Substituted furo[3,2-b]pyridines: Novel bioisosteres of 5-HT1F receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2003.09.091

Synthesis and evaluation of a series of 2,3,5- and 3,5-substituted furo[3,2-b]pyridines were undertaken in order to investigate their utility as bioisosteres of 5-HT_1F receptor agonist indole analogues, 1-3. The replacement proved to be effective, providing compounds with similar 5-HT _1F receptor affinity and improved selectivity when compared with the indole analogues. Through these studies we identified 4-fluoro-N-[3-(1-methyl- piperidin-4-yl)-furo[3,2-b]pyridin-5-yl]-benzamide (5), a potent and selective 5-HT_1F receptor agonist with the potential to treat acute migraine.

Full text of DOI:10.1016/j.bmcl.2003.09.091

Bioorganic & Medicinal Chemistry Letters 14 (2004) 167–170
Substituted furo[3,2-b]pyridines: novel bioisosteres of 5-HT1F
receptor agonists
a,
a
a
a
Brian M. Mathes, * Kevin J. Hudziak, John M. Schaus, Yao-Chang Xu,
a
a
a
a
David L. Nelson, David B. Wainscott, Suzanne E. Nutter, Wendy H. Gough,
b
b,y
a,{
Theresa A. Branchek, John M. Zgombick and Sandra A. Filla
aLilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
bSynaptic Pharmaceutical Corporation, 215 College Road, Paramus, NJ 07652, USA
Received 23 July 2003; revised 8 September 2003; accepted 27 September 2003
Abstract—Synthesis and evaluation of a series of 2,3,5- and 3,5-substituted furo[3,2-b]pyridines were undertaken in order to inves-
tigate their utility as bioisosteres of 5-HT1F receptor agonist indole analogues, 1–3. The replacement proved to be effective, pro-
viding compounds with similar 5-HT1F receptor affinity and improved selectivity when compared with the indole analogues.
Through these studies we identified 4-fluoro-N-[3-(1-methyl-piperidin-4-yl)-furo[3,2-b]pyridin-5-yl]-benzamide (5), a potent and
selective 5-HT1F receptor agonist with the potential to treat acute migraine.
#
2003 Elsevier Ltd. All rights reserved.
Serotonin (5-HT) is a neurotransmitter involved in the
regulation of a number of physiological functions in the
central nervous system and peripheral tissues. Mole-
Phebus and colleagues reported that a compounds affi-
nity for the 5-HT1F receptor was correlated to its
potency to inhibit dural plasma protein extravasation
(PPE) following electrical stimulation of the trigeminal
ganglion in the guinea pig, an effect predictive of clinical
1
cular cloning has identified seven 5-HT receptor sub-
families (5-HT –5-HT ), subdivided based on receptor
sequence homology, coupling to second messengers,
1
7
7
efficacy to ameliorate migraine symptoms. This corre-
and physiological effects. The 5-HT receptor family has
1
lation suggested that a potent and selective 5-HT1F
receptor agonist might be a novel anti-migraine ther-
apeutic devoid of the cardiovascular liabilities of non-
selective 5-HT1 agonist triptans. We have previously
reported several 3-alkylamino-5-arylamido-indole ana-
been further sub-classified into the 5-HT1A, 5-HT , 5-
1B
2
HT1D, 5-HT1E and 5-HT1F receptor subtypes. Suma-
triptan was the first 5-HT receptor agonist approved
1
3
for the treatment of migraine. Its clinical efficacy was
initially attributed to its 5-HT1B/1D receptor agonist
activities, in large part because it is a potent agonist at
these receptor subtypes. However, sumatriptan is a
logues as potent and selective 5-HT receptor ago-
1F
8
,9,10
nists.
Compound 1 (LY334370) exhibited high 5-
HT1F receptor affinity and selectivity over the 5-HT1B
and 5-HT1D receptors, but showed appreciable affinity
for the 5-HT1A receptor (Table 1). This compound was
4
potent 5-HT1F receptor agonist as well. Receptor
mapping studies have shown that the 5-HT1D receptor
resides only in neural tissues, whereas the 5-HT1B is
4
efficacious in the PPE migraine model and was clini-
11
5
distributed throughout neural and vascular tissues.
cally effective in treating migraine pain. Subsequent
Thus activation of the 5-HT1B receptor has been impli-
cated as a cause of vasoconstrictive properties and sub-
sequent adverse cardiovascular effects associated with
SAR studies focused on improving 5-HT1F receptor
selectivity while maintaining high 5-HT1F receptor
binding affinity and intrinsic agonist efficacy. Replacing
the indole nucleus with pyrrolo[3,2-b]pyridine, provid-
ing 2, resulted in a 5-fold decrease in 5-HT receptor
affinity (Table 1). While this analogue was more selec-
tive over the 5-HT1B and 5-HT1D receptors than 1, it
showed no improvement in its selectivity over the 5-
HT1A receptor. On the other hand, investigation of a
series of C-5 arylamido tryptamines identified 3, which
6
sumatriptan and other 5-HT receptor agonist triptans.
1
1
F
9
Keywords: Furo[3,2-b]pyridine; Bioisostere.
*
Corresponding author. Tel.: +1-317-277-7720; fax: +1-317-276-
600; e-mail: mathes_brian_m@lilly.com
Deceased, 8 November 2002.
7
y
{
E-mail: filla_sandra_a@lilly.com
0
960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.09.091

168
B. M. Mathes et al. / Bioorg. Med. Chem. Lett. 14 (2004) 167–170
Table 1. Comparison of the 5-HT1F receptor binding affinity and
selectivity of 5-arylamido analogues of 1a
conformations of the indole versus the benzofuran ana-
logues. Furthermore, Nichols and co-workers observed
that the 5-HT1A receptor was less discriminating than
5
-HT1F
(nM)
5-HT selectivity ratiob
the 5-HT subtype in its preference for 5-methoxy-N,N-
2
Structure
Cpd
K
i
1A/1F 1B/1F 1D/1F
dimethyltryptamine and 5-methoxy-a-methyltryptamine
1
3
compared to their benzofuran analogues. In an effort
to optimize for 5-HT1F receptor affinity and selectivity,
we considered that a bioisosteric replacement of this
1
1.6 (ꢁ0.4)
7
85
86
type might lead to variability between the 5-HT recep-
1
tor subtype affinities. We found no reports in the litera-
ture discussing the effect of bioisosteric replacements of the
indole nucleus on a ligands 5-HT1F receptor affinity. Thus,
we investigated the bioisosteric replacement of furan for
the pyrrole ring of the pyrrolo[3,2-b]pyridine nucleus, tar-
geting compounds 4 and 5. This report describes the
synthesis and SAR studies of these compounds.
2
3
4
5
7.6 (ꢁ1.2)
8.2 (ꢁ1.2)
13.5 (ꢁ1.8)
3.1 (ꢁ0.7)
7.3
160
130
42
960
200
19
32
We recently disclosed the synthesis of the C-3 N,N-
1
6
dimethylaminoethyl furo[3,2-b]pyridine analogue 4.
Compounds 5, 12, 13, and 14 were prepared in a similar
fashion, using the six step synthesis shown in Scheme 1.
1
6
65
Beginning with iodopyridine 6, a Mitsunobu coupling
1
7
with 7 yielded iodo aryl allyl ether intermediate 8.
Palladium-promoted cyclization, utilizing the method
1
8
described by Larock, afforded furo[3,2-b]pyridine 9 in
moderate yield. Studies suggested that the piperidine
nitrogen of the acylic precursor must be non-basic, as is
in the case of the N-Boc-protected allyl ether 8, in order
for cyclization to be effected to any appreciable extent.
For example, attempts to cyclize the analogous N-
methyl or N-H substituted analogues of 8 resulted in
very low isolated yields (ca. 10%) of cyclized product.
Reduction of the Boc protecting group of 9 to the
134
>1000 >1000
a
Affinities for receptors were determined in vitro by radioligand
binding assays using cell lines expressing the appropriate human 5-
HT receptor. Values are means of three or more experiments,
SEM is given in parentheses.
i
value (derived from two or more experiments) for the
-HT1A, 5-HT1B or 5-HT1D receptor versus the 5-HT1F receptor.
2
1ꢀ23
b
Ratio of the K
desired methyl group with LiAlH provided 10. The C-5
4
5
in addition to increased selectivity over the 5-HT1B and
-HT1D receptors, also demonstrated marked
improvement in selectivity over the 5-HT1A receptor.
5
a
1
0
However, this compound, like 2, also showed a 5-fold
decrease in 5-HT1F receptor binding affinity when com-
pared to 1.
As a continuation of our efforts in this area, we were
interested in investigating furo[3,2-b]pyridine as a bioi-
sostere of the indole nucleus. Furo[3,2-b]pyridine retains
the geometric and conformational attributes of indole,
but has differing physicochemical and electronic prop-
erties that may result in differences in 5-HT receptor
subtype recognition and subsequent activation. There
have been few reports regarding the successful replace-
1
2ꢀ15
ment of indole with benzofuran.
Typically, benzo-
furan isosteres of ligands targeting serotonergic
receptors exhibited decreased biological activity relative
to the indole analogues. However, these reports also
noted that there were 5-HT receptor subtype selectivity
differences with this bioisosteric replacement. Russell et
al. reported that the benzofuran analogue of 5-carbox-
amidotryptamine demonstrated reduced 5-HT1A and 5-
HT1D receptor binding affinities but increased 5-HT2A
receptor affinity, when compared with the indole parent
Scheme 1. Reagents and conditions: (a) PPh
temp, 89%; (b) Pd(OAc) , N
2
3
, DEAD, THF, room
NCl, NaO CH, DMF,
2
aCO
3
ꢂ
, n-Bu
4
2
ꢂ
80 C, 60%; (c) LiAlH
imine, Pd
THF (1:1), room temp, 73% (two steps); (e) ArCOCl, pyridine, 55 C.
4
, Et
2
O, 35 C, 61%; (d) (i) benzophenone
ꢂ
1
2
compound. They proposed this biological variation to
be based on differences between the preferred C-5 amide
2
(dba)
3
, (ꢁ)-BINAP, NaOtBu, toluene, 80 C; (ii) 1 NHCl/
ꢂ

B. M. Mathes et al. / Bioorg. Med. Chem. Lett. 14 (2004) 167–170
169
chloro substituent was converted to the corresponding
amine 11 utilizing a palladium-mediated amination
procedure that employed benzophenone imine as an
ammonia equivalent, followed by acid hydrolysis.
Acylation of the C-5 amine, providing 5, 12, 13, and 14,
completed the synthesis.
to 5, they were nevertheless more selective for the 5-
HT1F receptor, particularly versus the 5-HT1A receptor,
when compared to the indole analogues in Table 1. All
of these compounds showed good intrinsic efficacy in
the 5HT1F GTP-g-S functional assay, and were full
agonists at the 5-HT1F receptor.
1
9,20
Given the favorable 5-HT1F receptor selectivity profile
of tryptamine 3 versus C-3 piperidinyl analogues 1 and
Evaluation of the furo[3,2-b]pyridine nucleus as a bioi-
sosteric replacement for indole identified a novel series
of 5-arylamido-3-piperidinyl-furo[3,2-b]pyridines. These
studies demonstrated that the 5-HT1F receptor was less
discriminating in its preference for the indole nucleus
versus the furo[3,2-b]pyridine nucleus, as compared to
2
, we initially targeted C-3 N,N-dimethylaminoethyl
furo[3,2-b]pyridine 4 for study. Evaluation of the 5-HT1
receptor binding affinities of 4 indicated that like the
pyrrolo[3,2-b]pyridine analogue 2, this compound also
exhibited decreased 5-HT1F receptor affinity, and in fact
was about 2-fold less potent than 2 (Table 1). In addi-
tion, 4 showed less selectivity over the 5-HT1B and 5-
HT1D receptors when compared to either 1 or 2 or
tryptamine analogue 3. On the other hand, this com-
pound was more selective for the 5-HT1F receptor ver-
sus the 5-HT1A receptor than 1–3. We subsequently
evaluated the C-3 piperidinyl-furo[3,2-b]pyridine 5.
Surprisingly, this analogue demonstrated a notable
increase in 5-HT1F receptor binding affinity when com-
pared with any of the other analogues of 1. Moreover, 5
was also markedly more selective for the 5-HT1F recep-
tor versus the other 5-HT1 receptor subtypes tested,
including the 5-HT1A receptor. We further evaluated the
other 5-HT receptor subtypes, and in particular the 5-
1
HT1A receptor. This difference in selectivity suggested
that there is perhaps a significant interaction between the
indole NH and the receptor of some 5-HT receptor sub-
1
types that is not present in the case of the 5-HT1F recep-
tor–ligand interaction. Alternatively, the conformational
preference of the C-5 amide of the furo[3,2-b]pyridine
and indole analogues may differ, and the 5-HT1F recep-
tor may preferentially favor the low energy conforma-
tion of the furo[3,2-b]pyridine analogue.
We have identified a clear difference in the 5-HT1
receptor subtype affinities of furo[3,2-b]pyridine bio-
siosteres versus those of the parent indole analogues.
Thus, we have uncovered a novel approach to identify
compounds with high affinity and selectivity for the 5-
HT1F receptor. From these SAR studies, we identified 4-
fluoro-N-[3-(1-methyl-piperidin-4-yl)-furo[3,2-b]pyridin-
5-yl]-benzamide 5, a novel, potent and selective 5-HT1F
5
-arylamido-3-piperidinyl-furo[3,2-b]pyridine series by
preparing 12, 13, and 14 (Table 2). Like 5, these com-
pounds also demonstrated high 5-HT1F receptor bind-
ing affinity. While they demonstrated decreased
selectivity over the other 5-HT receptors as compared
1
Table 2. Comparison of the 5-HT1F receptor binding affinity, selectivity and functional activity of 5-arylamido-3-piperidinyl-furo[3,2-b]pyridine
analoguesa
5
-HT1F
(nM)
5-HT selectivity ratio
1B/1F
5-HT1F GTP-g-S
EC50 (nM)b max (% 5-HT)c
Cpd
R
K
i
1A/1F
134
1D/1F
E
5
3.1 (ꢁ0.7)
2.3(ꢁ0.2)
2.9 (ꢁ0.2)
3.0 (ꢁ0.5)
>1000
>1000
66.0 (ꢁ5.3)
91.7 (ꢁ1.5)
68.7 (ꢁ7.5)
27.7 (ꢁ1.0)
88
87
87
92
12
13
14
57
103
47
181
164
177
62
31
165
a
See footnote of Table 1 for 5-HT receptor binding parameters.
b
Stimulation of [ S]GTP-g-S binding in mouse LM(tk ) cells expressing the human 5-HT1F receptor.24 Values are expressed as mean values from at
35
ꢀ
least two separate experiments performed in triplicate, SEM is given in parentheses.
35
c
Maximum stimulation of [ S]GTP-g-S binding expressed relative to the maximal effect of 5-HT.

170
B. M. Mathes et al. / Bioorg. Med. Chem. Lett. 14 (2004) 167–170
receptor agonist that may have potential as a ther-
apeutic for acute treatment of migraine.
C.; Zgombick, J. M. 8th Congress of the International
Headache Society. Amsterdam, 10–14 June 1997.
. Filla, S. A.; Mathes, B. M.; Johnson, K. W.; Phebus,
L. A.; Cohen, M. L.; Nelson, D. L.; Zgombick, J. M.;
Erickson, J. A.; Schenck, K. W.; Wainscott, D. B.;
Branchek, T. A.; Schaus, J. M. J. Med. Chem., in
press.
0. Xu, Y.-C.; Johnson, K. W.; Phebus, L. A.; Cohen, M.;
Nelson, D. L.; Schenck, K.; Walker, C. D.; Fritz, J. E.;
Kaldor, S. W.; LeTourneau, M. E.; Murff, R. E.; Zgom-
bick, J. M.; Calligaro, D. O.; Audia, J. E.; Schaus, J. M.
J. Med. Chem. 2001, 44, 4031.
9
Acknowledgements
The authors would like to thank Mr. Steven Henry of
Eli Lilly and Company for helpful discussions regarding
the preparation of this manuscript, as well as Dr. Jeffrey
Schkeryantz of Eli Lilly for his scientific insights.
1
1
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N. M.; Phebus, L. A.; Johnson, K. W.; Schaus, J. M.;
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