Discovery of piperidine ethers as selective orexin receptor antagonists (SORAs) inspired by filorexant

Article abstract of DOI:10.1016/j.bmcl.2014.12.056

Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX₂R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX₂R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX₂R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX₁R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class.

Full text of DOI:10.1016/j.bmcl.2014.12.056

Accepted Manuscript
Discovery of Piperidine Ethers as Selective Orexin Receptor Antagonists (SO-
RAs) Inspired by Filorexant
Izzat T. Raheem, Michael J. Breslin, Joseph Bruno, Tamara D. Cabalu, Andrew
Cooke, Christopher D. Cox, Donghui Cui, Susan Garson, Anthony L. Gotter,
Steven V. Fox, C. Meacham Harrell, Scott D. Kuduk, Wei Lemaire, Thomayant
Prueksaritanont, John J. Renger, Craig Stump, Pamela L. Tannenbaum, Peter
D. Williams, Christopher J. Winrow, Paul J. Coleman
PII:
S0960-894X(14)01364-X
http://dx.doi.org/10.1016/j.bmcl.2014.12.056
BMCL 22301
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 October 2014
15 December 2014
16 December 2014
Please cite this article as: Raheem, I.T., Breslin, M.J., Bruno, J., Cabalu, T.D., Cooke, A., Cox, C.D., Cui, D., Garson,
S., Gotter, A.L., Fox, S.V., Meacham Harrell, C., Kuduk, S.D., Lemaire, W., Prueksaritanont, T., Renger, J.J., Stump,
C., Tannenbaum, P.L., Williams, P.D., Winrow, C.J., Coleman, P.J., Discovery of Piperidine Ethers as Selective
Orexin Receptor Antagonists (SORAs) Inspired by Filorexant, Bioorganic & Medicinal Chemistry Letters (2014),
doi: http://dx.doi.org/10.1016/j.bmcl.2014.12.056
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Discovery of Piperidine Ethers as Selective Orexin Receptor
Antagonists (SORAs) Inspired by Filorexant
Izzat T. Raheem,a Michael J. Breslin,a Joseph Bruno,e Tamara D. Cabalu,c Andrew
Cooke,a Christopher D. Cox,a Donghui Cui,c Susan Garson,b Anthony L. Gotter,b Steven
V. Fox,d C. Meacham Harrell,b Scott D. Kuduk,a Wei Lemaire,e Thomayant
Prueksaritanont,c John J. Renger,b Craig Stump,a Pamela L. Tannenbaum,d Peter D.
Williams,a Christopher J. Winrow,b and Paul J. Coleman.a
b
c
d
aDiscovery Chemistry, Neuroscience, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, In
Vivo Pharmacology, and e In Vitro Pharmacology, Merck Research Laboratories, West Point, PA 19486.
Abstract: Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor
(OX2R) have become attractive targets both as potential therapeutics for insomnia as well
as biological tools to help further elucidate the underlying pharmacology of the orexin
signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-
SORA class identified by systematic lead optimization beginning with filorexant, a dual
orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials.
Changes to the ether linkage and pendant heterocycle of filorexant were found to impart
significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays
sub-nanomolar binding affinity and functional potency on OX2R while maintaining
>1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1
receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical
pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM
sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes
to the piperidine ether class impart dramatic changes in receptor selectivity. To this end,
our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and
DORAs, providing access to a number of important biological tool compounds from a
single structural class.

Introduction
Orexin-A (OX-A) and orexin-B (OX-B) are hypothalmic neuropeptides that are
derived by the proteolytic cleavage of a common precursor peptide, prepro-orexin.1
Exogenous administration of orexin neuropeptides increases locomotor activity and
wakefulness in multiple species by signaling through two G-protein-coupled receptors,
orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R).2 Maintenance of wake has been
demonstrated genetically and pharmacologically to be a key function of the orexin system.
Dogs lacking functional OX2R and rodents whose prepro-orexin gene has been knocked
out demonstrate a narcoleptic phenotype with altered sleep/wake cycles and
hypersomnolence.3,4 Post-mortem studies of human narcoleptic patients reveal very few
surviving orexin-producing neurons in the hypothalamus, with low-to-absent levels of
orexins in the cerebral spinal fluid (CSF).5 Further, acute blockade of orexin signaling by
small-molecule dual orexin receptor antagonists (DORAs) has been shown to dose-
dependently promote sleep in rats, dogs, and mice, implicating the key role of orexins in
sleep/wake regulation.6 Recently, several potent DORAs have demonstrated clinical
proof of concept for the sleep-promoting effects of orexin blockade for the treatment of
primary insomnia (Figure 1).7 In particular, suvorexant and filorexant are potent DORAs
from our laboratories that are under clinical evaluation, and suvorexant (Belsomra) was
recently approved by the FDA as the first orexin receptor antagonist for the treatment of
insomnia.
PLACE FIGURE 1 HERE.
Figure 1. Representative dual orexin receptor antagonists (DORAs) that have advanced
into clinical trials.
Despite the prolific growth in orexin research over the past decade, much remains
to be learned about the function of the downstream neurological targets of the individual
orexin receptors. Receptor function has often been elucidated through the actions of OX-
A and OX-B. OX1R and OX2R mRNAs have overlapping but distinct distribution

patterns throughout the brain suggesting differentiated physiological roles for each
receptor subtype.8 Selective expression of OX2R in the histaminergic neurons in the
tuberomammillary nucleus (TMN), which plays a critical role in promoting arousal,
supports a primary role for OX2R in the sleep-promoting effects of DORAs through the
attenuation of histamine release.9 Experiments in mice with targeted genetic ablation of
both OXRs demonstrate that these dual-KO mice exhibit a narcoleptic phenotype similar
to that of prepro-orexin KO animals lacking the ligand. Ablation of the single gene
encoding OX2R results in mice with a milder narcolepsy phenotype while OX1R KO
mice appear to have normal sleep/wake states without any obvious behavioral
alterations.10 Emerging literature suggests OX1R antagonism has little influence on
orexin-mediated arousal, but a more subtle role in vigilance state gating resulting in a
lower threshold for sleep stage transitions, potentially influencing stage transitions and
sleep onset.11 Although antagonism of OX1R has not been shown to result in overt sleep-
promoting efficacy, many studies have implicated a role in the treatment of other
conditions such as substance abuse, withdrawal, obesity and mood disorders.8
Clearly a need exists for the development of highly selective orexin receptor
antagonists (SORAs) of OX1R and OX2R in order to better understand the underlying
pharmacology of each receptor. Recent publications from our laboratories have disclosed
the sleep-promoting effects of a novel triaryl 2-SORA structural class12a and a new
DORA series derived from subtle changes to filorexant.12b Herein, we disclose a hybrid
approach in which changes to the ether linkage and pendant heterocycle of filorexant
impart significant selectivity for OX2R, providing a novel piperidine ether 2-SORA series
for evaluation of sleep-promoting effects.
Results and Discussion
Filorexant (Figure 2) is a potent antagonist of both human OX1R and OX2R as
measured by a radioligand-displacement binding affinity assay (expressed as Ki values)
and a fluorometric imaging plate reader (FLIPR) assay (expressed as IC50 values). The
FLIPR assay provides a functional readout of orexin receptor antagonism in CHO cells
engineered to overexpress the human receptors.13 Filorexant has a low selectivity index
(SI) of 9.14 Importantly, it has demonstrated robust sleep efficacy in preclinical rat, dog,

and monkey models (decreased active wake, increased delta and REM sleep), and has
recently achieved clinical proof of concept in human subjects.15
PLACE FIGURE 2 HERE.
Figure 2. Profile of filorexant.
Beginning with filorexant, we initially sought to alter the DORA structural
framework to identify novel chemical space (Figure 3). Early SAR led us to return to the
2-triazolo moiety found in suvorexant. Additionally, to simplify our early synthetic
efforts, we deleted the stereogenic methyl group on the piperidine core, with the
assumption that any potency losses could be addressed by reinstallation of this group.
Modification of the southeastern aromatic ring identified representative racemic
compound PE-1 bearing comparable selectivity and potency relative to filorexant.
Truncation of the ether linkage by deletion of a single methylene group provided PE-2.
While this compound lost absolute binding affinity, it led to an important structural
modification that opened up new chemical space for the program. Replacement of the
southeastern aromatic ring with a naphthyl group (PE-3) provided a significant
improvement in binding affinity relative to PE-2, suggesting that biaryl substitutents
would be favored in this series. Reinstallation of the stereogenic methyl group resulted in
trans PE-4 that not only exhibited excellent OX2R binding affinity, but also displayed a
trend toward OX2R selectivity (SI= 13). This result prompted us to continue
optimization efforts within this structural class. Further structural modifications,
including introduction of a nitrogen in the southeastern aromatic ring and deletion of the
aromatic methyl group in the northwestern benzene ring, provided trans PE-5 with
OX2R selectivity further improved to SI= 35.
PLACE FIGURE 3 HERE.
Figure 3. Systematic progression of filorexant toward improved OX2R selectivity.

With a promising core identified in PE-5, we initiated systematic optimization of
the R1 and R2 positions with the goal of further improving OX2R selectivity (Table 1).
We learned quickly that the position of the southeastern arene nitrogen was crucial to
compound selectivity. Walking the nitrogen around the bicyclic framework led to a
steady improvement in OX2R selectivity to SI= 397, imparted by a 4-quinoline moiety
(Table 1, entries 1−6). For most of these compounds, however, this improved selectivity
came at the expense of intrinsic OX2R binding affinity. We next examined substitution
about the 4-quinoline group (Table 1, entries 7−14) and discovered a significant steric
and electronic impact of quinoline functionalization. A-ring substitution led universally
to compromised binding affinity and selectivity, while improvements were realized upon
substitution of the B-ring. Notably, halogen substituents at the 8-position provided
additional improvements in both intrinsic OX2R binding affinity and OX2R selectivity,
with a fluorine substituent being optimal. Resolution of the racemic 8-fluoro-4-quinoline
analog identified (R,R) isomer PE-6, the most selective piperidine ether compound
identified to date.
Table 1. Optimization and SAR of the piperidine ether framework.
PLACE TABLE 1 GRAPHIC HERE
Entry
R1
R2
hOX2R Ki
(nM)a
hOX1R Ki
(nM)
SIb
2-(1,2,3-triazolo)
0.3
7.5
9.3
10.5
415
900
35
1 (PE-5)
1-isoquinoline
5-isoquinoline
8-isoquinoline
2-(1,2,3-triazolo)
2-(1,2,3-triazolo)
55
97
2
3

2-(1,2,3-triazolo)
6.8
2700
397
4
4-quinoline
2-(1,2,3-triazolo)
2-(1,2,3-triazolo)
5.1
9.8
1030
760
202
78
5
6
5-quinoline
8-quinoline
2-CH3-4-quinoline 2-(1,2,3-triazolo)
28.9
149
180
5.2
2.6
0.9
1.3
0.6
63
3600
-
125
-
7
2-CF3-4-quinoline
3-Br-4-quinoline
6-Br-4-quinoline
8-Br-4-quinoline
8-Cl-4-quinoline
8-F-4-quinoline
8-F-4-quinoline
8-F-4-quinoline
8-F-4-quinoline
8-F-4-quinoline
8-F-4-quinoline
2-(1,2,3-triazolo)
2-(1,2,3-triazolo)
2-(1,2,3-triazolo)
2-(1,2,3-triazolo)
2-(1,2,3-triazolo)
2-(1,2,3-triazolo)
2-(1,2,3-triazolo)
3-pyridyl
8
-
-
9
470
1100
510
910
965
19000
1360
1200
-
90
10
423
567
700
1608
302
1236
1500
-
11
12
13
14c (PE-6)
15c
16c
5-(1,2,4-triazolo)
2-pyrimidyl
1.1
0.8
370
17c
18c
N(CH3)2
a Binding Ki values were determined using a radioligand-displacement binding assay. Data presented are
for racemates unless otherwise noted. bSelectivity index (SI) for OX2R over OX1R as calculated from the
Ki. c Data presented for the more potent (R,R) enantiomer.
With an optimal eastern and central portion in place, we reinvestigated the
southwestern R2 position (Table 1, Entries 14−18). While replacement of the 1,2,3-
triazolo moiety with other arenes bearing multiple nitrogens (i.e. pyrimidine or 1,2,4-
triazolo) was tolerated and maintained similar binding affinity and OX2R selectivity to
PE-6, more dramatic functional alterations resulted in decreased OX2R selectivity
through significant loss in OX2R binding affinity. We ultimately selected PE-6 for
further characterization as the lead compound from this novel structural class.

The 1st generation racemic synthesis of PE-6 is highlighted in Scheme 1. RuO2-
catalyzed homogenous hydrogenation of 2-methyl-5-hydroxypyridine under highly
forcing conditions provides a mixture of the racemic cis and trans diastereomers of key
piperidine building block 1. Unfortunately, under these conditions, the desired cis
diastereomer is formed as the minor component, in a >4:1 diasteromeric ratio. Standard
amide coupling provides 3, which then undergoes a Mitosunobu reaction with 8-fluoro-4-
hydroxyquinoine and a subsequent separation on chiral stationary phase to provide PE-6
in <2% overall yield from mixture 1.
PLACE SCHEME 1 HERE.
Scheme 1. 1st generation synthesis of PE-6.
Given the very low yields and racemic nature of the above route, we sought to
develop an enantioselective synthesis of PE-6 while improving the efficiency of overall
synthetic sequence. Scheme 2 highlights our 2nd generation route. The sequence begins
with CoSalen-catalyzed hydrolytic kinetic resolution (HKR) of hexene-1-oxide to
provide 4.16 Employing a unique substrate-controlled reverse-Cope cyclization,17
reasonable yields of cis benzyl-piperidine-N-oxide 5 were obtained in high ee following
slight modification of the published procedure.
Silylation to 6 followed by
hydrogenolysis to 7 furnished a protected form of our key chiral piperidine building
block. We discovered that incorporation of the silyl group facilitated a higher yielding
amide coupling. To this end, coupling of 7 and 2, followed by removal of the protecting
group, and finally a Mitsunobu reaction with 8-fluoro-4-hydroxyquinoline furnished the
desired cis enantiomer of PE-6 in 60% overall yield from single enantiomer 7, a
significant improvement over our original route.
PLACE SCHEME 2 HERE.
Scheme 2. Enantioselective synthesis of key chiral building block 7 and elaboration to
PE-6.
While numerous functionalized 4-hydroxyquinolines are commercially-available,
our lead optimization efforts required access to variants of this aromatic core. In order to

gain efficient access to novel building blocks, we optimized a known protocol to facilitate
a 1-pot synthesis.18 In this sequence, Meldrum’s acid was initially treated with
triethylorthoformate under forcing conditions to form intermediate int-8, which was
treated in situ with functionalized aniline of choice to provide carboxy-quinolone 8. The
reaction mixture was subsequently diluted with diphenylether in an open vessel and
heated to 270 °C to effect the desired decarboxylation to 9. Upon cooling and trituration
with diethyl ether, 9 could be isolated by a simple filtration.
PLACE SCHEME 3 HERE.
Scheme 3. 1-pot synthesis of non-commercial 4-hydroxyquinolines.
PE-6 is a highly selective 2-SORA displaying in vitro OX2R potency comparable
to filorexant, with 1608-fold and 217-fold selectivities in binding affinity and FLIPR
potency, respectively (Figure 4). It has favorable physicochemical properties with an
HPLC LogD of 2.35, 3–4% free fraction in human and rat plasma, and an aqueous
solubility of 161 µM at neutral pH. PE-6 was not a potent reversible inhibitor of
CYP3A4, 2D6 or 2C9, (IC50= 25.4 µM, >50 µM and 21.4 µM, respectively) and was also
not a time-dependent inhibitor of CYP3A4. PE-6 is highly selective only for OX2R,
showing no significant off-target activities when screened against a Panlabs panel (165
assays) of receptor and enzyme targets with melatonin identified as the only activity of
note (Ki >5 µM) representing a greater than 5000-fold margin over OX2R binding affinity.
PLACE FIGURE 4 HERE.
Figure 4. Profile of PE-6.
The pharmacokinetics of PE-6 in Sprague–Dawley rats and beagle dogs are
reported in Table 2. After intravenous administration, PE-6 exhibited low-to-moderate
clearance and a short terminal half-life in both species. The oral bioavailability was 60%
in dogs and 19–50% in rats, with peak plasma concentrations achieved rapidly in both
species

Table 2. Pharmacokinetics of compound PE-6 in rat and dog.
Intravenous (IV) administration
Oral (PO) administration
Dose
[mg/kg]
2
Cl
[mL/min/kg]
22.5
t1/2
[h]
0.4
Dose
AUC
Cmax
Tmax
[h]
F
Species
[mg/kg]
[%]
[µM•h]
3.9
[µM]
Rat
Rat
10
30
3
19
50
60
30.1
16
15.7
5.65
0.5
Dog
0.125
6.2
0.7
0.38
PE-6 achieved 72% receptor occupancy at a plasma level of 9.5 µM after a 30
mg/kg oral dose (t= 30 min) to rats.19 At this dose, levels in the CSF were low at 339 nM,
which is consistent with the fact that PE-6 is a substrate for rat P-glycoprotein (Pgp),
with a basaolateral-apical to apical-basolateral (B-A/A-B) ratio of 5.8. Given its high
passive permeability (Papp= 34 x 10-6 cm/s) and a lower B-A/A-B ratio (2.5) in the human
Pgp transporter assay, we chose to advance PE-6 into EEG-telemetry studies to evaluate
sleep efficacy.
PE-6 administered orally to rats at 30 mg/kg significantly attenuated active wake
relative to vehicle (20% vitamin E TPGS) for 30 minutes following treatment (Figure 5).
These changes were accompanied by sleep promotion characterized by increases in both
delta and REM sleep, although the effect on the latter was modest. Qualitatively, these
changes in sleep architecture are similar not only to filorexant and other DORAs, but also
to MK-1064, a 2-SORA evaluated in our laboratory, where increases in both delta and
REM sleep have been observed.12a From an efficacy standpoint, the responses to 30
mg/kg PE-6 are shorter-lived and diminished in magnitude relative to those observed for
filorexant, which exhibits similar in vitro potency toward OX2R,13a,20 the receptor
primarily responsible for the sleep promoting effects of orexin receptor antagonists.9
While differences in OX1R selectivity between PE-6 and filorexant are potentially
involved, direct efficacy comparisons with filorexant are not appropriate given the shorter
half-life of PE-6 and the increased Pgp efflux of this compound. Future studies
describing the differential effects of OX1R and OX2R antagonism on sleep efficacy will
need to evaluate multiple DORAs and SORAs with sleep-promoting effects that have
been normalized for target engagement to account for compound-specific differences in
pharmacokinetics and brain exposure.

PLACE FIGURE 5 HERE.
Figure 5. Proportional sleep induced by PE-6. Mean time in active wake, light sleep,
delta sleep and REM sleep in rats during oral administration of 30 mg/kg of PE-6 (open
symbols) or vehicle (20% vitamin E TPGS, closed circles) monitored for 30 min prior
and 2 h post-dose. Treatment occurred during the active phase at 09:00 (ZT [Zeitgeber
Time] 17:00; 7 h prior to lights on) indicated by the gray vertical bar. Data shown are
mean values in 10 minute intervals (-SEM) from 3 consecutive days of treatment
administered in a balanced cross-over design such that each subject received drug and
vehicle (N=6). Compound condition was compared to vehicle using a mixed-model
ANOVA applied within subjects at each time point in the R statistical computing
environment (version 3.0.1, cran.us.r-project.org; the R Foundation for Statistical
Computing, Vienna, Austria) and significance determined using a linear mixed effects
model. Significant differences between mean conditions at each time point are indicated
by grey vertical lines and significance level by tick marks at the top of each graph (short,
medium, long; p < 0.05, 0.01, 0.001).
Through the course of the lead optimization efforts in the piperidine ether series
described above, we identified compounds that span the orexin selectivity spectrum from
DORA to 2-SORA. Additional efforts from our laboratories have subsequently identified
structurally related piperidine ether 1-SORAs, which will be the subject of a forthcoming
manuscript. Three representative molecules are highlighted in Figure 6. By replacing the
fluoroquinoline of 2-SORA PE-6 with a 4-methoxyisoquinoline, OX1R potency is
restored providing PE-7, an extremely potent DORA with SI <2. Conversely,
replacement of the 2-methylpiperidine with a 4,4-difluroropiperidine and alteration of the
arene connectivity completely reverses orexin receptor selectivity, and provides PE-8, a
potent 1-SORA with an OX1R SI= 434.21 This degree of “tunable” diversity in orexin
receptor selectivity from a single structural class highlights a unique opportunity to
employ piperidine ether orexin receptor antagonists as tools to further interrogate the
biology and pharmacology of the orexin signaling pathway. These studies are on-going,

and will be reported in due course. Importantly, the significant changes in receptor
selectivity imparted by subtle alterations in compound structure in the piperidine ether
series underscore the challenges associated with the rational design of SORAs resulting
from a lack of understanding of the origin of their selectivity.22
PLACE FIGURE 6 HERE.
Figure 6. Representative 2-SORA, DORA, and 1-SORA piperdine ethers highlighting
the wide selectivity range attainable by this compound class.
In summary, we have described the discovery of a novel class of piperidine ether
2-SORAs obtained by systematic modification of the clinically validated filorexant series.
These modifications include truncation of the ether linkage and incorporation of bicyclic
heterocycles that impart selectivity for the orexin 2 receptor. Additional changes to the
western amide resulted in the identification of PE-6, displaying sub-nanomolar binding
affinity for OX2R with >1600-fold binding selectivity over OX1R. PE-6 significantly
attenuated active wake and promoted sleep in rats after oral dosing in a manner
qualitatively similar to filorexant. Subtle alterations to the bicyclic heterocycle and/or the
piperidine core have resulted in the identification of very potent DORA and 1-SORA
molecules from the same piperidine ether series. Access to a range of orexin selectivities
from a single structural class provides a unique set of tool molecules to help further
interrogate the underlying pharmacology of the orexin signaling pathway.
Acknowledgements
The authors thank the Merck West Point NMR and Mass Spectrometry facilities
for assistance in characterizing the compounds presented in this manuscript.
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14. SI= hOX1R Ki / hOX2R Ki
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28, 5.

Vehicle
PE-6

Discovery of Piperidine Ethers as Selective Orexin Receptor Antagonists (SORAs)
Inspired by Filorexant
Izzat T. Raheem,a Michael J. Breslin,a Joseph Bruno,e Tamara D. Cabalu,c Andrew
Cooke,a Christopher D. Cox,a Donghui Cui,c Susan Garson,b Anthony L. Gotter,b Steven
V. Fox,d C. Meacham Harrell,b Scott D. Kuduk,a Wei Lemaire,e Thomayant
Prueksaritanont,c John J. Renger,b Craig Stump,a Pamela L. Tannenbaum,d Peter D.
Williams,a Christopher J. Winrow,b and Paul J. Coleman.a
DORA
H3C
N
O
N
O
N
N
N
OCH3
2-SORA
H3C
CH3
H3C
PE-7
hOX2R Ki= 0.24 nM
hOX1R Ki= 0.41 nM
N
N
O
O
N
O
N
O
N
N
N
F
N
N
1-SORA
F
F
Filorexant
PE-6
F
hOX2R Ki= 0.6 nM
hOX1R Ki= 965 nM
N
O
N
O
N
N
N
PE-8
hOX2R Ki= 521 nM
hOX1R Ki= 1.3 nM