Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties

Article abstract of DOI:10.1016/j.bmcl.2015.04.066

Abstract Antagonism of orexin receptors has shown clinical efficacy as a novel paradigm for the treatment of insomnia and related disorders. Herein, molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that w

Full text of DOI:10.1016/j.bmcl.2015.04.066

Bioorganic & Medicinal Chemistry Letters 25 (2015) 2488–2492
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification of MK-8133: An orexin-2 selective receptor antagonist
with favorable development properties
a
a
b
b
Scott D. Kuduk a, , Jason W. Skudlarek , Christina N. DiMarco , Joseph G. Bruno , Mark H. Pausch ,
Julie A. O’Brien b, Tamara D. Cabalu c, Joanne Stevens b, Joseph Brunner b, Pamela L. Tannenbaum b,
Susan L. Garson d, Alan T. Savitz d, Charles M. Harrell d, Anthony L. Gotter d, Christopher J. Winrow d,
John J. Renger d, Paul J. Coleman a
⇑
a Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
b Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA
c Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA
d Department of Neuroscience, 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:
Antagonism of orexin receptors has shown clinical efficacy as a novel paradigm for the treatment of
insomnia and related disorders. Herein, molecules related to the dual orexin receptor antagonist
filorexant were transformed into compounds that were selective for the OX2R subtype. Judicious selec-
tion of the substituents on the pyridine ring and benzamide groups led to 6b; which was highly potent,
OX2R selective, and exhibited excellent development properties.
Received 17 March 2015
Revised 17 April 2015
Accepted 20 April 2015
Available online 29 April 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Orexin
Insomnia
GPCR
Antagonist
Sleep
Introduction
Recently, Merck received FDA approval of the first DORA
suvorexant (BelsomraÒ) for the treatment of insomnia (Fig. 1).
Orexin neuropeptides and their receptors have a critical role in
maintaining wakefulness thus generating significant interest in
targeting the orexin receptors for sleep and wake disorders.
These excitatory neuropeptides, named hypocretin1 and orexin
(most commonly used),2 have been characterized via genetic and
biochemical approaches.3 Orexinergic neurons localized in the
lateral hypothalamus generate orexin neuropeptides (OX-A and
OX-B), and signal via two G-protein-coupled receptors (GPCR’s),
Orexin Receptor 1 (OX1R) and Orexin Receptor 2 (OX2R).3
Orexin receptors are dispersed in areas of the brain that direct
wake, vigilance and reward seeking behaviors. During the normal
wake period, orexin signaling is most active and falls nearly silent
during the sleep period.4–6 Numerous companies have described
dual OX1R and OX2R orexin receptor antagonists (DORAs), or selec-
tive orexin receptor antagonists (SORAs), and a few have advanced
through late stage clinical development.7–10 Numerous reviews are
available in this context.11–16
Another DORA, filorexant, was discovered and advanced into clin-
ical development by the same discovery team.17 In addition to
DORAs, novel tri-aryl OX2R Selective Orexin Receptor Antagonists
(SORAs) have been described by Merck.18–20
Some limited SAR data has been reported for filorexant at the
carboxamide, O-methylene linkage, and fluoro-pyridine regions
of the molecule, but all within the framework of DORAs.17,21
More recently, we have shown that elimination of the methylene
linking unit and replacement of the pyridine with quinoline hete-
rocycles has led to OX2R SORAs within the filorexant chemotype
(Fig. 2).22 For example, compound 1, lacking the methylene linkage
and possessing a quinoline heterocycle, was found to be a very
potent and highly OX2R SORA (FLIPR IC50’s: OX1R>10,000 nM;
OX2R = 47 nM). The related isoquinoline 2 was found to be a
DORA (FLIPR IC50’s: OX1R = 25 nM; OX2R = 36 nM). Genetic studies
suggested that the OX2R rodent knockout has a stronger sleep phe-
notype relative to OX1R and there is an active discussion in the
field whether an OX2R SORA would have a potential advantage
over a DORA.23 Herein, we describe the surprising SAR switch of
⇑
Corresponding author. Tel.: +1 267 337 6913; fax: +1 215 261 6076.
E-mail address: skuduk@noviratherapeutics.com (S.D. Kuduk).
the DORA
2 into a 2-substituted pyridine OX2R SORA, and
http://dx.doi.org/10.1016/j.bmcl.2015.04.066
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

S. D. Kuduk et al. / Bioorg. Med. Chem. Lett. 25 (2015) 2488–2492
2489
Me
for determining receptor subtype selectivity between human OX2R
and OX1R.24
Me
Me
O
Me
In order to get a sense of the potential for the 2-substituted
pyridines to exhibit orexin antagonist activity and potential OX2R
selectivity, a simple methyl scan of the four positions on the pyri-
dine ring was conducted (Table 1). Compounds 3 and 4 with sub-
stitution at the 5- and 6-positions, maintained reasonable
binding (Ki’s = 7.6–182 nM) and functional activity in a FLIPR assay
(IC50 = 9–745 nM), with a modest preference for OX2R over OX1R
(16- to 23-fold). This served as the first indication that SORAs could
be generated from DORA lead 2. Moreover, the 4-methyl pyridine
5b showed high affinity at OX2R (Ki = 2.6 nM) and was also 49-fold
selective for OX2R over OX1R with excellent potency (OX2R
IC50 = 16 nM). Lastly, the 3-methyl pyridine 6 showed very weak
affinity for both receptor subtypes. Although the selectivity of 5b
was below a preferred target of >100ꢀ for OX2R over OX1R, it
was promising that a quinolone ring system was not required to
generate a SORA and an encouraging sign that selectivity could
be discovered from isoquinoline 2 with a relatively modest change.
Having observed an OX2R preference with substitution at the 4-
position, replacements for the methyl group in 5b were examined
to measure effects on potency and selectivity (Table 2).
Appropriate substitutions on the pyridine proved critical as the
simple pyridine (5a) lost almost a thousand-fold in binding affinity.
Larger alkyl groups such as ethyl (5c), trifluoromethyl (5d), and
alkynyl (5e) increased affinity and functional antagonism, but
had attenuated selectivity. Nitrile 5f exhibited very similar func-
tional potency to the isoelectronic alkyne 5e, but with exceptional
preference (ꢁ300-fold) for OX2R. To follow this up, additional elec-
tron-withdrawing groups were examined. Ester 5g showed some-
what reduced affinity relative to the nitrile, but 82-fold subtype
selectivity was notable. The di-methyl amide also exhibited high
preference for OX2R (>100-fold), but was considerably weaker
(OX2R IC50 = 95 nM) than the nitrile or ester. Halogens (5i–l) pro-
vided potent antagonists with high affinity, especially for the larger
nuclei, but selectivity remained in the 37–68-fold range; similar to
that seen for methyl. Additional heteroatom containing groups
such as methoxy (5m) and thiomethyl (5n) provided potent, high
affinity antagonists, but selectivity was still quite modest.
N
O
N
N
O
N
N
N
N
N
O
N
N
Cl
F
Suvorexant
Filorexant
Figure 1. MRL clinical DORAs.
Me
Me
N
N
O
N
O
N
O
N
O
N
N
N
N
N
1 (SORA)
2 (DORA)
Me
N
Me
N
O
O
N
O
N
O
N
N
N
N
N
R
R
N
Figure 2. Evolution to piperidine SORAs.
subsequent optimal carboxamide selection leading to the identifi-
cation of SORA clinical candidate MK-8133.
Compounds prepared herein were evaluated for OX2R and OX1R
binding affinity (Ki) through in vitro radioligand competition bind-
ing assays using membranes from CHO-K1 cells overexpressing the
human orexin receptors.21 Moreover, cell-based functional FLIPR
(fluorometric imaging plate reader) assays in which Ca2+ fluxes
were measured as functional determinants of orexin receptor
antagonist activities, were also conducted as the readout of choice
Table 1
Pyridine SARa
Me
N
R
O
N
O
N
N
Compd
R
OX2R BIND (Ki, nM)
OX1R BIND (Ki, nM)
OX2R FLIPR (IC50, nM)
33
OX1R FLIPR (IC50, nM)
745
FLIPR ratio (OX1R/2R)
N
3
7.6
12
23ꢀ
Me
N
4
2.6
37
9
142
16ꢀ
Me
N
N
5b
6
2.6
166
16
788
ND
49ꢀ
Me
Me
621
4756
ND
ND
a
Values represent the average of n P 2 experiments.

2490
S. D. Kuduk et al. / Bioorg. Med. Chem. Lett. 25 (2015) 2488–2492
Table 2
4-Pyridyl SARa
Me
N
O
N
O
N
N
N
R
Compd
R
OX2R BIND (Ki, nM)
OX1R BIND (Ki, nM)
OX2R FLIPR (IC50, nM)
OX1R FLIPR (IC50, nM)
FLIPR ratio (OX1R/2R)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
H
Me
Et
CF3
C„CH
C„N
CO2Me
CON(Me)2
F
Cl
Br
I
OMe
SMe
SO2Me
N(Me)2
Ph
2400
2.6
0.6
0.2
0.6
1.6
3.9
6.5
3.9
1.4
1.8
0.4
1.3
0.2
0.9
4.5
3.8
14,000
170
57
64
49
830
310
470
430
120
130
59
140
39
350
1400
360
nd
16
11
18
10
13
22
95
34
11
10
7.2
13
6.7
16
130
45
nd
790
310
370
—
49ꢀ
28ꢀ
21ꢀ
23ꢀ
293ꢀ
82ꢀ
>105ꢀ
68ꢀ
51ꢀ
37ꢀ
57ꢀ
49ꢀ
16ꢀ
33ꢀ
12ꢀ
54ꢀ
240
3800
1800
>10,000
2300
550
380
410
620
110
510
1500
2400
a
Values represent the average of n P 2 experiments.
Methylsulfone (5o) gave a very similar profile, but the dimethy-
lamine lost substantial activity in the FLIPR assay. Lastly, a lipophi-
lic group in the form of a phenyl ring (5q) provided a similar
preference for OX2R relative to methyl 5b, but ꢁ4-fold reduced
potency. Overall, the nitrile group was optimal providing for very
high selectivity while maintaining good binding affinity and
FLIPR potency.
To further build upon the cyanopyridine finding, a series of
ortho-substituted benzamides were evaluated as replacements
for the triazole benzamide in 5f. In addition to functional potency,
human microsomal stability and physicochemical parameters such
as solubility and lipophilicity were assessed to guide further
prioritization of compounds (Table 3). The parent triazole 5f
possessed desirable low human intrinsic clearance
(<16 mL/min/kg) and exhibited reasonable solubility (148 M) at
a
l
pH 7. Replacement of the triazole with a methyl oxadiazole hetero-
cycle (6a) led to a slight drop in OX2R potency, although other
desirable properties such as selectivity, microsomal stability and
good solubility were maintained. A 2-pyrimidine group (6b), which
has been utilized in the identification of DORAs such as filorexant,
gave a very similar in vitro profile to the oxadiazole in terms of
potency and low intrinsic clearance, but with an additional
increase in solubility. As the oxadiazole heterocycle is often
employed as an ester isostere, a number of esters were also
Table 3
Amide scana
Me
N
O
R
O
N
CN
Compd
R
OX2R FLIPR (IC50, nM)
OX1R FLIPR (IC50, nM)
FLIPR ratio
Microsomal Cl (human)
Sol (pH 7)
HPLClogD
N
N
N
N
5f
13
25
3800
8400
293ꢀ
361ꢀ
16
23
148
162
3.0
3.0
N
6a
O
Me
6b
28
4900
174ꢀ
17
183
2.9
N
N
6c
6d
6e
6e
6f
CO2Me
CO2Et
CO2iPr
OCHF2
CH2CF3
21
21
38
37
32
ꢁ10,000
7100
3300
>10,000
>10,000
>490ꢀ
349ꢀ
87ꢀ
< 16
37
nd
43
132
151
121
115
Insol.
95
2.9
3.2
3.6
Insol.
3.6
>314ꢀ
>312ꢀ
a
Values represent the average of n P 2 experiments.

S. D. Kuduk et al. / Bioorg. Med. Chem. Lett. 25 (2015) 2488–2492
2491
examined. Methyl (6c) and ethyl (6d) esters were quite similar
with respect to FLIPR potency and selectivity, although the ethyl
had higher intrinsic clearance. The larger isopropyl ester 6e led
to a decrease in functional antagonism and erosion of OX2R prefer-
ence relative to methyl and ethyl. While the methyl ester did show
low microsomal clearance, it was anticipated that plasma stability
would be an issue, and 6c did prove to be unstable in both rat and
human plasma. Lastly, difluoromethyl ether 6e and trifluoroethyl
6f showed good FLIPR potency and high selectivity, but were the
most lipophilic (HPLC logD = 3.6) amongst the compounds in
Table 3. This increase in lipophilicity led to higher intrinsic clear-
ance and significantly lower solubility for 6e and 6f.
Given the promising in vitro profiles noted in Table 3, com-
pounds 5f, 6a, and 6b were taken on for further characterization.
Pharmacokinetic parameters of these three compounds were
determined in rat and dog after intravenous and oral administra-
tion. Amongst the group, triazole 5f exhibited the lowest oral
bioavailability (<20%) in both species, and was moderate clearance
in rat and high clearance in dog. Oxadiazole 6a and pyrimidine 6b
demonstrated low to moderate plasma clearance and high oral
bioavailability in dog (>50%). In rat, pyrimidine 6b exhibited mod-
erate clearance and an oral bioavailability of 80%. Oxadiazole 6a
also demonstrated moderate clearance in rat, but had an oral
bioavailability of only 26% (Table 4).
permeability in LLC-PK1 cells (33 ꢀ 106 cm/s) and was a weak sub-
strate for rat P-gp efflux (ER = 2.3) and a non-substrate for human
P-gp efflux (ER = 0.7).25 In rats, the CSF to plasma concentration
ratio (0.1) was similar to the unbound fraction in plasma, indicat-
ing that P-gp has apparently little effect on the brain distribution of
6b in this species. Furthermore, this compound was not a CYP
(cytochrome P450) inhibitor or inducer, showing minimal poten-
tial for drug–drug interactions. Compound 6b had no appreciable
off-target affinities when measured against a panel of 115 biolog-
ical targets (Ricerca) at a concentration of 10 lM. Lastly, pyrim-
idine 6b, which showed excellent pharmaceutical properties as a
crystalline form suitable for development, was identified with sol-
ubility at pH 7.4 of 0.25 mg/mL; exceptional for compounds of this
class.
Compound 6b was further characterized in vivo for its ability to
attenuate arousal The resulting sleep architecture was measured in
ambulatory mice, rats and dogs implanted with radio-telemetry
transmitters measuring electrocorticogram (ECoG) and elec-
tromyogram (EMG) activity as previously described.26 When dosed
to mice at 30 mg/kg (P.O. in 20% Vit. E TPGS), 6b significantly atten-
uated active wake while increasing slow wave sleep (SWS) with no
associated effect on rapid eye movement (REM) sleep (Fig. 3). No
significant effects of the compound at this high dose were observed
in mice harboring with a targeted disruption of the Hcrtr2 gene
encoding OX2R, demonstrating that these effects were selectively
mediated through its target receptor. In rats, dose dependent
decreases in active wake were seen in the 2 h following treatment
with 1 and 3 mg/kg of the compound, and were associated with
significant increases in both SWS and REM sleep. In beagles, sub-
stantially lower doses, 0.01 and 0.05 mg/kg, were efficacious in
promoting sleep, likely attributable to increased free fraction and
central exposure in these animals. In this case, dose dependent
reductions in active wake relative to the vehicle condition were
accompanied by increases in non-REM NREM I and NREM II sleep,
the latter characterized by a greater preponderance of delta sleep.
There was a trend toward increased REM sleep that did reach sig-
nificance following treatment with either dose in dogs.27
Pyrimidine 6b emerged as a leading compound and was
selected for additional in vitro and in vivo characterization. This
compound was predicted to have low human clearance and good
bioavailability. The level of plasma protein binding for 6b varied
significantly across species. At a concentration of 1 lM, the
unbound fraction in human, rat, dog, and monkey plasma was
2.8%, 7.6%, 16.6%, and 23.9%, respectively. In terms of achieving
adequate drug levels in the CNS, 6b exhibited high passive
Table 4
Rat and dog PK data
#
Rat F
Rat t1/2
(h)
Rat
Cl
Rat
Vdss
Dog F
Dog t1/2
(h)
Dog
Cl
Dog
Vdss
a
a
a
a
(%)a
(%)a
The synthetic route used to access target molecules detailed in
this manuscript is shown in Scheme 1. Hydrogenation of 7 provides
a 4:1 mixture of trans:cis piperidines. This is a modified route from
what has been described previously17,28 in that the minor cis pro-
duct was used in our previous disclosure to access targets via a
Mitsunobu inversion. In this work, after SFC separation of 9 to
obtain the desired trans (2R, 5S) enantiomer 10, a protecting group
5f
6a 26
6b 80
17
1.7
1.3
4.3
18
30
37
1.7
1.3
1.3
13
54
53
1.1
1.5
0.8
27
4.6
15
1.5
0.54
0.97
a
F% oral bioavailability, half-life is represented in hours, Cl in mL/min/kg. Wistar
Han rats (n = 2). Oral dose = 10 mg/kg in PEG400:Tween80/water 40:10:50, IV
dose = 2 mg/kg in DMSO/PEG400/water 20:60:20.
Figure 3. Effects of compound 6b on mean time in active wake, SWS, and REM sleep in mice and rats, and in active wake, NREM I, NREM II, and REM sleep 1 h following
administration. Vehicle (20% Vitamin E TPGS, po) and compound 6b (30 mg/kg mouse; 1 & 3 mg/kg rat; 0.01 & 0.05 mg/kg canine) was administered in a balanced cross-over
design such that each subject received both vehicle and drug treatments (5 days of consecutive treatments for mouse and dogs; 3 days for rat). Mean within-subject change
relative to vehicle is shown (N = 7 [mouse WT], N = 6 [OX2R KO]; N = 16 [rat], N = 6 [canine]); ⁄p<0.05, ⁄⁄p<0.01, ⁄⁄⁄p<0.001, paired within subject t test versus vehicle.

2492
S. D. Kuduk et al. / Bioorg. Med. Chem. Lett. 25 (2015) 2488–2492
b
a
c
N
HN
CbzN
CbzN
OH
OH
OH
OH
7
8
9
10
d
F
g
e, f
HN
+
N
N
O
O
N
Boc
OH
CN
R
O
N
N
12
11
CN
CN
5a, 6a-f
13
Scheme 1. Reagents and conditions: (a) H2, PtO2, MeOH, HCl, 55 °C; (b) CbzCl, TEA, CH2Cl2; (c) chiral SFC; (d) Boc2O, H2, Pd/C (10%), EtOAc; (e) NaH, DMSO, rt; (f) HCl, dioxane,
0 °C; (g) T3P, DIEA, DMF.
9. Herring, W. J.; Snyder, E.; Budd, K.; Hutzelmann, J.; Snavely, D.; Liu, K.; Lines, C.;
Roth, T.; Michelson, D. Neurology 2012, 79, 2265.
10. Kuduk, S. D.; Winrow, C. J.; Coleman, P. J. Ann. Rep. Med. Chem. 2013, 48, 73.
switch was executed to afford 11. Subsequent substitution reac-
tions were carried out as exemplified with 2-fluoro-5-cyanopy-
ridine 12, followed by removal of the Boc protecting group to
afford 13. Lastly, coupling of amine 13 with the appropriate car-
boxylic acid using the reagent T3P provided target compounds
for evaluation.
11. Coleman, P. J.; Cox, C. D.; Roecker, A. J. Curr. Top. Med. Chem. 2011, 11, 696.
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In summary, we have described the alteration of the isoquino-
line ring in piperidine ether DORA 2 into a 2-pyridyl OX2R selective
series of orexin antagonists. It was found that after excision of the
phenyl group of the isoquinoline ring, the position where a sub-
stituent was placed on the 2-pyridyl ring played a key role in mod-
ulating DORA versus SORA selectivity. The critical discovery was
that a cyano group at the 4-position of the pyridine ring resulted
not only in potent functional antagonism, but provided the highest
OX2R selectivity amongst all the groups examined. Further SAR
modification of the aryl carboxamide led to highly potent SORA
pyrimidine 6b with excellent development properties, now identi-
fied as MK-8133. MK-8133 proved to highly efficacious in rodent
polysomnography sleep studies as well as non-rodent species
and those studies will be the subject of future reports.
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Acknowledgments
The authors wish to thank the West Point NMR and Mass
Spectrometry analytical teams for their assistance in characteriza-
tion of compounds reported in this manuscript. The authors also
thank Mr. Jeff Fritzen and Dr. Carmela Molinaro for synthetic opti-
mization studies. This Letter is dedicated to Professor Iwao Ojima
on the occasion of his 70th birthday.
References and notes
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27. Satellite pharmacokinetic data was collected in each study (AUC’s are 0–1). In
mice: 30 mg/kg: AUC = 11.3 uM h, Cmax = 5.7 uM, in rats: 1 mg/kg:
AUC = 0.23 uM h, Cmax = 0.18 uM, 3 mg/kg: AUC = 0.95 uM h, Cmax = 0.73 nM,
in dogs: 0.01 mg/kg: AUC 0.02 uM*h, Cmax = 0.012 uM, 0.05 mg/kg:
AUC = 0.06 uM h, Cmax = 0.040 nM.
28. Kuduk, S. D.; Skudlarek, J. W. PCT Int. Appl. 2013, WO 2013059222 A1.