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
*
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
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