Bioorganic & Medicinal Chemistry Letters
Biaryls as potent, tunable dual neurokinin 1 receptor antagonists
and serotonin transporter inhibitors
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Andrew P. Degnan , George O. Tora, Ying Han, Ramkumar Rajamani, Robert Bertekap, Rudolph Krause,
Carl D. Davis, Joanna Hu, Daniel Morgan, Sarah J. Taylor, Kelly Krause, Yu-Wen Li, Gail Mattson,
Melissa A. Cunningham, Matthew T. Taber, Nicholas J. Lodge, Joanne J. Bronson, Kevin W. Gillman,
John E. Macor
Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Depression is a serious illness that affects millions of patients. Current treatments are associated with a
number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown
to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of
animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent
dual NK1R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate sub-
stituents, the SERT/NK1R ratio could be tuned to afford a range of target selectivity profiles. This effort
culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain
uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demon-
strated the ability to maintain NK1 receptor saturation (>88% occupancy) while titrating the desired level
of SERT occupancy (11–84%) via dose selection.
Received 9 February 2015
Accepted 30 April 2015
Available online 2 June 2015
Keywords:
Neurokin 1
NK1
SERT
SSRI
Serotonin transport inhibitors
Neuroscience discovery
Ó 2015 Elsevier Ltd. All rights reserved.
Major depressive disorder is a serious and debilitating illness
that has a lifetime prevalence in the United States of >16%.1 It is
a leading cause of disability as measured by years lost to disability
and is the fourth leading contributor to the global burden of dis-
ease as measured by disability-adjusted life years.2 The treatment
of depression was revolutionized in 1988 with the approval of flu-
oxetine, the first serotonin-selective reuptake inhibitor (SSRI), in
the United States.3 Despite the improvements in safety and tolera-
bility made by the advent of this and other SSRIs, these agents have
been associated with a number of negative side effects, including
sexual dysfunction, weight gain, nausea, insomnia, and somno-
lence.3 As such, there remains a serious unmet medical need that
awaits the identification of new pharmacological approaches for
the treatment of depression.
Neurokinin 1 receptor (NK1R) antagonists were first reported to
have anti-depressant activity in clinical trials in 1998 by Kramer
and co-workers.4 In these trials, aprepitant (1) showed improve-
ment in symptoms of anxiety and depression that was comparable
to the well-established SSRI, paroxetine. Aprepitant was found to
be well-tolerated at all doses, with adverse events comparable to
those of placebo. For example, sexual side effects occurred in 26%
of study participants given paroxetine versus 3% given aprepitant.
Despite this early promising result, a subsequent dose-finding
study with aprepitant failed to show superior efficacy to placebo
and development for depression was discontinued.5
More recently, it has been suggested that NK1R antagonists
potentiate the antidepressant effects of SSRIs.6 For instance, it
has been shown that combination of sub-active doses of citalo-
pram or paroxetine with an inactive dose of NK1R antagonist
GR205171 reduces immobility of Swiss mice in the forced swim
test.7 A similar result was observed in our own labs using parox-
etine and aprepitant in the gerbil forced swim test.8 As a part of
our studies, ex vivo occupancy of both the NK1 receptor and the
serotonin transporter (SERT) was measured. It was found that by
maintaining high NK1 receptor occupancy, the SERT occupancy
could be reduced while retaining activity in the gerbil forced swim
test. This result offered the hope of delivering an antidepressant
with fewer side effects than with an SSRI alone.
It was in this context that we undertook the development of a
dual NK1R/SERT antagonist.9 From the occupancy experiments
described above, it appeared that high NK1 receptor occupancy
would allow us to reduce SERT occupancy and, theoretically, reduce
the potential for SSRI-related side effects. Our studies suggested a
SERT inhibition/NK1R antagonism IC50 ratio of approximately 10
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Corresponding author. Tel.: +1 203 677 5750; fax: +1 203 677 7702.
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.