, DEAD, THF; (c) TFA:CH2Cl2 (1:1).
protected 3-hydroxyazetidine 9. Mitsunobu coupling
between 9 and 3-hydroxypyridine gave the protected
pyridyl ether 10. Subsequent de-protection of the Boc
group with a solution of TFA and methylene chloride
(1:1) resulted in the desired 3-((3-azetidinyl)oxy)pyridine
(11).
To prepare 5-substituted pyridyl ethers, the Boc-pro-
tected (S)-3-pyrrolidinol (12) was ®rst coupled with
either 3-bromo-5-hydroxypyridine or 2-chloro-3-bromo-
5-hydroxypyridine (13) under Mitsunobu conditions to
obtain the desired ether 14 as shown in Scheme 3.
Addition of trimethylsilylacetylene to 14 under Sonoga-
shira conditions7 provided the aryl acetylenes 15. The
trimethylsilyl group was subsequently removed to
obtain 16. The pyridyl ether 17 was obtained from 16
after treating the compound with a solution of
TFA:CH2Cl2 (1:1). Using a Stille coupling reaction,8 the
vinyl analogue 19 was prepared from the aryl bromide
14. The methyl analogue 21 was obtained from Mitsu-
nobu coupling between 12 and 2-chloro-3-methyl-5-
hydroxypyridine.
Since 7 was a racemic compound, the corresponding
enantiomers were prepared to evaluate the binding
activities of each enantiomer. As shown in Table 1, the
(R)-isomer (R)-7 was about 4-fold more active than 7
with an IC50 of 45 nM. On the other side, the (S)-isomer
(S)-7 was more than 2-fold less active than 7. These
results indicated that (R)-isomer was considerably more
active than the (S)-isomer.9 We then explored the
structure±activity relationships of the pyridine portion
of the core structure and the results are shown in Table 2.
A general trend was observed. In all cases, substitution
of a chloride at the 2 position of the pyridine analogues
resulted in an increase of the binding anity (ex. 17b
versus 17a and 19b versus 19a). When nonaromatic
alkyl groups were added at the 5 position of the pyridine
ring, the acetylene substitution 17a,b resulted in the
highest binding activity (62 and 46 nM for the des-
chloro and chloro analogues, respectively), followed by
the methyl 21, and vinyl 19a,b analogues. We then
3-Aryl substituted pyridyl ethers were prepared accord-
ing to Scheme 4. p-Nitrophenylcarbonate Wang resin
was allowed to react with (S)-3-pyrrolidinol in the pre-
Table 1. The a4b2 nAChR binding data on pyridyl ethers10
Entry
n
R
IC50 (nM)
7
8
11
3a
3b
3c
(R)-7
(S)-7
1
2
0
1
1
1
1
1
H
H
H
209 (157±278)a
204 (132±314)
>10,000
92 (61±138)
>10,000
>10,000
CH3
CH2CH3
CH(CH3)2
H
45 (21±99)
449 (118±1720)
H
Scheme 2. (a) (i) H2, Pd/C, (ii) Boc2O, DIEA, Dioxane:H2O (1:1); (b)
3-Hydroxypyridine, PPh3, DEAD, THF; (c) TFA:CH2Cl2 (1:1).
aThe values in the parenthesis represent 95% con®dence limits.

J. Lee et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1063±1066
1065
Scheme 3. (a) PPh3, DEAD, THF; (b) Trimethylsilylacetylene, Pd(PPh3)4, CuI, Et3N, THF; (c) 2-chloro-3-methyl-5-hydroxypyridine, PPh3, DEAD,
THF; (d) n-Bu3SnCH=CH2, Pd(PPh3)4, Toluene; (e) TBAF, THF; (f) TFA:CH2Cl2 (1:1).
Scheme 4. (a) (S)-3-pyrrolidinol, DIEA, DMF; (b) PPh3, DEAD, 3-bromo-5-hydroxypyridine or 2-chloro-3-bromo-5-hydroxypyridine, THF; (c)
Arylboronic acid, LiCl, Pd(PPh3)4, Na2CO3, Toluene, EtOH; (d) 95% TFA/H2O.
explored aromatic substitution on the 5 position of the
pyridine ring. The addition of a phenyl ring at the posi-
tion (27b) was well tolerated with an IC50 of 75 nM.
When substituted phenyls were examined, 4-cyano
phenyl substitution (27f) gave the most potent binding
activity with an IC50 of 22 nM. Generally, para sub-
stitution (27f) gave better binding activity than the
meta-isomers (e.g., 27d,j). The binding activity of the
pyridine substituted analogue 27h was similar to the one
observed with the phenyl analogue 27b (65, and 75 nM
respectively).
Table 2. The a4b2 nAChR binding data on pyridyl ethers10
In summary, we prepared novel pyridyl ethers as ligands
for the a4b2 nAChR subtype. Variation of the size of the
azacycle and substitution on the pyridine had dramatic
e€ects on receptor binding anity with IC50 ranging
from 22 to >10,000 nM. The optimum binding anity
was observed when the ring size was a 5-membered
ring. A clear separation of the binding anity was
observed with enantiomers (R)-7 and (S)-7. Increase in
the binding activity was observed when the 2 position of
the pyridine was substituted with a chloride. Additional
binding activity was gained when the 3 position of the
pyridine was substituted with a 4-cyanophenyl group.
The in vivo analgesic activities of the novel pyridyl
ethers will be reported in due course.
Entry
R
X
IC50 (nM)
17a
17b
19a
19b
21
CCH
CCH
CHCH2
CHCH2
CH3
Br
Ph
Ph
3-OMe-Ph
3-OMe-Ph
4-CN-Ph
4-CN-Ph
4-Pyr
4-Pyr
3-Cl-Ph
3-Cl-Ph
H
Cl
H
Cl
Cl
Cl
H
Cl
H
Cl
H
62 (44±89)a
46 (18±114)
883 (408±1900)
140 (111±1760)
64 (26±160)
94 (55±159)
1820 (560±5990)
75 (25±226)
1120 (760±1650)
58 (38±88)
544 (67±4400)
22 (13±38)
571 (188±1740)
65 (33±126)
940 (380±2320)
103 (50±205)
25
27a
27b
27c
27d
27e
27f
27g
27h
27i
27j
Cl
H
Cl
H
Acknowledgement
Cl
We wish to thank Dennis Hlasta for reviewing the
manuscript.
aThe values in the parenthesis represent 95% con®dence limits.

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J. Lee et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1063±1066
toni-Kaplan, M.; Mckenna, D. G.; Wasicak, J. T.; Holladay,
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