(R)-3-(N-Methylpyrrolidin-2-ylmethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl) -1H-indole derivatives as high affinity h5-HT1B/1D ligands

Article abstract of DOI:10.1016/S0960-894X(03)00779-0

A series of (R)-3-(N-methylpyrrolidin-2-ylmethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl) -1H-indole derivatives (2) have been prepared using parallel synthesis, and their structure-activity relationship studied. High affinity human 5-HT _1B/1D (h5-HT_1B/1D) ligands have been identified.

Full text of DOI:10.1016/S0960-894X(03)00779-0

Bioorganic & Medicinal Chemistry Letters 13 (2003) 3419–3421
(R)-3-(N-Methylpyrrolidin-2-ylmethyl)-5-(1,2,3,6-
tetrahydropyridin-4-yl)-1H-indole Derivatives as High Affinity
h5-HT1B/1D Ligands
Ian Egle,* Neil MacLean, Lidia Demchyshyn, Louise Edwards, Abdelmalik Slassi
y
and Ashok Tehim
NPS Pharmaceuticals Inc., 6850 Goreway Dr., Mississauga, Ontario, Canada L4V 1V7
Received 21 April 2003; revised 14 July 2003; accepted 22 July 2003
Abstract—A series of (R)-3-(N-methylpyrrolidin-2-ylmethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives (2) have been
prepared using parallel synthesis, and their structure–activity relationship studied. High affinity human 5-HT1B/1D (h5-HT1B/1D
ligands have been identified.
)
#
2003 Elsevier Ltd. All rights reserved.
Migraine is a chronic disease characterized by episodic
attacks of intense, unilateral headache pain. Often
associated with the attack are secondary symptoms that
include nausea and vomiting, photophobia, and phono-
phobia. Although the episode will resolve on its own in
a few hours to a few days, the debilitating nature of the
attacks necessitates treatment to alleviate the discomfort
experienced. It is estimated that over 200 million people
worldwide suffer from migraine headaches in one form
ability and duration of action, the majority of them
have still been shown to contract the human coronary
6
artery in vitro, and up to 40% of all attacks and up to
25% of all patients do not respond to any of these
7
drugs.
Although 5-HT1B receptors are found in human tri-
geminal ganglia, they are also abundantly expressed in
vascular smooth muscle. It is now postulated that much
of the vasoconstrictive liability of the triptans is a result
of their high 5-HT1B affinity. 5HT1D receptors appear to
be absent in vascular tissue, but are identified in the tri-
geminal ganglia. Electrical stimulation of the trigeminal
nerves induces release of neuropeptides such as calcito-
nin gene-related peptide (CGRP). Subsequently, plasma
protein extravasation into the dura occurs, resulting in
vasodilation, inflammation and pain. Consistent with
this model is the fact that the elevated levels of CGRP
observed during a migraine attack are normalized by
sumatriptan, with concurrent relief of the migraine.
1
,2
or another.
Sumatriptan has for years been the treatment of choice
for migraine sufferers. It is a potent h5-HT1B/1D recep-
tor agonist, with K values of 3.4 and 7.7 nM at the h5-
i
3
HT1D and h5-HT1B receptors, respectively. Despite its
success, sumatriptan possesses several shortcomings
that have spurred the search for better therapies. These
shortcomings include poor oral bioavailability, short
half-life and the tendency for migraine attacks to reoc-
cur, and angina-like side effects, possibly resulting from
4
8,9
coronary artery vasoconstriction. Due to this, the use
of sumatriptan for patients with coronary heart disease
Although still under debate, this neurogenic hypo-
thesis has been the impetus for the search for h5-HT
1
D
5
4
is contraindicated. While a new generation of triptan
drugs have shown significant improvement in bioavail-
agonists that are selective over h5-HT .
1B
Our efforts in the field of h5-HT1D selective agonists led
to the discovery of ALX-0646 (1). This potent and
selective ligand has a K of 8ꢀ1 and 610ꢀ147 nM for
i
*
Corresponding author. Tel.: +1-905-677-0831; fax: +1-905-677-
10,11
the h5-HT and h5-HT receptors, respectively. It
is currently in clinical trials for the treatment of acute
1
D
1B
9
595; e-mail: iegle@npsp.com
y
Current address: Memory Pharmaceuticals Corp., 100 Philips Park-
way, Montvale, NJ 07645, USA
1
2
migraine.
0
960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00779-0

3420
I. Egle et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3419–3421
t
ꢂ
Scheme 1. (a) Oxalyl chloride, DMF, CH
e) 30% TFA/CH Cl , Á; (f) RNCO, CH
2
Cl
Cl
2
; (b) 5-bromoindole, CH
2
Cl
, or RNCS, CH Cl , or RSO
2
; (c) LiAlH
Cl, Et N, CH Cl .
3 2 2
4
, THF, Á; (d) BuLi, THF, ꢁ78 C, then N-Boc-4-piperidone;
(
2
2
2
2
2
2
2
Table 1. Binding profile of series 2 at the cloned human 5-HT1B and 5-HT1D receptors
Compd
X
R
h5-HT1D
h5-HT1B
i
K (h5-HT1B)/
K
i
(nM)a
K
i
(nM)a
K
i
(h5-HT1D)
Sumatriptan
3.43
7.73
2.2
19
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
SO
SO
SO
2
2
2
4-MeOPh
1-Napthyl
4-MePh
0.76ꢀ0.27
0.88ꢀ0.16
0.80ꢀ0.19
0.38ꢀ0.00
3.0ꢀ1.8
14ꢀ3
23ꢀ5
17ꢀ5
2
NHCO
NHCO
NHCO
NHCO
NHCO
NHCO
NHCO
NHCS
NHCS
NHCS
NHCS
NHCS
NHCS
NHCS
4-ClPh
3.8ꢀ1.4
14ꢀ5
10
4.6
2
Cyclohexyl
1-Adamantyl
Ph
4-MeOPh
4-MePh
1-Napthyl
Cyclohexyl
1-Adamantyl
Ph
4.0ꢀ1.1
11ꢀ4
0.45ꢀ0.10
0.42ꢀ0.01
0.31ꢀ0.00
0.45ꢀ0.14
2.0ꢀ0.8
4.8ꢀ1.211
4.2ꢀ0.8
3.0ꢀ0.4
3.8ꢀ1.6
13ꢀ5
10
9.7
8.4
6.3
7.0
8.5
2.7
5.2
3.9
4.6
5.6ꢀ1.239
0.68ꢀ0.16
ꢀ10
5.8ꢀ2.0
ꢀ0.4
4-ClPh
0.56ꢀ0.121.5
.4 0.46ꢀ0.022
0.38ꢀ0.06
4-MeOPh
4-MePh
1-Napthyl
ꢀ0.6
1.5ꢀ0.3
3.2ꢀ0.6
0.70ꢀ0.18
aK
values are reported as the mean of two independent determinationsꢀSEM.
i
various electrophiles in parallel to generate the
compounds for this study (2a–q).
The receptor binding affinities of compounds 2a–q are
depicted in Table 1. All compounds reported here
exhibited high affinity for the h5-HT1D receptor, with Ki
values ranging from 0.31 nM (compound 2i) to 5.6 nM
(compound 2l). Selectivity over h5-HT1B was modest,
however, with compound 2b having the best selectivity,
an h5-HT1B/1D ratio of 26:1. Due to this, the functional
activity of this series of compounds was not investi-
gated. There was no significant difference between the
ureas and thioureas, while the sulphonamides were
typically less potent but more selective. The affinities of
the compounds were not found to be particularly sensi-
tive to the nature of the lipophilic R group; however,
aromatic groups were somewhat preferred over aliphatic
groups.
As a continuation of our efforts in this area, this paper
describes the results of one of our endeavors to investi-
gate the effect of changing both the N,N-dialkylethyl-
amine substituent at position 3 of the indole nucleus,
and the substituent on the nitrogen of the tetra-
hydropyridine ring of 1, providing compounds of the
general structure 2.
The series was prepared starting with (R)-N-Cbz-proline
(3), the acid chloride of which was condensed with 5-
bromoindole to yield ketone 4 (Scheme 1).
1
3,14
The
ketone and the carbamate were simultaneously reduced
with LiAlH . Lithium halogen exchange with three
4
equivalents of BuLi and trapping provided alcohol 6. It
While we failed in our initial goal to produce a series of
h5-HT1D ligands selective over h5-HT , to date the
t
1B
was found to be unnecessary to protect the indole
nitrogen prior to the lithiation. Treatment of 6 with
TFA induced elimination and deprotection to provide
the secondary amine 7. This amine was reacted with
efficacy of highly selective h5-HT1D compounds has yet
to be demonstrated in clinical trials. If the mechanism of
action of triptan antimigraine drugs is indeed due to a
direct vasoconstrictive effect rather than, or in addition

I. Egle et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3419–3421
3421
to, inhibition of neuropeptide release, then some com-
1
7. Diener, H.-C.; Limmroth, V. Expert Opin. Investig. Drugs
2001, 10, 1831.
5
bination of h5-HT1B/1D activity is in fact desirable.
8
4
9
. Humphrey, P. P. A.; Goadsby, P. J. Cephalalgia 1994, 14,
01.
. Longmore, J.; Dowson, A. J.; Hill, R. G. Curr. Opin.
In summary, a series of highly affinitive h5-HT1B/1D
ligands have been identified using parallel synthesis
techniques. Several compounds with subnanomolar
affinity for the human 5-HT1D receptor were developed.
CPNS Invest. Drugs 1999, 1, 39.
1
1
2
1
0. Isaac, M.; Slassi, M. IDrugs 2001, 4, 189.
1. Slassi, A.; Isaac, M.; Arora, J. Expert Opin. Ther. Patents
001, 11, 625.
2. Kamboj, R.. IBC’s 3rd Annual Conference on Migraine:
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