Synthesis and biological evaluation of pyridine-modified analogues of 3-(2-aminoethoxy)pyridine as novel nicotinic receptor ligands

Article abstract of DOI:10.1016/S0960-894X(02)00740-0

Analogues of the potent nicotinic receptor agonist 3-(2-aminoethoxy)pyridine substituted at the 5′ and 6′-positions of the pyridine ring were synthesized and tested in vitro for nicotinic receptor binding activity (displacement of [³H](-)cytisine from whole rat brain synaptic membranes). The substituted analogues exhibited K_i values ranging from 0.076 to 319 nM compared to a K_i value of 26 nM for compound 1. Among the compounds tested, 5′-vinyl-6′-chloro substituted 1 was the most potent.

Full text of DOI:10.1016/S0960-894X(02)00740-0

Bioorganic & Medicinal Chemistry Letters 12 (2002) 3321–3324
Synthesis and Biological Evaluation of Pyridine-Modified
Analogues of 3-(2-Aminoethoxy)pyridine as
Novel Nicotinic Receptor Ligands
Nan-Horng Lin,* Liming Dong, William H. Bunnelle,
David J. Anderson and Michael D. Meyer
Neurological and Urological Diseases Research, D-47W, Pharmaceutical Products Division,
Abbott Laboratories, 100 Abbott ParkRoad, Abbott Par k, IL 60064-3500, USA
Received 11 June 2002; accepted 13 August 2002
0
0
Abstract—Analogues of the potent nicotinic receptor agonist 3-(2-aminoethoxy)pyridine substituted at the 5 and 6 -positions of the
3
pyridine ring were synthesized and tested in vitro for nicotinic receptor binding activity (displacement of [ H](À)cytisine from whole
rat brain synaptic membranes). The substituted analogues exhibited K values ranging from 0.076 to 319 nM compared to a K value
i
i
0
0
of 26 nM for compound 1. Among the compounds tested, 5 -vinyl-6 -chloro substituted 1 was the most potent.
2002 Elsevier Science Ltd. All rights reserved.
#
Recent evidence indicating the therapeutic potential of
neuronal nicotinic receptor (NNR) ligands for the
treatment of central nervous system (CNS) disorders as
well as the diversity of brain NNR subtypes have sug-
gested an opportunity to develop subtype-selective
NNR ligands for the treatment of specific CNS dis-
those with mono- or dimethyl substituents, or unsub-
stituted amino groups. These compounds have been
screened in assays that measured binding affinity to
central NNR. In this paper we describe the structure–
activity studies of N1-substituted analogues of 3.
1À4
orders with reduced side effect liabilities.
recently identified A-84543 (1), a member of a novel
We have
series of 3-pyridyl ether compounds, as a potent neuro-
5
nal nicotinic receptor ligand. Several compounds of
this class were found to possess sub-nanomolar affinity
5
for NNR and activate specific subtypes of NNR. To
explore the structural requirements for potent interac-
tion with NNR, structural modifications of this com-
N1-substituted analogues were prepared based on the
reaction sequences shown in Schemes 1–3. The starting
chiral alcohol 3 was prepared from the corresponding
amino acid by reduction with borane. (Scheme 1) For-
mation of the pyridyl ether may be accomplished in two
distinct ways. One involves the formation of a tosylate
followed by displacement with a substituted hydroxy-
pyridine under basic conditions. Alternatively, acti-
vation of an alcohol under Mitsunobu reaction
conditions allows ether formation.
0
6À8
pound were undertaken. Recently,
we demonstrated
that the binding affinity of analogues of A-84543 (1) can
be modulated by varying the substituents on pyridine
ring. For example, compound 2, which possesses a large
phenyl group when compared with A-84543, possesses
similar binding potency compared with 1. We have also
identified compound 3, an analogue lacking a cyclic ring
structure but with potent binding activity. In order to
probe the necessity of the heterocyclic ring on the
binding and potency, a large number of N1-sub-
stituted analogues of 3 have been prepared, including
Scheme 2illustrates how primary, secondary and ter-
tiary amines can be obtained from a common Boc pro-
tected intermediate. Thus, alkylation of the Boc
protected amine with methyl iodide provides the sec-
ondary amine after removal of the protecting group
under acidic conditions. The dimethylamine analogue was
prepared under Eschweiler–Clarke reaction conditions.
*Corresponding author. Fax: +1-847-935-5466; e-mail: nanhorng.
lin@abbott.com
0
960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00740-0

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N.-H. Lin et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3321–3324
Table 1. Binding data for dimethylamino-pyridine substituted ana-
logues
0
3
Compd
R
R
[ H](À)Cytisine
a
binding K
i
(nM)
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
5-Cl
5-Br
5-CF
5-NO
6-Me
6-OMe
6-Cl
5-Cl, 6-Cl
5-Br, 6-Cl
6-Cl
6-Cl
6-F
6-F
5-Br, 6-Cl
5-Br, 6-Cl
32.6Æ4.6
74Æ3
50Æ9
3
250Æ31
260Æ79
140Æ10
406Æ40
79Æ28
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
16Æ16
H
7.1Æ2.3
42Æ7.0
42Æ5
(R)-Me
(S)-Me
(R)-Me
(S)-Me
(R)-Me
(S)-Me
(R)-Me
(S)-Me
(R)-Me
(S)-Me
(S)-Et
Scheme 1.
70Æ15
100Æ45
12Æ7.0
31Æ9
5-Me, 6-Cl
5-Me, 6-Cl
5-(4-Py–CH¼CH-), 6-Cl
5-(4-Py–CH¼CH-), 6-Cl
5-(4-Py–CH¼CH-), 6-Cl
5-(4-Py–CH¼CH-), 6-Cl
5-Br, 6-Cl
7.2Æ0.1
9.6Æ1.1
0.10 Æ0.02
0.37Æ0.06
3.6Æ0.7
4.6Æ1.5
320Æ40
5.5Æ3.2
b
b
b
b
(S)-CH
(S)-CH
2
Ph
Ph
2
(S)-CH
2
CH Cl
2
5-CF
3
a
The ability of compounds to displace [3H](À)cytisine binding to
13
whole rat brain membranes was performed as described. Values are
the meansÆSEM; n=3–4. In all cases, the Hill co-efficient was close to
unity indicative of an interaction with a single class of binding sites.
b
The geometry of the double bond is trans.
Scheme 2.
substituents on binding affinity, as reflected by dis-
3
placement of [ H](À)cytisine from rat brain membranes,
is shown in Tables 1–3. We first examined the effect of
the amino group on the binding potency. In general,
compounds having a dimethylaminoethoxy group possess
the weakest receptor binding affinity. The methylamino
analogues have comparable binding potency to that of
amino compounds (cf. 13, 36 and 50; 15, 38 and 52).
With this information in hand, we then investigated the
effect of pyridyl substituents on the binding affinity. In
the dimethylamino series, replacement of the 3-pyridyl
moiety of 3 with either a 5-chloro or bromopyridyl
group (4 and 5) caused only a 2-fold decrease in binding
Scheme 3.
3
affinity towards the [ H](À)cytisine binding site. In con-
Further elaboration of the pyridine substituents may be
accomplished after ether formation as illustrated in
Scheme 3. It has been demonstrated previously that a
bromide may be activated with palladium catalyst to
trast, a dramatic decrease in binding affinity was
observed for analogue 6 (K =250 nM) which has a
i
8
5-trifluoromethypyridyl substituent. Replacement of the
CF group with a nitro group has a similar effect on the
3
9
form aryl and vinyl compounds under Suzuki and
1
binding affinity. With regard to the C6 position, when a
chloro atom is incorporated, as in analogue 10, a com-
parable affinity with the 5-chloro compound 4 is
observed. Replacement of Cl with an electron-donating
methoxy group (9) resulted in a 5-fold decrease in
binding affinity. In contrast, a similar affinity is
observed when the chloro was substituted with a methyl
group.
0
Heck reaction conditions. The alkyl analogues may be
prepared employing a nickel catalyst with the corre-
1
1
sponding Grignard reagents.
A major subtype of NNR in the brain is labeled with
3
3
high affinity by [ H](À)nicotine and [ H](À)cytisine and
1
2
is composed of a4 and b2subunits. The effect of the

N.-H. Lin et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3321–3324
3323
Table 2. Binding data for methylamino-pyridine substituted analoguesa Table 3. Binding data for amino-pyridine substituted analoguesa
0
3
0
3
Compd
R
R
[ H](À)Cytisine
Compd
R
R
[ H](À)Cytisine
a
i
Binding K (nM)
a
Binding K
i
(nM)
27
28
29
30
31
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
H
H
H
H
H
H
H
H
H
H
5-Cl
5-NH
5-NO
5-CF
6-Me
6-OMe
6-Cl
5-Cl, 6-Cl
5-Br, 6-Cl
6-Cl
6-Cl
6-F
17Æ4
37Æ4
27Æ4
49
50
51
52
53
54
55
56
57
H
5-Cl
6-Cl
6-Cl
6-F
6-F
5-Br, 6-Cl
5-Br, 6-Cl
140Æ26
5.3Æ1.7
(R)-Me
(S)-Me
(R)-Me
(S)-Me
(R)-Me
(S)-Me
(R)-Me
(S)-Me
(R)-Me
(S)-Me
(S)-Et
(S)-CH
(S)-Et
(S)-CH Ph
(S)-Et
(S)-Et
2
4.5Æ0.3
2
560Æ110
1500Æ160
43Æ10
6.6Æ2.5
3
8.7Æ0.4
1.5Æ0.3
620Æ5
1.5Æ0.9
22Æ5
5-Me, 6-Cl
5-Me, 6-Cl
0.98Æ0.17
0.52Æ0.07
0.081Æ0.003
0.076Æ0.039
0.18Æ0.04
9.9Æ0.9
13Æ7
b
H
14.3Æ0.4
5.9Æ1.8
41.0Æ5.6
11Æ3
58
59
5-(4-Py–CH¼CH–), 6-Cl
5-(4-Py–CH¼CH–), 6-Cl
5-(4-Py–CH¼CH–), 6-Cl
b
(R)-Me
(S)-Me
(R)-Me
(S)-Me
(R)-Me
(S)-Me
(R)-Me
(S)-Me
(R)-Me
b
60
61
b
2
Ph 5-(4-Py–CH¼CH–), 6-Cl
6-F
69Æ4
62
63
64
65
5-Br, 6-Cl
15Æ38
5-Br, 6-Cl
5-Br, 6-Cl
5-Me, 6-Cl
5-Me, 6-Cl
5-(4-Py–CH¼CH–), 6-Cl
1.5Æ0.3
11.0Æ3.2
0.57Æ0.15
5.5Æ0.9
0.077Æ0.032
2.6Æ2.1
85Æ38
2
5-Br, 6-Cl
6-F
6-Cl
100Æ27
39Æ7
15.0Æ0.8
b
b
a
3
The ability of compounds to displace [ H](À)cytisine binding to
13
(S)-CH
(S)-CH
(S)-CH
2
2
2
Ph 5-(4-Py–CH¼CH–), 6-Cl
whole rat brain membranes was performed as described. Values are
the meansÆSEM; n=3–4. In all cases, the Hill co-efficient was close to
Ph
Ph
5-Br, 6-Cl
H
6-F
690Æ29
220Æ74
unity indicative of an interaction with a single class of binding sites.
b
(S)-Et
The geometry of the double bond is trans.
a
3
The ability of compounds to displace [ H](À)cytisine binding to
whole rat brain membranes was performed as described.13 Values are
the meansÆSEM; n=3–4. In all cases, the Hill co-efficient was close to
unity indicative of an interaction with a single class of binding sites.
0
the ethoxy side chain have an effect on the nicotinic
receptors, various 2 -substituted analogues were eval-
To examine whether substituents at the C2 position of
0
b
The geometry of the double bond is trans.
uated for their nicotinic binding affinity. We first inves-
tigated the dimethylamino series. Table 1 reveals that
0
the corresponding parent analogue 12. Another 10-fold
decrease is observed when the C2 methyl group was
It is also interesting that compounds having halo sub-
stituents at both the C5 and C6 positions of the pyridyl
ring increased receptor binding affinity (cf. 10 and 11; 13
and 17). A further increase in potency was observed
when the C5 bromo atom was replaced with a 4-vinyl-
pyridine moiety (cf. 18 and 22; 17 and 21). The binding
potency at either the C5- or C6-position appears to be
governed by both electronic and steric effects. A simple
steric effect cannot account for the high affinity of the
vinylpyridine analogue (21) that has a large group at the
the C2 methyl analogue (18) is 4-fold less potent than
0
replaced with a benzyl functionality (18 vs 25). In the
case of the 5-(4-vinylpyridyl), 6-Cl analogues, the order
of binding potency of the C2 -substituted analogues is
0
Me >Et >CH Ph. The same SAR trend is also
2
observed in the amino series with the 5-Br, 6-Cl com-
pound. In contrast to both the dimethylamino and
amino series, no effect in binding potency is observed
0
5
-position. It has been demonstrated that the OMe (9)
when a methyl group was introduced at the C2 position
substitution lead to weaker affinity than the Me (8)
substitution, despite the larger size in volume. There-
fore, it appears that electronic effects may play some
role in determining binding affinity. The same SAR
trend was also observed in the methylamino and amino
series (Tables 2and 3).
(35 vs 41) in the methylamino series. However, replacing
methyl with a benzyl group caused an 8-fold decrease in
binding potency (41 vs 46).
With this information in hand, we then turned our
0
attention to scrutinize the effect of chirality at the C2
position on the binding potency. Examining the binding
affinities of the Me analogue in the dimethylamino ser-
In general, Table 1 reveals that the 5-(4-Py–CH¼CH–),
0
6
-Cl analogue (21) is the most potent compound in the
ies, the configuration of the C2 chiral center does not
dimethylamino series. With the exception of the 5-NO2,
-CF and 6-OMe groups, the F, Cl, Br and Me, moieties
have much effect on the binding affinity. No significant
difference in binding activity is observed when stereo-
chemistry is changed from R to S (13 vs 14; 19 vs 20). A
similar trend is also observed in the amino series (50 vs
51; 54 vs 55). In contrast to those results, the chirality at
5
3
(15, 10, 5, and 8) were tolerated at both C5 and C6-
positions. With regard to the methylamino series, the
most potent compound identified is the 5-(4-Py-CH
0
¼
CH–), 6-Cl analogue (44) which possesses a K value
i
C2 position shows a selected effect on the binding
of 0.077 nM. As shown in Table 3, 5-(4-Py–CH¼CH–),
-Cl analogue (59) is also the most potent compound in
the amino series.
potency in the methylamino series. As indicated in
Table 2, a 6-fold decrease in potency is observed when
the stereochemistry is changed from R to S with the
6

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N.-H. Lin et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3321–3324
fluoro analogues. In general, the S-enantiomer is 6–10
times more potent than the corresponding R-enantio-
mer in the methylamino series.
3. Meyer, E. M.; de Fiebre, C. M.; Hunter, B. E.; Simpkins,
C. E.; Frauworth, N.; de Fiebre, N. E. C. Drug Dev. Res. 1994,
31, 127.
. Garvey, D. S.; Carrera, G. M.; Arneric, S. P.; Shue, Y.-K.; Lin,
4
N.-H.; He, E.; Lee, E.; Lebold, S. A: US Patent 5 409 946, 1995.
. Abreo, M. A.; Lin, N.-H.; Garvey, D. S.; Gunn, D. E.;
Hettinger, A.-M.; Wasicak, J. T.; Pavlik, P. A.; Martin, Y. C.;
Donnelly-Roberts, D. L.; Anderson, D. J.; Sullivan, J. P.;
Williams, M.; Arneric, S. P.; Holladay, M. W. J. Med. Chem.
In summary, we have shown that varying the sub-
stituent pattern at the amino group of the aminoethoxy
moiety of compound 3 alters the binding properties of
these compounds. The binding affinities (Tables 1–3)
indicate that large substituents are well tolerated at the
C5 position of the pyridine ring. In general, the SAR of
this series followed the trend as observed in the A-84543
series with only a few exceptions. This study has also
shown that methylamino and amino compounds possess
similar binding potency. The most potent analogue
5
1
996, 39, 817.
6. Lin, N.-H.; Gunn, D. E.; Li, Y.; He, Y.; Bai, H.; Ryther,
K. B.; Kuntzweiler, T.; Donnelly-Roberts, D. L.; Anderson,
D. J.; Campbell, J. E.; Sullivan, J.; Arneric, S. P.; Holladay,
M. W. Bioorg. Med. Chem. Lett. 1998, 8, 249.
7
. Lin, N.-H.; Abreo, M. A.; Gunn, D. E.; Lebold, S. A.; Lee,
E.; Wasicak, J. T.; Hettinger, A.-M.; Daanen, J. F.; Garvey,
D. S.; Campbell, J. E.; Sullivan, J.; Williams, M.; Arneric, S. P.
Bioorg. Med. Chem. Lett. 1999, 9, 2747.
identified is compound 44 (K =0.077 nM) that pos-
i
sesses a binding potency that is comparable with that of
ABT-594 (K =0.05 nM), a potent nicotinic receptor
agonist.
i
8
. Lin, N.-H.; Li, Y.; He, Y.; Holladay, M. W.; Kuntzweiler,
T.; Anderson, D. J.; Campbell, J. E.; Arneric, S. P. Bioorg.
Med. Chem. Lett. 2001, 11, 631.
9
. Suzuki, A. Acc. Chem. Res. 1982, 15, 178.
10. Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2 .
1. Tamao, K.; Kodama, S.; Nakajima, I.; Kumada, M. Tetra-
References and Notes
1
1
1
2
. Holladay, M. W.; Lebold, S. A.; Lin, N.-H. Drug Dev. Res.
995, 35, 191.
. Arneric, S. P.; Sullivan, J. P.; Williams, M. In Psycho-
hedron 1982, 22, 3347.
12. Flores, C. M.; Rogers, S. W.; Pabreza, L. A.; Wolfe, B. B.;
Kellar, K. J. Mol. Pharmacol. 1991, 41, 31.
13. Pabreza, L. A.; Dhawan, S.; Kellar, K. J. Mol. Pharmacol.
1990, 39, 9.
pharmacology: Fourth Generation of Progress; Bloom, E.,
Kuper, D. J., Eds.; Raven: New York, 1995; p 95.