Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs)

Article abstract of DOI:10.1016/j.bmcl.2013.10.045

The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX ₁R/OX₂R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.

Full text of DOI:10.1016/j.bmcl.2013.10.045

Bioorganic & Medicinal Chemistry Letters 23 (2013) 6620–6624
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor
antagonists (2-SORAs)
a
b
b
b
Swati P. Mercer a, , Anthony J. Roecker , Susan Garson , Duane R. Reiss , C. Meacham Harrell ,
Kathy L. Murphy b, Joseph G. Bruno d, Rodney A. Bednar d, Wei Lemaire b, Donghui Cui c,
Tamara D. Cabalu c, Cuyue Tang c, Thomayant Prueksaritanont c, George D. Hartman a,
Steven D. Young a, Christopher J. Winrow b, John J. Renger b, Paul J. Coleman a
⇑
a Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
b Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA
c Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA
d The West Point Facility for Automation and Screening (WP FAST), Merck Research Laboratories, West Point, PA 19486, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due
to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-
of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) orexin receptor
antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor
antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small mol-
ecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as
potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this
series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 2 October 2013
Revised 22 October 2013
Accepted 23 October 2013
Available online 30 October 2013
Keywords:
Orexin receptor antagonists
Selective orexin-2 receptor antagonists
Insomnia
Hypocretin
Rat sleep EEG
The orexin receptors, OX1R and OX2R, are G-protein coupled
receptors that are functionally expressed in the brain. Activation
of these receptors through the action of endogenous neuropeptides
orexin-A and orexin-B promotes wakefulness in animals and
humans.1 Hence, reversible blockade of orexin signaling may offer
benefits in the treatment of insomnia.
In support of this hypothesis, Merck, Actelion Pharmaceuticals
and GlaxoSmithKline have demonstrated clinical proof-of-concept
for the treatment of primary insomnia with their advanced dual
orexin receptor antagonists (DORAs) suvorexant (MK-4305), filo-
rexant (MK-6096), almorexant (ACT-078573) and SB-649868.2–4
These studies have clearly increased attention in the potential of
the DORA mechanism of action. However, less is known about
the pharmacology of selective OX2R antagonism. Recently, a selec-
tive OX2R antagonist (JNJ-10397049) was reported to show in vivo
efficacy in the rat upon peripheral administration.5–7 However,
there are conflicting reports in the literature on the role of OX2R
antagonism in sleep promotion.8 Herein, the discovery and optimi-
zation of an OX2R selective series of 2,5-diarylnicotinamides is
described. Improvements in potency, selectivity, and oral
bioavailability will be discussed as well as in vivo efficacy in
electroencephelographic (EEG) telemetrized rats.
Compounds synthesized in this report were initially screened
for OX2R and OX1R potency through an in vitro radioligand binding
assay in which the inhibition of binding of a high affinity radioli-
gand to membranes from human cells overexpressing the orexin
receptor is measured and reported as Ki. Compounds were then
screened through a cell-based functional FLIPR (fluorometric imag-
ing plate reader) assay in which Ca2+ flux is measured as a func-
tional determinant of orexin binding.3,9 Receptor binding was
used as the primary screen for determining potency and selectivity
for the 2,5-diarylnicotinamides. In order to improve the utility of
ligands for pharmacological elucidation, we used the functional
FLIPR assay to determine whether compounds of interest are in-
deed dual or selective antagonists. All compounds with greater
than 20-fold OX2R functional selectivity are determined to be
selective and thus meet the criteria for pharmacological
elucidation.1c
Several 2,5-diarylnicotinamides were identified as potent OX2R
antagonists from high-throughput screening efforts. Compound 1
(Fig. 1) is a representative 2,5-diarylnicotinamide OX2R antagonist
with a 200-fold selectivity in the binding assay. Initial exploration
of the 2,5-diarylnicotinamide series began with variation of the
⇑
Corresponding author. Tel.: +1 215 652 5074; fax: +1 215 652 7310.
E-mail address: swati_mercer@merck.com (S.P. Mercer).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.10.045

S. P. Mercer et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6620–6624
6621
Table 1
Me
Amide Moiety SAR
O
O
HN
A
D
Me
Me
O
R2
R1
O
B
N
N
C
N
Me
1
N
hOX2R Ki = 17.0 nM, hOX1R Ki = 3350 nM
N
Figure 1. 2,5-Diarylnicotinamide HTS lead.
Compound R1
R2
H
hOX2R
hOX1R
hOX1R/
hOX1R (Ki,
Selectivity)
bindinga,b
(Ki, nM)
bindinga,b
(Ki, nM)
Me
O
O
O
O
Cl
1
17.0
3550
208
(a)
OMe
N
Me
OH
N
O
O
N
N
4
5
6
Me 580
1900
273
3.3
91
92
2
3
N
N
H
3.0
(c), (d)
(b)
Me
R1
R2
O
R1
R2
O
Me 78.5
7250
N
N
R3
N
Me
OMe
7
8
H
H
22.0
4.8
2975
833
135
174
N
N
N
N
NMe2
Scheme 1. Synthesis of 2,5-diarylnicotinamides. Reagents and reaction conditions:
(a) 3,5-dimethylphenyl boronic acid, PCy3, Pd2(dba)3, Cs2CO3, dioxane, 80 °C, 24 h,
95% then 1.0 M KOH, 25 °C, THF/MeOH, 24 h, 99%; (b) R1R2NH, EDC, HOBt, DIEA, DMF,
100 °C, 3 h, 16–75%; (c) 1.0 M KOH, 25 °C, THF/MeOH, 24 h, 99% then R1R2NH, EDC,
HOBt, DIEA, DMF, 100 °C, 3 h, 30–99%; (d) R3B(OH)2, PCy3, Pd2(dba)3, Cs2CO3, dioxane,
95 °C, 24 h, 15–90%. PCy3 = tricyclohexylphosphine, Pd2(dba)3 = tris(dibenzylidene-
acetone)dipalladium, Cs2CO3 = cesium carbonate, EDC = N-(3-dimethylaminopro-
OMe
9
H
H
H
40.5
18.0
4.1
3350
1105
236
83
61
58
10
11
F
F
pyl)-N0-ethylcarbodiimide
hydrochloride,
HOBt = 1-hydroxybenzotriazole,
DIEA = diisopropylethylamine.
CF3
OMe
OMe
D-ring of 1 followed by modification of the A-ring of the molecule
through library synthesis.
12
H
0.7
462
660
Differentiation of the D-ring in 1 was carried out by subjecting
intermediate 2 to Suzuki–Miyaura cross-coupling conditions with
3,5-dimethylphenylboronic acid (Scheme 1).10 Subsequent hydro-
lysis of the methyl ester afforded 2,5-diarylnicotinic acid 3 which
served as the scaffold for an amide coupling library with various
benzylamines. Alternatively, the A-ring of such a compound was
explored through initial hydrolysis of intermediate 2 followed by
peptide coupling with the desired benzylamine (Scheme 1). With
the amide group installed, the resulting 2-aryl-5-chloronicotina-
mide served as the scaffold for a Suzuki–Miyaura cross-coupling li-
brary which utilized various arylboronic acids and esters.
Initial D-ring exploration on the 2,5-diarylnicotinic acid scaffold
showed that N-methylation of the amide moiety (4) was not toler-
ated and resulted in a 30-fold reduction in OX2R binding potency
and a 60-fold decrease in selectivity for OX2R over OX1R relative
to compound 1 (Table 1). The indoline compound 5, although more
potent than 1, was 3-fold less selective than 1. The quinoxaline
compound 6 was not only 4-fold less potent than 1 but also had
3-fold less selectivity for OX2R over OX1R.
The electronic and steric effects of various substituents on the
D-ring were also explored. The 4-methoxyphenyl compound 7
was equipotent to 1 and possessed a similar selectivity profile.
The 4-dimethylaminophenyl compound 8 was 3-fold more potent
than 1 and showed similar selectivity for OX2R over OX1R. Substi-
tution at the 3-position, as exemplified by the 3-methoxyphenyl
compound 9, decreased potency and selectivity relative to 1.
Incorporation of an electron withdrawing group such as the
a
Values are the mean of two or more independent experiments.
See Ref. 5 for assay details.
b
3-methyl-4-fluorophenyl substituent in compound 10 resulted in
an equipotent compound relative to 1 with a 3-fold decrease in
selectivity. Also, the 3-fluoro-4-trifluoromethylphenyl substituent
in compound 11 imparted a 4-fold boost in potency and a 3-fold
decrease in selectivity relative to 1. The 3,4-dimethoxyphenyl moi-
ety in 12 afforded a 20-fold boost in potency and a 3-fold increase
in OX2R selectivity (hOX2R Ki = 0.7 nM, hOX1R Ki = 462 nM, hOX1R/
hOX2R = 660) when compared to 1. Thus, compound 12 was the
basis for further exploration.
Rat pharmacokinetics was assessed for compound 12. This com-
pound had high clearance (66 mL/min/kg) and relatively low bio-
availability (12%) in the rat.11 Efforts were therefore undertaken
to explore the A-ring of 12 with the aim of improving pharmacoki-
netic parameters (Table 2). Substitution of the 3,5-dimethylphenyl
moiety in 12 with a 3-fluoro-5-methylphenyl group led to com-
pound 13 which afforded an equipotent compound with slightly
improved clearance in dog.12 Decreasing bulk from the 3-fluoro-
5-methylphenyl compound 13 to the 3,5-difluorophenyl
compound 14 led to a 10-fold decrease in potency, whereas the
incorporation of the larger 3,5-trifluoromethylphenyl group
rendered 15 even less potent than 14. The 3-chlorophenyl contain-
ing 16 was less potent than 12 and showed a slightly higher

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S. P. Mercer et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6620–6624
Table 2
A-ring SAR
OMe
HN
R3
O
OMe
N
N
Compound
R3
hOX2R bindinga,b (Ki, nM)
hOX1R bindinga,b (Ki, nM)
hOX1R/hOX1R (Ki, selectivity)
Dog iv PKc (Cl, mL/min/kg)
12
13
0.7
462
660
6.9
0.8
8.3
1073
5150
1341
620
3.9
ND
F
F
14
F
CF3
15
16
17
121
1.3
0.6
65000
747
537
ND
7.3
5.7
CF3
574
Cl
Cl
1087
1811
F
Cl
18
0.07
94.5
1351
3.2
Cl
a
b
c
Values are the mean of two or more independent experiments.
See Ref. 5 for assay details.
Dosed at 0.125 mpk in 100% DMSO in cassette format.
clearance in dog. Compound 17 which incorporated a 3-chloro-5-
fluorophenyl moiety is equipotent to 12 and showed a slight
improvement in dog clearance. Gratifyingly, 3,5-dichlorophenyl
containing 18 not only showed a 10-fold boost in potency relative
to 12, but also showed a 2-fold increase in selectivity and overall
decreased clearance in dog. The potency and selectivity profile,
coupled with low clearance in the dog, set compound 18 apart
from other compounds in this series and was thus synthesized
on larger scale for further evaluation. The last synthetic step for
compound 18 via the original route, a Suzuki–Miyaura coupling,
was low yielding (15%). Hence, a modified synthetic route for 18
was explored (Scheme 2).
Methyl-2-chloro-5-iodonicotinate 19 was subjected to a Suzu-
ki–Miyaura cross-coupling reaction with 3,5-dichlorophenyl boro-
nic acid which afforded the desired intermediate 20 in acceptable
(56%) yield.13 It should be noted that no significant formation of
bis-coupled or dehalogenated adducts was observed. A subsequent
Suzuki–Miyaura cross-coupling reaction on 20 with 3-pyridylbo-
ronic acid at elevated temperature yielded 21. Standard hydrolysis
and amide bond formation with 3,4-dimethoxybenzylamine affor-
ded the leading compound 18 in multi-gram quantities (see
Supporting information).
Cl
O
O
I
OMe
Cl
OMe
(a)
N
Cl
N
Cl
19
20
(b)
Cl
Cl
OMe
OMe
HN
O
(c)
Cl
O
N
Cl
OMe
N
N
N
21
18
Scheme 2. Modified synthesis of compound 18. Reagents and reaction conditions:
(a) 3,5-dichlorophenyl boronic acid, Cs2CO3, PdCl2(dppf), DMF/water, 0 °C ? 25 °C,
3 h, 56% (b) 3-pyridylboronic acid, Cs2CO3, PdCl2(dppf), DMF/water, 100 °C, 2.5 h,
62%; (c) 1.0 M KOH, 25 °C, THF/MeOH, 24 h, then 3,4-dimethoxybenzylamine, EDC,
HOBt, NMM, DMF, 25 °C, 3 h, 70%, over 2 steps. PdCl2(dppf) = [1,10-Bis(diphenyl-
phosphino)ferrocene]dichloropalladium(II). NMM = 4-methylmorpholine.

S. P. Mercer et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6620–6624
6623
Table 3
Properties of Compound 18
Cl
OMe
OMe
HN
Cl
O
N
N
18
Property
18
hOX2R Kia (nM)
0.07
12.0
94.5
292
hOX2R FLIPRa (nM)
hOXjR Kia (nM)
hOX1R FLIPRa (nM)
hOX1 Ki/hOX2R Ki (selectivity)
hOX1R FLIPR/hOX2R FLIPRi (selectivity)
1378
24
logP
3.6
ffb (h,r)
3.2%, 4.7%
6.4 (h)
0.19
P-gpc (BA/AB)
Brain/plasmad
Dog PK (mono HCI salt)
Cl (mL/min/kg)
t1/2
3.2
2.1 h
37
%F
Rat PK (mono HCl salt)
Cl (mL/min/kg)
t1/2
39
0.9 h
%F
55
e
Panlabs (IC50
)
>100-fold selectivity
a
b
c
See Ref. 5 for assay details. All potency data has an n > 3.
Determined by equilibrium dialysis. See Ref. 5 for assay details.
See Ref. 5 for assay details.
3.0 mg/kg PO in rat on mono-HCl salt; 1 h timepoint. See Ref. 5 for assay details.
Panlabs (MDS Pharma): Merck Screen (165-assays).
d
e
Figure 2. Effect of compound 18 on rat sleep architecture as measured by EEG (15
mpk, PO, vehicle = 20% Vitamin E TPGS in water). The vertical line at the top of each
panel indicating the state of arousal refer to statistically significant data points.
The overall profile of compound 18 is illustrated in Table 3.
Compound 18 has 0.07 nM binding potency against OX2R and a
functional potency of 12 nM. It also shows a 1400-fold binding
selectivity and 24-fold functional selectivity for OX2R over OX1R.
This compound has a plasma free-fraction of 4.7% in rat and 3.2%
in human and alogP of 3.6. CSF sampling in rats after oral dosing
of compound 18 indicates that CNS penetration is somewhat lim-
ited (CSF/plasma = 0.2%), possibly due to P-glycoprotein (P-gp)
activity. The compound is a human P-gp substrate (BA/AB efflux
ratio = 6.4 in human MDR1-expressed LLCPK cells) and is likely a
P-gp substrate in rat as well.14 Pharmacokinetic studies of 18 in
rat and dog showed low to moderate clearance (3.2 mL/min/kg in
dog and 39 mL/min/kg in rat), a short half-life (2.1 h in dog and
0.9 h in rat) and oral bioavailability (37% in dog and 55% in rat).
Also, compound 18 possessed greater than 100-fold functional
selectivity over 165 other targets (MDS Pharma, Merck Screen).15
Due to these promising results, compound 18 was studied in
the rat sleep EEG model. This model involved a crossover study
design in rats with centrally implanted EEG-telemetry devices.
EEG and electromyographic (EMG) signals were scored automati-
cally every ten seconds and assigned one of the four states of
arousal (active wake, light sleep, REM sleep or delta sleep).16 The
resulting changes in sleep architecture were then plotted in thirty
minute increments against vehicle treatment (Fig. 2). When com-
pound 18 was dosed orally in rats at 15 mg/kg during their active
period, a decrease in active wake and light sleep was observed with
a concomitant increase in delta and REM sleep.17
efficacy in the rat sleep EEG model. Additional studies on related
2-SORAs will be reported in due course.
Acknowledgments
We thank C.W. Ross III, J.S. Murphy, V. Van Nostrand, D. Rudd,
K.D. Anderson, K.L. Hoffman and M.M. Zrada for analytical support,
M.J. Bogusky and S.L. Varga for NMR assistance and R. Woodward
for the synthesis of 19 (now commercially available).
Supplementary data
Full experimental details for the synthesis of 18 are provided as
an attachment to this manuscript. Supplementary data associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.bmcl.2013.10.045.
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In conclusion, initial high-throughput screening efforts identi-
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nists. This series of compounds was optimized through library
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preclinical species; See Ref. 3a.
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17. Exposures for rat EEG experiment with compound 18 at an oral dose of
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