Identification of an orally active Opioid Receptor-like 1 (ORL1) receptor antagonist 4-{3-[(2R)-2,3-dihydroxypropyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1- yl}-1-[(1S,3S,4R)-spiro[bicyclo[2.2.1]heptane-2,1′-cyclopropan] -3-ylmethyl]piperidine as clinical ca

Article abstract of DOI:10.1021/jm900581g

Our efforts to optimize prototype opioid receptor-like 1 (ORL1) antagonist 1 led to the discovery of 4-{3-[(2R)-2, 3-dihydroxypropyl]-2-oxo-2,3-dihydro-1H- benzimidazol-1-yl}-1-[(1S,3S,4R)-spiro[bicyclo[2.2.1]heptane-2, 1′-cyclopropan]-3-ylmethyl]piperidi

Full text of DOI:10.1021/jm900581g

J. Med. Chem. 2009, 52, 4091–4094 4091
DOI: 10.1021/jm900581g
hydro-2H-benzimidazol-2-one (1, J-113397)asthe firstpotent
and selective small molecule ORL1 antagonist.10 1 has trisub-
stituted piperidine and benzimidazolidinone structure and
shows high affinity for the ORL1 receptor with greater than
600-foldselectivityover opioidμ, κ, andδ receptors. 1 behaves
as an antagonist at the ORL1 receptor in in vitro functional
assays and in vivo assays. Therapeutic targets for ORL1
antagonists have been explored with 1, and blockage of
ORL1 demonstrated antihyperalgesic effects in various ani-
mal models without analgesic effects in acute pain models.11
Since wide distribution of NC/OFQ and ORL1 receptors in
the brain suggested broad functions of peptide and its recep-
tors, we are conducting clinical trials of 10 for multiple target
indications with an experimental medicine approach.
Various classes of ORL1 antagonists have been also re-
ported (Structures are shown in Supporting Information
Figure S-1), including N-(4-amino-2-methylquinolin-6-yl)-2-
(4-ethylphenoxymethyl)benzamide (2, JTC-801),12 phenylpi-
peridine (3, SB612111),13 spiropiperidines (4-6),14 benzimi-
dazole(7),15 cycloalkanopyridine(8),16 andaminoquinazoline
(9).17 Among them, 2 has efficacious and potent antinocicep-
tive effects in animal acute pain models and only entered
clinical trials as a novel type of analgesic.12
1 has become an important pharmacological tool for the
elucidation of NC/OFQ-ORL1 systems roles in pain modula-
tion and other physiological functions. Numerous studies
have employed 1 as a tool to confirm ORL1 receptor mediated
NC/OFQ effects. In our previous report, we demonstra-
ted that subcutaneous injection of 1 inhibited hyperalgesia
induced by intracerebroventricular injection of NC/OFQ
(0.1 nmol). Further characterization revealed that 1 could
not move forward as a preclinical candidate because of its
drug metabolism and pharmacokinetics (DMPK) profiles,
that is, poor oral bioavailability. Thus, we revisited modifica-
tion of benzimidazolidinone analogues.
Our goals were to investigate the detailed structure-activity
relationships (SAR) of benzimidazolidinone derivatives and to
identify potent and orally available ORL1 antagonists. We
tried three approaches for the improvement of metabolic
stability without loss of ORL1 potency and selectivity: (1)
replacement of the cyclooctyl ring with various kinds of
cycloalkane groups; (2) introduction of a variety of hydrophilic
substituents at the piperidine ring; (3) introduction of a variety
of hydrophilic substituents on the benzimidazolidine nitrogen.
In this paper, we report on the characterization of 1 and the
SAR of benzimidazolidinone analogues (Figure 1). We iden-
tify potent and orally active diol compounds and describe
their in vitro and in vivo characterizations.
Identification of an Orally Active Opioid
Receptor-like 1 (ORL1) Receptor Antagonist
4-{3-[(2R)-2,3-Dihydroxypropyl]-2-oxo-2,3-
dihydro-1H-benzimidazol-1-yl}-1-[(1S,3S,4R)-
spiro[bicyclo[2.2.1]heptane-2,10-cyclopropan]-
3-ylmethyl]piperidine as Clinical Candidate
Atsushi Satoh, Takeshi Sagara, Hiroki Sakoh,
Masaya Hashimoto, Hiroshi Nakashima, Tetsuya Kato,
Yasuhiro Goto, Sayaka Mizutani, Tomoko Azuma-Kanoh,
Takeshi Tani, Shoki Okuda, Osamu Okamoto,
Satoshi Ozaki, Yoshikazu Iwasawa, Hisashi Ohta,* and
Hiroshi Kawamoto*,‡
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd.,
Okubo-3, Tsukuba 300-2611, Ibaraki, Japan
Received May 5, 2009
Abstract: Our efforts to optimize prototype opioid receptor-like
1 (ORL1) antagonist 1 led to the discovery of 4-{3-[(2R)-2,
3-dihydroxypropyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-
1-[(1S,3S,4R)-spiro[bicyclo[2.2.1]heptane-2,10-cyclopropan]-3-
ylmethyl]piperidine 10. 10 showed potent ORL1 antagonistic activ-
ity, excellent selectivity over other opioid receptors, and in vivo
efficacy after oral dosing. Currently clinical trials of 10 are underway.
In 1994, the ORL1a receptor was identified as a fourth
opioid receptor using a cloning technique.1 This G-protein-
coupled receptor has significant sequence homology with
classical opioid receptors (μ, κ, δ); however, none of the
classical opioid ligands show significant affinity for the
ORL1 receptor. Nociceptin, also named orphanin FQ (NC/
OFQ), is a peptide consisting of 17 amino acids that was
identified as an endogenous ligand for ORL1 receptor in
1995.2 Although NC/OFQ is homologous with the classical
opioid peptide dynorphin A, it has no significant activity at
the classical opioid receptors. NC/OFQ and ORL1 receptors
are widely distributed in the central nervous systems, and the
physiological roles of the NC/OFQ-ORL1 system have been
the focus of intense research. In addition to investigations
using NC/OFQ, studies involving ORL1-deficient mice
showed that this system may play important roles in pain
regulation,3 learning and memory,4 food intake,5 anxiety,6
and cardiovascular system,7 among others,8 thus prompting
many pharmaceutical companies to identify small molecules
as potent and selective ORL1 agonists and antagonists.9
We previously reported the discovery of 1-[(3R,4R)-1-cy-
clooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-di-
Synthetic routes are summarized in Scheme 1. Chiral
tosylate 19 was prepared from (1S,3R,6S)-2,10-spirocyclopro-
pane(bicycle[2.2.1]heptane)-10-norbornylmethanol 18, which
was synthesized by a known procedure reported by
Merck Research Laboratories.18 Alkylation of commercially
available piperidine analogue 11 with tosylate 19 in the
*To whom correspondence should be addressed. For H.O.: phone,
81-29-877-2259; fax, 81-29-877-2027; e-mail, hisashi_ohta@merck.com.
For H.K.: phone, 81-29-877-2000; fax, 81-29-877-2029; e-mail, hiroshi.
kawamoto@po.rd.taisho.co.jp.
‡ Current address: Medicinal Chemistry Laboratories, Taisho Phar-
maceutical Co. Ltd.
i
presence of Pr2NEt in N-methyl-2-pyrrolidinone (NMP)
a Abbreviations: ORL1, opioid receptor-like 1; NC/OFQ, nociceptin/
orphanin FQ; SAR, structure-activity relationship; DMPK, drug
metabolism and pharmacokinetics; NMP, N-methyl-2-pyrrolidinone;
TsCl, p-toluanesulfonyl chloride; MsCl, methanesulfonyl chloride; P-
gp, P-glycoorotein; PK, pharmacokinetics; CHO, Chinese hamster
ovary; hERG, human ether-a-go-go related gene.
afforded 12. The preparation of N-isopropylidene pro-
tected alkyl diol benzimidizolidinones 13-15 was achieved
by treating 12 with NaH in N,N0-dimethylformamide (DMF)
followed by corresponding commercially available (S)-
2,2-dimethyl-1,3-dioxolane-4-methanol p-toluenesulfonate,
r
2009 American Chemical Society
Published on Web 06/19/2009
pubs.acs.org/jmc

4092 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14
Satoh et al.
Figure 2. SAR summary of benzimidazolidinone class.
With the replacement of the cyclooctyl ring with various
kinds of cycloalkane groups, a metabolite identification study
of 1 revealed that oxidation was the major metabolism and the
cyclooctyl group was one of the major metabolic sites. Thus,
substituent effects at R1 for the improvement of metabolic
stability were investigated. Various substituents were tested as a
cyclooctyl replacement to obtain detailed SAR. We previously
reported that the N-methylene linker (nonsubstituted) and
alkane group are essential to show full antagonistic activities.10
The outline of R1 modification is shown in Supporting
Information Figure S-2. Various kinds of cycloalkanes, substi-
tuted or nonsubstituted cyclopropyl rings to medium sized rings
(such as cyclopentylmethyl, cyclohexylmethyl, cycloheptyl-
methyl, cyclooctylmethyl, cyclononylmethyl, cyclodecylmethyl),
spiroalkane (such as spiro[2.5]octanemethyl, spiro[3.5]no-
nanemethyl, spiro[4.5]decanemethyl, spiro[2.4]heptanemethyl,
spiro[3.4]octanemethyl, spiro[4.4]nonanemethyl), bicyclohep-
tane (such as methylbicyclo[2.2.1]heptylmethyl, dimethylbicy-
clo[2.2.1]heptylmethyl, spirocyclopropanebicycloheptaneme-
thyl), and branched alkanes (such as 3,3-dimethylbutane, 3,3-
dithylbutane, 1-methylcyclobutaneethyl, 1-methylcyclopenta-
neethyl, 1-methylcyclohexaneethyl) were tested. Unfortunately,
cyclooctyl replacement alone could not achieve sufficient levels
of metabolic stability without loss of ORL1 potency (data not
shown). Among them, the spirocyclopropanebicycloheptane
ring was found as the most balanced cyclooctyl replacement in
regard to ORL1 binding affinity and metabolic stability.
Figure 1. Identification of 10. Footnote letters indicate the follow-
ing: (a) Pharmacokinetic study was conducted in fasted Sprague-
Dawley rats (n = 3) dosed at 3 mg/kg (1) and 1 mg/kg (10) for
intravenous dosing and dosed at 10 mg/kg (1) and 3 mg/kg (10) for
oral dosing as a solution in water. (b) Rat and human microsomal
stabilities were determined by % parent compound (1 μM) remain-
ing after 30 min (37 °C) incubation with rat liver microsomes (0.25
mg protein/mL) or human liver microsomes (0.25 mg protein/mL).
(c) Predicted hepatic availability (FH %) in humans was determined
by serum incubation method.21
Scheme 1. Synthesis of Diol Compoundsa
With the introduction of a variety of hydrophilic substituents
at the piperidine ring, the effects of hydrophilic functional
group substitution at the R2 position for improvement of
metabolic stability were investigated. Unfortunately, introduc-
tion of basic or acidic functional groups tended not to improve
metabolic stability. Only few functionalities (such as amino-
methyl, carboxyl) dramatically improved metabolic stability.
However, these compounds did not show any in vivo antagon-
ism in mice even at 10 mg/kg subcutaneous injection because of
decreases in brain/receptor accessibility. Meanwhile, insertion
of neutral functional groups (hydroxy, dihydroxy, amide, etc.)
generally led to metabolically unstable compounds except
dihydroxypropylurea derivatives, whereas these functionalities
decreased brain penetration. Diolurea derivatives also did not
demonstrate in vivo efficacy at 10 mg/kg subcutaneous injec-
tion in a mouse locomotor model (data not shown).
Unfortunately, there was no R2substituentthat was consis-
tent with metabolic stability and receptor accessibility, even if
R1 was newly identified spirocyclopropanebicycloheptane ring.
With the introduction of a variety of hydrophilic substitu-
ents into the benzimidazolidinone nitrogen, the effects of
hydrophilic substituents at the urea position were investi-
gated. Introduction of basic functional groups, especially
methylaminoethyl group, dramatically improved metabolic
stability without losing ORL1 affinity. However, these analo-
gues did not show in vivo efficacy, similar to substituents
at R2, because of low receptor accessibility. Although we
expected that diol analogues may have low brain penetrability
a Reagents: (a) 19, iPr2NEt, NMP, 100 °C, 39%; (b) (S)-2,2-dimethyl-
1,3-dioxolane-4-methanol p-toluenesulfonate, NaH, DMF, 80 °C, 80%
(for 13), 74% (for 14); (c) (R)-2,2-dimethyl-1,3-dioxolane-4-methanol p-
toluenesulfonate, NaH, DMF, 80 °C, 95%; (d) 21, NaH, DMF, 120 °C,
55%; (c) aqueous HCl/MeOH, 61% (for 10), 72% (for 16), 66% (for 17);
(f) TsCl, Et3N, AcOEt, quant; (g) MsCl, Et3N, THF, quant.
(R)-2,2-dimethyl-1,3-dioxolane-4-methanol p-toluenesulfo-
nate, or 1,3-isopropylidene protected 1,2,3-triol 2-mesylate
21. Mesylate 21 was prepared from 20, which was synthesized
by a known method.19 Finally, deprotection of isopropyli-
denes of 13-15 with aqueous HCl in methanol yielded desired
compounds 10, 16, 17 as hydrochloride salts.
The structure-activity relationship of the benzimidazolidi-
none class is summarized in Figure 2.

Letter
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14 4093
and may not show in vivo efficacy, surprisingly only neutrally
functional diol groups at the R3 position led to metabolically
stable analogues with in vivo efficacious profiles.
predicted FH of these analogues was consistent with in vivo
oral bioavailability. These results indicated that 10, 16, and
17 can be orally available in human (Table 3).
From these results, diol units were combined with spirocy-
clopropane-bicycloheptane ring, and three representative diol
compounds 10, 16, and 17 were identified. Detailed profiles of
diol compounds are shown in Table 1-4. Diol analogues 10,
16, and 17 showed potent single digit nanomolar binding
affinity and full antagonistic activities for ORL1 receptors.
Excellent selectivity over other opioid receptors was exhibited
by comparing with binding affinity data to μ, κ, and
δ (Table 1). In vivo antagonistic activity in an ORL1-driven
efficacy model that inhibited reduction of locomotor activity
induced by ORL1 agonist was also demonstrated at 30 mg/kg
oral dosing in ICR mice. The brain/plasma ratio was com-
paratively high despite having diol groups, especially for 10
(Table 2). In addition, these analogues had acceptable DMPK
profiles, much improved microsomal stabilities compared
with that of prototype 1, and moderate oral bioavailability
(F = 17-33%) in rats. Moreover, human hepatic availability
(FH) was predicted by in vitro serum incubation method
previously reported by our laboratory.20 Consequently, these
compounds were predicted to have very good hepatic avail-
ability (FH = 83-96%) in humans. In the case of rats, the
Demonstrating in vivo efficacy required a relatively high
dose (30 mg/kg), since 10, 16, and 17 had P-glycoprotein
(P-gp) susceptibility in mice but not in humans. Therefore,
brain penetrability (brain/plasma ratio) was measured in P-gp
deficient CF-1(-/-) mice to predict human brain penetrabil-
ity. As a result, despite the diol functional group, 10, 16, and
17 had much higher brain penetrability than in ICR mice that
were used in the in vivo antagonism study. These data suggest
that 10, 16, and 17 should demonstrate more potent in vivo
efficacy in humans than in mice (Table 4).
10 had the most balanced profile and was chosen for further
evaluation. 10 was a weak competitive inhibitor for CYP2D6
with an IC50 of 16 μM, whereas 10 was not an inhibitor for
CYP1A2, CYP2C8, CYP2C9, and CYP3A4 with IC50 of
>100 μM and low binding affinity to the hERG K+ channel,
as measured in MK-499 binding assay (IC50 = 25 μM).
Furthermore, excellent genotoxic profiles were exhibited; mi-
crobial mutagenesis assay was negative, in vitro alkaline
elution assay was negative, and in vitro chromosomal aberra-
tion assay was negative (Supporting information Table S-1).
In a dog telemetry study for evaluation of cardiovascular
effects, no significant changes in cardiovascular variables were
detected up to 5 mg/kg. From all in vitro and in vivo data, 10
was moved forward to clinical trial.
Table 1. In Vitro Profiles of Diol Compoundsa
binding affinity IC50 (nM)
μc κd
GTPyS
antagonism,
IC50 (nM)f
In conclusion, our efforts to optimize prototype ORL1
antagonist 1 led to the discovery of 4-{3-[(2R)-2,3-dihydrox-
ypropyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-[(1S,-
3S,4R)-spiro[bicyclo[2.2.1]heptane-2,10-cyclopropan]-3-yl-
methyl]piperidine 10. 10 had potent ORL1 antagonistic
activity and excellent selectivity over other opioid receptors
and showed in vivo efficacy after oral dosing and good brain
penetrability. 10 is currently undergoing a clinical trial.
compd ORL-1b
δe
10
16
17
2.3 ( 0.2 4500 ( 200 10000 ( 900 >10000
1.9 ( 0.1 2700 ( 100 6800 ( 300 >10000
2.3 ( 0.2 6200 ( 800 11000 ( 1700 >10000
16 ( 7
29 ( 7
15 ( 3
a All values are the mean of more than three independent determina-
tions performed in duplicate. b Displacement of [125I]Tyr14-nociceptin.
c [3H]diprenorphin, d [3H]U-69593. e [3H]Naltrindole binding from CHO
cells stably expressing cloned human ORL1, opioid μ, opioid κ, and
opioid δ receptors, respectively. f IC50 values on nociceptin-produced
Table 4. P-gp Susceptibility and Brain Penetrability in CF-1(-/-) Mice
of Diol Compounds
[
35S]GTPγS binding to ORL1-expressed in CHO cells.
brain penetrability in
CF-1(-/-) miceb
Table 2. In Vivo Profiles of Diol Compounds
P-gp substrate assaya
brain penetrability
brain levels brain/plasma
plasma (nM)b (nmol/g brain)b
in vivo
antagonism
compd (% reversal)a
L-mdr1a L-MDR1 plasma
(human)
brain levels
(nM) (nmol/g brain) plasma ratio
brain/
compd (mouse)
ratio
10
16
17
4.3
7.3
1.4
1.7
2.8
0.087
0.078
0.10
0.56
0.42
0.43
6.4
5.6
4.1
10
16
17
85
77
69
0.19 ( 0.06
0.35 ( 0.10
0.54 ( 0.24
0.19 ( 0.05
0.28 ( 0.08
0.25 ( 0.09
1.0
0.79
0.48
13.2
a P-gp susceptibility assay was conducted by using human L-MDR1
and mouse L-mdr1a transfected porcine renal epithelial (LLC-PK1) cell
monolayers.21 Transcellular transport ratio of L-MDR1 and L-mdr1a
was calculated as basal-to-apical versus apical-to-basal transported
amounts. b Plasma and brains of CF-1(-/-) mice were collected at 1 h
after drug administration (0.3 mg/kg, sc), and drug concentrations were
measured (n = 3 mice/group).
a Data show antagonistic activity of analogues (30 mg/kg, po) against the
reduction in locomotor activity produced by an ORL1 agonist for 30 min in
mice (n = 6-12). Values are expressed as % reversal of the agonist
response. b Plasma and brains of mice were collected at 3 h after drug
administration (30 mg/kg, po), and drug concentrations were measured
(n = 3 mice/group). Each value represents mean ( sd of three animals.
Table 3. Drug Metabolism and Pharmacokinetic Profiles of Diol Compounds
in vitro metabolic stability
rat PKc
microsomal stability
(% remaining)a
predicted hepatic
availability,b FH (% remaining)
iv
compd
human
rat
human
rat
CLp ((mL/min)/kg)
t1/2 (h)
Vdss (L/kg)
F (%)
10
16
17
53
54
45
70
66
74
96
91
83
30
17
17
56
34
63
1.1
1.4
1.3
4.8
3.7
5.3
33
17
22
a Rat and human microsomal stabilities were determined by % parent compound (1 μM) remaining after 30 min (37 °C) of incubation with rat liver
microsomes (0.25 mg protein/mL) or human liver microsomes (0.25 mg protein/mL) (n = 3). b Predicted hepatic availability (FH, %) in human and rat
was determined by serum incubation method. c Pharmacokinetic study was conducted in fasted Sprague-Dawley rats (n = 3) dosed at 1 mg/kg for
intravenous dosing and dosed at 3 mg/kg for oral dosing as a solution in water.

4094 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14
Satoh et al.
Acknowledgment. The authors thank Hirokazu Ohsawa
and Dr. Shigeru Nakajima for analytical and spectra studies;
Mikiko Hata, Daisuke Ichikawa, Kazumi Koga, and Hirohide
Nambu for in vitro assays and in vivo pharmacological experi-
ments; and Dr. Takashi Yoshizumi for helpful discussions.
(10) Kawamoto, H.; Ozaki, S.; Itoh, Y.; Miyaji, M.; Arai, S.;
Nakashima, H.; Kato, T.; Ohta, H.; Iwasawa, Y. Discovery of
the first potent and selective small molecule opioid receptor-
like (ORL1) antagonist:1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxy-
methyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one
(J-113397). J. Med. Chem. 1999, 42, 5061-5063.
(11) Okuda, S.; Murai, T.; Tanaka, T.; Miyaji, M.; Nishino, M.;
Kaizu-Iguchi, T.; Ise, S.; Kawamoto, H.; Ozaki, S.; Ohta, H.
Effects of the selective NOP receptor antagonist J-113397 and its
inactive enantiomer on nociception. Eur. J. Pharmacol., submitted.
(12) (a) Shinkai, H.; Ito, T.; Iida, T.; Kitano, Y.; Yamada, H.; Uchida, I.
4-Aminoquinolines: novel nociceptin antagonists with analgesic
activity. J. Med. Chem. 2000, 43, 4667-4677. (b) Yamada, H.;
Nakamoto, H.; Suzuki, Y.; Ito, T.; Aisaka, K. Phamacological
profiles of a novel opioid receptor-like1 (ORL1) receptor antago-
nist, JTC-801. Br. J. Pharmacol. 2002, 135, 323-332.
Supporting Information Available: Purity results from HPLC
analysis for all target compounds, experimental procedures and
characterization data for all new compounds, in vitro biological
assays, and in vivo pharmacological experiments. This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Mollereau, C.; Parmentier, M.; Mailleux, P.; Butour, J.;
Moisand, C.; Chalon, P.; Caput, D.; Vassart, G.; Meunier, J.-C.
ORL-1, a novel member of the opioid receptor family Cloning,
functional expression and localization. FEBS Lett. 1994, 341, 33–
38. (b) Fukuda, K.; Kato, S.; Mori, K.; Nishi, M.; Takeshima, H.;
Iwabe, N.; Miyata, T.; Houtani, T.; Sugimoto, T. cDNA cloning and
regional distribution of a novel member of the opioid receptor family.
FEBS Lett. 1994, 343, 42–46. (c) Chen, Y.; Fan, Y.; Liu, J.; Mestek,
A.; Tian, M.; Kozak, C. A.; Yu, L. Molecular cloning, tissue
distribution and chromosomal localization of a novel member of
the opioid receptor gene family. FEBS Lett. 1994, 347, 279–283. (d)
Pan, Y.-X.; Cheng, J.; Xu, J.; Rossi, G.; Jacobson, E.; Ryan-Moro, J.;
Brooks, A. I.; Dean, G. E.; Standifer, K. M.; Pasternak, G. W.
Cloning and functional characterization through antisense mapping
of a k3-related opioid receptor. Mol. Pharmacol. 1995, 47, 1180–1188.
(2) (a) Reinsceid, R. K.; Nothacker, H.-P.; Bourson, A.; Ardati, A.;
Henningsen, R. A.; Bunzow, J. R.; Grady, D. K.; Langen, H.;
Monsma, F. J., Jr.; Civelli, O. Orphanin FQ: a neuropeptide that
activates an opioid like G protein-coupled receptor. Science 1995,
270, 792-794. (b) Meunier, J.-C.; Mollereau, C.; Toll, L.; Suaudeu,
C.; Moisand, C.; Alvinerie, P.; Butour, J.-L.; Guillemot, J.-C.;
Ferrara, P.; Monsarrat, B.; Mazarguil, H.; Vassart, G.; Parmentier,
M.; Constentin, J. Isolation and structure of the endogenous agonist
of opioid receptor-like ORL-1 receptor. Nature 1995, 377, 532-535.
(3) Mogil, J. S.; Grisel, J. E.; Reinscheid, R. K.; Civelli, O.; Belknap, J.
K.; Grandy, D. K. Orphanin FQ is a functional anti-opioid
peptide. Neuroscience (Oxford, U.K.) 1996, 75, 333-337.
(4) (a) Manabe, T.; Noda, Y.; Mamiya, T.; Katagiri, H.; Houtani, T.;
Nishi, M.; Noda, T.; Takahashi, T.; Sugimoto, T.; Nabeshima, T.;
Takeshima, H. Facilitation of long-term potentiation and memory
in mice lacking nociceptin receptors. Nature (London) 1998, 394
(6693), 577-581. (b) Sandin, J.; Georgieva, J.; Schott, P. A.; Orgen,
S. O.; Terenius, L. Nociceptin/orphanin FQ microinjected into
hippocampus impairs spinal learning in rats. Eur. J. Neurosci. 1997,
9, 194-197. (c) Yu, T. P.; Fein, J.; Phan, T.; Evans, C. J.; Xie, C.-W.
Orphanin FQ inhibits synaptic transmission and long-term protec-
tion in rat hippocampus. Hippocampus 1997, 7, 88-94.
(5) Pomonis, J. D.; Billington, C. J.; Levine, A. S. Orphanin FQ
agonist of orphan opioid receptor ORL-1, stimulates feeding in
rats. NeuroReport 1996, 8, 369-371.
(6) Jenck, F.; Moreau, J.-L.; Martin, J. R.; Kilpatrick, G. J.; Reinscheid,
R. K.; Monsma, F. J., Jr.; Nothacker, H.-P.; Civelli, O. Orphanin FQ
acts as an anxiolytic to attenuate behavioral response to stress. Proc.
Natl. Acad. Sci. U.S.A. 1997, 94, 14854-14858.
(7) (a) Champion, H. C.; Katwitz, P. J. Nociceptin, an endogenous ligand
for ORL1 receptor, has novel hypotensive activity in the rat. Life
Sci. 1997, 60, 241-245. (b) Gumusel, B.; Hao, Q.; Hyman,
A.; Chang, J.-K.; Kapusta, D. R.; Lippton, H. Nociceptin: an
endogenous agonist for central opioid like1 (ORL1) receptors pos-
sesses systemic vasorelaxant properties. Life Sci. 1997, 60, 141-145.
(8) Champion, H. C.; Wang, R.; Hellstrom, W. J. G.; Kadowitz, P. J.
Nociceptin, a novel endogenous ligand for ORL1 receptor, has
potent erectile activity in the cat. Am. J. Physiol: Endocrinol.
Metab. 1997, 273, E214-E219.
(9) (a) Chiou, L.-C.; Liao, Y. Y.; Fan, P.-C.; Kuo, P.-H.; Wang, C.-H.;
Riemer, C.; Prinssen, E. P. Nociceptin/orphanin FQ peptide
receptors: pharmacology and clinical implications. Curr. Drug
Targets 2007, 8, 117-135. (b) Bignan, G. C.; Connolly, P. J.;
Middleton, S. A. Recent advances towards the discovery of
ORL-1 receptor agonists and antagonists. Expert Opin. Ther.
Pat. 2005, 15, 357-388. (c) Zaveri, N. Peptide and nonpeptide
ligands for the nociceptin/orphanin FQ receptor ORL1: research
tools and potential therapeutic agents. Life Sci. 2003, 73, 663-678.
(d) Ronzoni, S.; Peretto, I.; Giardina, G. A. M. Lead generation
and lead optimization approaches in the discovery of selective,
non-peptide ORL-1 receptor agonists and antagonists. Expert
Opin. Ther. Pat. 2001, 11, 525-546.
(13) Zaratin, P. F.; Petrone, G.; Sbacchi, M.; Garnier, M.; Fossati, C.;
Petrillo, P.; Ronzoni, S.; Giardina, G. A. M.; Scheideler, M. A. Modi-
fication of nociceptin and morphine tolerance by the selective ORL-1
antagonist SB-612111. J. Pharmacol. Exp. Ther. 2004, 308, 454-461.
(14) (a) Goto, Y.; Arai-Otsuki, S.; Tachibana, Y.; Ichikawa, D,; Ozaki,
S.; Takahashi, H.; Iwasawa, Y.; Okamoto, O.; Okuda, S.; Ohta, H.;
Sagara, T. Identification of a novel spiropiperidine opioid receptor-
like 1 antagonist class by a focused library approach featuring 3D-
pharmacophore similarity. J. Med. Chem. 2006, 49, 847-849. (b)
Arai, T.; Nishikimi, Y.; Imamura, S.; Kamiyama, K.; Kobayashi,
M. Preparation of Spiro Compounds As Nociceptin Receptor
Binders. WO200226714, 2002. (c) Ito, F.; Koike, H.; Sudo, M.;
Yamagishi, T.; Ando, K. Preparation of Spiropiperidine Com-
pounds As Ligands for the ORL-1 Receptor. WO2003000677, 2003.
(15) (a) Okamoto, O.; Kobayashi, K.; Kawamoto, H.; Ito, S.; Satoh, A;
Kato, T.; Yamamoto, I.; Mizutani, S.; Hashimoto, M.; Shimizu, A.;
Sakoh, H.; Nagatomi, Y.; Iwasawa, Y.; Takahashi, H.; Ishii, Y.; Ozaki,
S.; Ohta, H. Idetification of novel benzimidazole series of potent and
selective ORL1 antagonist. Bioorg. Med. Chem. Lett. 2008, 18, 3278-
3281. (b) Okamoto, O.; Kobayashi, K.; Kawamoto, H.; Ito, S.;
Yoshizumi, T.; Yamamoto, I.; Hashimoto, M.; Shimizu, A.; Taka-
hashi, H.; Ishii, Y.; Ozaki, S.; Ohta, H. Novel ORL1-selective
antagonists with oral bioavailability and brain penetrability. Bioorg.
Med. Chem. Lett. 2008, 18, 3282-3285. (c) Kobayashi, K.; Kato, T.;
Yamamoto, I.; Shimizu, A.; Mizutani, S.; Asai, M.; Kawamoto, H.;
Ito, S.; Yoshizumi, T.; Hirayama, M; Ozaki, S.; Okamoto, O.; Ohta,
H. Optimization of a benzimidazole series as opioid receptor-like 1
(ORL1) antagonists: SAR study directed toward the improvement
in the selectivity over hERG activity Bioorg. Med. Chem. Lett. 2009,
19, 3100-3103. (d) Kobayashi, K.; Uchiyama, M.; Takahashi, H.;
Kawamoto, H.; Ito, S.; Yoshizumi, T.; Nakashima, H.; Kato, T.;
Shimizu, A.; Yamamoto, I; Asai, M.; Miyazoe, H.; Ohno, A.;
Hirayama, M.; Ozaki, S.; Tani, T.; Ishii, Y.; Tanaka, T.; Mochi-
dome, T.; Tadano, K.; Fukuroda, T.; Okamoto, O.; Ohta, H. 2-
Cyclohexylcarbonylbenzimidazoles as potent, orally active and
brain penetrable opioid receptor-like 1 (ORL1) antagonists. Bioorg.
Med. Chem. Lett. 2009, 19, 3096-3100.
(16) Yoshizumi, T.; Takahashi, H.; Takahashi, H.; Miyazoe, H.;
Sugimoto, Y.; Tsujita, T.; Kato, T.; Ito, H.; Kawamoto, H.; Hirayama,
M.; Ichikawa, D.; Azuma-Kanoh, T.; Ozaki, S.; Shibata, Y.; Tani, T.;
Chiba, M.; Ishii, Y.; Okuda, S.; Tadano, K.; Fukuroda, T.; Okamoto,
O.; Ohta, H. A novel class of cycloalkano[b]pyridines as potent and
orally active opioid receptor-like 1 antagonist with minimal binding
affinity to the hERG K+ channel. J. Med. Chem. 2008,51,4021-4029.
(17) Okano, M.; Mito, J.; Maruyama, Y.; Masuda, H.; Niwa, T.;
Nakagawa, S.; Nakamura, Y.; Matsuura, A. Discovery and struc-
ture-acivity relationships of 4-aminoquinazoline derivatives, a
novel class of opioid receptor like-1 (ORL1) antagonists. Bioorg.
Med. Chem. 2009, 17, 119-132.
(18) Kuethe, J. T.; Zhao, D.; Humphrey, G. R.; Journet, M; McKeown, A.
E. Asymetric Diels-Alder reactions of chiral cyclopropylidene imide
dienophiles: preparation of gem-dimethyl- and spirocyclopropane
norbornyl carboxylic acids. J. Org. Chem. 2006, 71, 2192-2195.
(19) Forbes, D. C.; Ene, D. G.; Doyle, M. P. Stereoselective synthesis of
substituted 5-hydroxy-1,3-dioxanes. Synthesis 1998, 879-882.
(20) (a) Shibata, Y.; Takahashi, H.; Chiba, M.; Ishii, Y. Prediction of
hepatic clearance and availability by cryopreserved human hepa-
tocytes: an application of serum incubation method. Drug Metab.
Dipos. 2002, 30, 892-896. (b) Shibata, Y.; Takahashi, H.; Ishii, Y.
A convenient in vitro screening method for predicting in vivo drug
metabolic clearance using isolated hepatocytes suspended in ser-
um. Drug Metab. Dipos. 2000, 28, 1518-1523.
(21) Ohe, T.; Sato, M.; Tanaka, S.; Fujino, N.; Hata, M.; Shibata, Y.;
Kanatani, A.; Fukami T.; Yamazaki, M.;Chiba, M.;Ishii, Y. Effect
of P-glycoprotein-mediated efflux on cerebrospinal fluid/plasma
concentration ratio. Drug Metab. Dispos. 2003, 31, 1251-1254.