Diarylacetylene piperidinyl amides as novel anxiolytics

Article abstract of DOI:10.1016/j.bmcl.2006.02.027

N-Phenyl-2-[1-[3-(2-pyridinylethynyl)benzoyl]-4-piperidine]acetamide (9) and related piperidine acetamide derivatives have good oral activity in the elevated plus maze, an animal model predictive of clinical efficacy for the treatment of anxiety. Modest affinity was observed for the neurokinin NK-1 and 2 receptors, which are known to be involved in the regulation of mood and emotion.

Full text of DOI:10.1016/j.bmcl.2006.02.027

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3065–3067
Diarylacetylene piperidinyl amides as novel anxiolytics
Cheryl P. Kordik,* Chi Luo, Maryann Gutherman, Anil H. Vaidya, Daniel I. Rosenthal,
Jeffrey J. Crooke, Sandra L. McKenney, Carlos R. Plata-Salaman and Allen B. Reitz
Drug Discovery Division, Johnson & Johnson Pharmaceutical Research and Development LLC,
Welsh and McKean Roads, Spring House, PA 19477, USA
Received 16 January 2006; revised 8 February 2006; accepted 8 February 2006
Available online 31 March 2006
Abstract—N-Phenyl-2-[1-[3-(2-pyridinylethynyl)benzoyl]-4-piperidine]acetamide (9) and related piperidine acetamide derivatives
have good oral activity in the elevated plus maze, an animal model predictive of clinical efficacy for the treatment of anxiety. Modest
affinity was observed for the neurokinin NK-1 and 2 receptors, which are known to be involved in the regulation of mood and
emotion.
Ó 2006 Elsevier Ltd. All rights reserved.
The pathological condition of anxiety is a prevalent and
debilitating disorder.1 Clinical anxiety disorders are de-
scribed in the Diagnostic and Statistical Manual, Vol. 4
and include generalized anxiety disorder, panic disorder,
agoraphobia, and obsessive-compulsive disorder.2 There
are significant opportunities for new anxiolytics that are
not sedating or addictive and are broadly effective across
different patient populations and types of anxiety. Neu-
rokinin receptors NK-1 and 2 have been implicated in
mood and emotion, and investigated as targets for the
treatment of anxiety.3 No drug currently marketed for
anxiety acts through this unique mechanism of action,
although the NK-1 antagonist aprepitant has recently
been approved as an anti-emetic.4
When the antidepressant activity for aprepitant was de-
scribed, we initiated a program to discover new neurok-
inin receptor antagonists. We focused our early efforts
on modifications of the neurokinin modulator CGP-
48923 (1).6 In our design strategy, the chiral centers were
removed, while several of the electrostatic and hydro-
phobic interactions were retained. Specifically, we pro-
posed to add hydrophobic substitution appended to
the benzyl group of 1 via a suitable spacer (viz., 2).
R1
HN
O
N
O
O
Me
N
NH
N
Neurokinin receptors are currently divided into three
main subtypes, designated NK-1, 2, and 3. Their endog-
enous agonists are the tachykinin family of peptides,
exemplified by substance P (NK-1 selective) and neur-
okinins A and B (NK-2 and 3 selective, respectively).
Considerable attention has focused on the development
of small-molecule antagonists of the NK-1 receptor for
depression, since early clinical trials appeared to suggest
that NK-1 receptor antagonists may alleviate depression
in humans.5
Me
linker
R2
1, CGP 48923
2
The synthesis was initiated by the reaction of N-benzyl-
4-piperidinone (3) with the appropriate stabilized Wittig
reagent to give 4 (Scheme 1). Hydrogenolysis of 4 pro-
vided 5, which was then reacted with 3-iodobenzoyl
chloride to afford 6. Copper- and palladium-mediated
coupling7 of 3-ethynylpiperidine provided 7, which was
converted to amide targets first by base-mediated hydro-
lysis of the ester to form 8 followed by amide formation
under standard conditions to give 9 (Table 1). In addi-
tion, we prepared 4-hydroxyphenyl congener 10 because
it was a metabolite of 9 (see below) and fluorinated
derivatives 11–13 in order to block this metabolism, by
Keywords: Anxiolytics; Neurokinin; Diarylacetylenes; Piperidines;
Sonogashira coupling; Elevated plus maze.
*
Corresponding author. Tel.: +1 215 628 7986; e-mail:
ckordik@prdus.jnj.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.02.027

3066
C. P. Kordik et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3065–3067
Compounds 9–14 were tested for binding at the neu-
rokinin NK-1 and 2 receptors (hNK1-U373MG and
hNK2-CHO cells, respectively). Although and
9
metabolite 10 had relatively little binding to these
receptors, both the 2- and 4-fluorophenyl compounds
11 and 12 had modest binding with IC50s of 61 lM.
Surprisingly, 2,4-difluorophenyl congener 13 had sig-
nificantly less NK-1 and 2 binding. Compound 14,
in which the pyridine ring of 9 was now a phenyl,
had a similar level of activity as for 9. In addition,
9 was tested at 62 other GPCRs, ion channels, and
uptakes sites at 1 and 10 lM. Other than 60% inhibi-
tion of the GABA transporter at 10 lM, only weak
activities were observed at the peripheral benzodiaze-
pine, glycine, SK+ Ca2+ channels, and the peripheral
imidazoline I2 receptor.
We also determined anxiolytic efficacy of 9, 10, and 13
in established animal models predictive of clinical util-
ity. The primary animal model used was the reversal
of DOI-induced head shake in mice. Anti-depressant
therapy is associated with down-regulation of the 5-
HT2a and 5-HT2 c receptors. Further, antisense down-
regulation of 5-HT2a in mice is associated with antide-
pressant effects.8 Therefore, we determined the effects
of test compounds on head shakes induced by 1-
[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI),
which has high affinity as an agonist for 5-HT2A/2C
receptors.9 This model is useful because it is expected
to be sensitive to compounds that modulate serotoner-
gic pathways, either directly or indirectly. This model
may also be useful for the examination of new, atyp-
ical anxiolytic agents. Compounds 9 and 10 had the
same potency in this test with 20 mg/kg po minimum
effective doses (MEDs), and 13 was more active with a
0.1 mg/kg MED po (Table 2).
Scheme 1. General synthetic pathway.
Table 1. Diarylacetylene piperidinyl amides
R2
O
N
H
R1
N
X
O
Compound
R1
R2
X
NK-1a
NK-2a
9
10
11
12
13
14
H
H
F
H
OH
H
F
N
N
N
N
N
C
37
18
11
n.t.
96 (0.64)
96 (1.0)
16
97 (0.55)
96 (1.0)
H
F
F
8
7
The elevated plus maze (EPM) is a widely used animal
test of anxiety.10 It models spontaneous behavioral
patterns in response to interactions with the environ-
ment. The EPM takes advantage of the innate fear
of rodents for open spaces with novelty as the major
source for this fear. A conflict develops due to the
stimuli of the novel environment which produces both
an approach drive (curiosity) and an avoidance drive
H
H
28
n.t. is not tested.
a % inhibition at 10 lM (IC50, lM).
the use of the appropriate aniline in coupling with 8.
Phenylacetylene 14 was also prepared by the use of ethy-
nylbenzene in reaction with 6.
The oral bioavailability of compound 9 in rats was
determined to be 65% with a t1/2 of 3.1 h after adminis-
tration of 40 mg/kg po. The metabolic stability of 9 was
evaluated in human and rat liver microsomes. Signifi-
cant levels of unchanged 9 remained after 90 min incu-
bation (63% in rat and 35% in human). The major
metabolite involved hydroxylation of the phenyl ring.
We therefore prepared para-hydroxy compound 10.
Comparison of synthetic 10 with that prepared metabol-
ically revealed that they were identical. Compound 10
was more metabolically stable than 9 with 97% and
80% remaining in rat and human liver microsomes,
respectively, after 90 min incubation. However, the bio-
availability of 10 was quite low (<2% at 3 and 10 mg/kg
po), so that it was not considered further. In order to
potentially block hydroxylation on the aryl ring, we pre-
pared fluorinated derivatives 11–13.
Table 2. In vivo testing data
R2
O
N
R1
H
N
X
O
Compound
Elevated plus
maze (MED, po)
DOI-induced headshakes
(MED, po)
9
10
13
1.0
3.0
1.0
20.0
20.0
0.1

C. P. Kordik et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3065–3067
3067
such as fear of the unknown properties of the environ-
Acknowledgments
ment. Current marketed anxiolytics are active in the
EPM, which can detect both anxiolytic and anxiogenic
effects. Compounds 9 and 10 displayed 1.0 and
3.0 mg/kg MEDs upon oral administration, and 13
had a 1.0 mg/kg MED po.
We thank Dr. S. Daniel Benjamin, Hoau-Yan Wang,
Steve Coates and Kevin Pan for their helpful
contributions.
We examined 2,4-difluoro 13 in more detail and were
surprised to find that it was actually less metabolically
stable than 9 in liver microsomes, with only 0.1 (rat)
and 15% (human) remaining after 60 min incubation,
due to oxidative metabolism of the piperidine ring.
In rats it displayed a 7.0% oral bioavailability with
a 2.7 h t1/2 when dosed at 15 mg/kg po, but surprising-
ly had 38–71% bioavailability in cynomologous mon-
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