Synthesis and biological evaluation of imidazole derivatives as novel NOP/ORL1 receptor antagonists: Exploration and optimization of alternative pyrazole structure

Article abstract of DOI:10.1016/j.bmcl.2009.06.095

Nonpeptidic small-molecule NOP/ORL1 receptor antagonists with an imidazole scaffold were designed and synthesized to investigate alternatives to the pyrazole analog. Systematic modification of the original pyrazole lead [Kobayashi et al., Bioorg. Med. Che

Full text of DOI:10.1016/j.bmcl.2009.06.095

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4611–4616
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of imidazole derivatives as novel
NOP/ORL1 receptor antagonists: Exploration and optimization
of alternative pyrazole structure
*
Yuichi Sugimoto , Kensuke Kobayashi, Masanori Asai, Akio Ohno, Koji Yamada, Satoshi Ozaki,
Hisashi Ohta, Osamu Okamoto
Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Nonpeptidic small-molecule NOP/ORL1 receptor antagonists with an imidazole scaffold were designed
and synthesized to investigate alternatives to the pyrazole analog. Systematic modification of the original
pyrazole lead [Kobayashi et al., Bioorg. Med. Chem. Lett. 2009, 19, 3627; Kobayashi et al., Bioorg. Med.
Chem. Lett., in press] to change the heterocyclic core, substituted side chain, and pendant functional group
demonstrated that examining the structure–activity relationship for novel templates allowed the identi-
fication of potent, fully substituted 4-aminomethyl-1H-imidazole and 2-aminomethyl-1H-imidazole.
These compounds exhibited excellent potency for ORL1 receptor with minimal P-gp efflux and/or
reduced hERG affinity.
Received 9 April 2009
Revised 19 June 2009
Accepted 24 June 2009
Available online 1 July 2009
Keywords:
Nociceptin
Orphanin FQ
ORL1 receptor
Antagonist
Imidazole
Ó 2009 Elsevier Ltd. All rights reserved.
The fourth member of the opioid receptor family was discov-
ered in 1994 and was called opioid receptor-like 1 (ORL1),2 also
known as nociceptin (NOP) receptor, using cDNA expression clon-
ing techniques.3 Its endogenous ligand, nociceptin (Orphanin FQ),
is a novel heptadecapeptide and was isolated from brain extracts
in 1995.4 Although ORL1 receptor is a member of the G-protein
coupled receptor (GPCR) superfamily with close homology to clas-
of drugs for some human disorders involving pain and anxiety or
for the treatment of Parkinson’s disease.9
Recently, several research groups have reported findings related
to the search for small-molecule ORL1 antagonists, describing non-
peptide ligands such as benzimidazolones10 and related com-
pounds,11 benzimidazoles,12 indolinones,13 spiropiperidines,14
aryl piperidines,15 4-aminoquinolines,16 and indolyl-oxadiazole.17
Some of these ligands possess very high selectivity for the ORL1
receptor versus other opioid receptors.
In the course of our search for an ORL1 antagonist, 1,5-diaryl-3-
aminomethyl-1H-pyrazole 1 (Fig. 1) was confirmed as a primary
hit compound via high-throughput screening (HTS) of in-house
compound libraries. In previous structure–activity relationship
(SAR) investigations, we found novel pyrazole derivatives which
showed potent antagonistic activity against ORL1 receptor.1 We
initiated a core structure optimization study with the aim of
exploring an alternative pyrazole moiety. As a result of preliminary
modification of the core part, we identified imidazole analogs 2
and 3 as active prototypes and which deserved further derivation.
Herein, we describe synthesis, SAR investigation and evaluation of
novel imidazole scaffolds as ORL1 antagonists.
sical opioid (
thetic agonists selective for
significant affinity for ORL1 receptor.5
l
, d, and
j
) receptors, native opioid peptides and syn-
l
, d, and receptors do not show
j
The ORL1 receptor and NOP are mainly distributed in the brain
and central nervous system (CNS).5,6 It has been observed that NOP
is involved in modulating pain mechanisms in the spinal cord and
forebrain. Several in vivo studies with NOP and its peptide analogs
have demonstrated that NOP modulates a variety of biological
functions, such as feeding, learning, diuresis, drug addiction, car-
diovascular function, and locomotor activity and that it controls
the release of neurotransmitters including serotonin and dopamine
at peripheral and central sites.7 ORL1 receptor may also be relevant
in the treatment of CNS disorders including anxiety and drug
abuse.7,8 Therefore, the identification of potent, small-molecule
agonists and antagonists of nociceptin could provide new classes
Our initial efforts toward understanding the SAR of the lead
molecule were focused on replacing the core part with other
five-membered heterocycles. The results of this study are summa-
rized in Table 1. Pyrazole compounds 4 and 5 were prepared to
evaluate the effect of a substituent at C-4 position. A methyl group
* Corresponding author. Tel.: +81 29 877 2222; fax: +81 29 877 2029.
E-mail addresses: yuichi_sugimoto@merck.com, osamu_okamoto@merck.com
(Y. Sugimoto).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.06.095

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Y. Sugimoto et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4611–4616
R2
R2
R2
N
NH
R3
NH
R3
NH
R3
R1
R1
N
R1
N
N
N
N
1
2
3
Figure 1. Structures of pyrazole (1) and imidazole (2, 3) compounds.
Table 1
Table 1 (continued)
Effect of heterocycle on central part
a
Compound
ORL1 IC50 (nM)
Me
NH
13
14
200
N
N
Cl
Cl
Me
Me
>1000 (25%)
>1000 (44%)
>1000 (40%)
>1000 (19%)
O
Cl
a
Compound
ORL1 IC50 (nM)
15b
N
4
130
28
N
Me
N
N
N
N
N
Me
Me
16c
N
N
N
5
N
N
Me
Me
N
17d
6
28
N
a
Binding affinities for the ORL1 receptor. Numbers in parentheses indicate %
M.
4-Chlorophenyl part is replaced by phenyl group.
4-Chlorophenyl part is replaced by 3,4-difluorophenyl group.
4-Chlorophenyl part is replaced by 3,5-difluorophenyl group.
inhibition at 1
l
Me
b
N
c
7
8
9
520
850
620
N
N
d
N
N
increased the ORL1 affinity fourfold. Compounds 6–9 were pre-
pared to evaluate the effect of imidazole nuclei. Optimal binding
affinity for ORL1 was achieved with 1,2-diaryl-5-methylimidazole
6. As for 4,5-diarylimidazole compounds, a substitution pattern
similar to that of compound 7 was preferable to regioisomer 8.
Another 1,2-diarylimidazole 9 had activity comparable to 7. Thia-
zole 10, oxazole 11, triazole 12, and furan 14 resulted in poor affin-
ity or loss of affinity for ORL1. However, pyrrole analog 13
possessed moderate activity. Incorporation of other heterocycles
without substitution at the bottom also had a detrimental effect
on activity.
In order to reduce the lipophilicity of imidazole 6, we modified
the phenyl group into a more hydrophilic ring similar to that of
pyridine. The synthesis of representative analog 25 is outlined in
Scheme 1. Functionalization of the 2-position of commercially
available 2,3-dichloropyridine 18 followed by cyanidation using
Zn(CN)2 and addition of sodium 6-methyl-3-pyridineamide gave
the pyridinecarboxamidine derivative 20. A cyclization reaction
of 21, obtained by alkylation of the amidine moiety in 20, provided
ethyl 1,2-dipyridinyl-imidazole-4-carboxylate 22. Ethyl ester was
converted in two steps, DIBAL-H reduction and MnO2 oxidation,
Me
N
S
O
N
10
11
12
>1000 (7%)
>1000 (28%)
>1000 (48%)
N
N
N
N

Y. Sugimoto et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4611–4616
4613
EtOOC
Me
O
N
NH Cl
N
Me
N
NH Cl
N
Cl
Cl
Cl
a
b
c
N
H
N
N
N
CN
Me
18
19
20
21
Me
COOEt
Me
N
CHO
N
N
N
N
N
d
e, f
g
25
Me
Me
Cl
Cl
N
N
22
23
Scheme 1. Reagents: (a) Zn(CN)2, Pd(PPh3)4, 64%; (b) 6-methyl-3-pyridineamine, NaHMDS, 57%; (c) ethyl 3-bromo-2-oxobutanoate, 75%; (d) 4 N HCl/dioxane, 38%; (e)
DIBAL-H, 56%; (f) MnO2, 88%; (g) (1S, 3R)-3-fluorocyclopentanamine hydrochloride, Et3N, NaBH3CN-1/2ZnCl2, 28%.
into imidazole-4-carbaldehyde 23. Finally, compound 23 was
subjected to a reductive amination reaction with (1S,3R)-3-fluoro-
cyclopentanamine18 to produce the desired compound 25. Close
analogs were also prepared by a similar reaction sequence employ-
ing corresponding congeners. Several pyridine analogs were pre-
pared and the selected derivatives (24, 26–28) are summarized
in Table 2.
as a radioligand to evaluate hERG liability, for example QT prolon-
gation followed by lethal cardiac arrhythmia. A P-glycoprotein (P-
gp) transporter efflux assay was used to determine if a compound
is a P-gp substrate.22 Performance in this assay proved to be deci-
sive in selecting potential CNS drug candidates for in vivo assess-
ments of brain penetration. Additionally, the accuracy of efflux
ratio (B–A/A–B) measurements may be compromised for com-
pounds displaying apparent permeability of Papp <10.
The first phase of our SAR investigation involved the evaluation
of simple derivatives related to prototypical compound 6 in order
to define the optimal substituent. Although methyl analog 24
had activity comparable to 6, the isopropyl derivative 27 exhibited
a fivefold increase in potency against ORL1 relative to 6. To find a
synergistic effect on potency without significant affinity for the
These new imidazole compounds were tested for competitive
binding affinity for human ORL1 receptors transfected into Chinese
hamster ovary (CHO) cells using [125I][Tyr14] nociceptin as a radio-
ligand, with the results expressed as IC50. Functional antagonism
was also determined by stimulation of [35S] GTP
cS binding to
CHO-ORL1 membranes.19 We carried out the human ether-a-go-
go related gene (hERG) K+ channel assay20 using [35S]MK-49921
Table 2
Profiles of 1,2-diarylimidazole (24–28) and 1-arylimidazole (29) compounds
R2
F
R1
NH
NH
F
N
N
N
N
N
N
Me
Me
Cl
F
29
a
b
c
g
Compound
R1
R2
Binding IC50 (nM)
GTP
c
S IC50 (nM)
hERG IC50 (nM)
Human P-gp
B–A/A–Bd
NT
5.1
19.7
22.9
21.8
3.2
Log Pf
pKa
e
Papp
24
25
26
27
28
29
Me–
Me–
Et–
H
F
F
H
F
26
NTh
3.7
2.3
9.6
2.3
4.5
19,000
31,000
15,000
9900
15,000
34,000
NT
3.99
3.38
3.91
4.87
4.26
3.90
8.20
7.36
7.38
8.12
7.28
7.74
9.1
3.2
4.7
1.4
8.6
16.8
20.6
25.0
24.1
34.0
iPr–
iPr–
a
Binding affinities for the ORL1 receptor.
b
c
Antagonist activities in the GTPcS functional assay.
Displacement binding assay of [35S]MK-499 in membranes derived from HEK293 cells stably transfected with the hERG gene and expressing the Ikr channel protein. See
Ref. 20.
d
Efflux ratio. See Ref. 22.
e
f
Apparent permeability (10À6 cm/s).
Calculated using ACD/log P DB supplied by Advanced Chemical Development Inc.
Calculated using ACD/pKa DB supplied by Advanced Chemical Development Inc.
Not tested.
g
h

4614
Y. Sugimoto et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4611–4616
Table 3
increased affinity for the potassium channel (24 vs 25 and 27 vs
28). Another significant concern for CNS activity is a compound’s
susceptibility to P-gp mediated transport. Although all tested com-
pounds (25–28) displayed good permeability (Papp = 17–25), most
of the potent analogs (26–28) were highly susceptible substrates
for P-gp (B–A/A–B ratio = 20–23). In contrast, a small alkyl group
had a positive effect in reducing susceptibility to P-gp efflux and
25 was only moderately susceptible for P-gp (B–A/A–B ratio = 5).
Next, we performed a drug metabolism study for representative
derivative 26 (Table 3). In vitro metabolic stabilities using human
and rat liver microsomes24 were relatively high (82–85%); how-
ever, the rat pharmacokinetic (PK) profile needs improvement
due to its short half-life and high clearance followed by low oral
bioavailability (F 10%). With regard to substitution pattern, the aryl
group on the bottom was replaced with alkyl moieties to confirm
whether aromatic substituents are essential. On the basis of previ-
ous research,17 we examined several alkyl groups together with
the other aryl part at the C-1 position. Of the alkyl derivatives
examined, a methyl group was accepted as the optimal C-2 substi-
tuent and benchmark compound 29 had an activity comparable to
25 with negligible hERG inhibitory activity and acceptable P-gp
susceptibility (Table 2).
As the second lead optimization attempt for finding an alterna-
tive imidazole template, we carried out replacement of the methyl
group on imidazole ring 7 with alkyl, cycloalkyl or fluoroalkyl moi-
eties to confirm which alkyl substituent was better suited as a skel-
eton. The results for the alkyl analogs are shown in Table 4. As
observed for compounds 32, 35, and 36, tert-butyl and cycloalkyl
groups rendered the molecule inactive, whereas cyclobutyl 34
and isobutyl 38 retained potency. Interestingly, relatively small
and branched groups increased the potency by threefold in the
case of ethyl 30 and 3-pentyl 37 and 15-fold in the case of isopro-
pyl 31 versus parent compound 7. Attempts to introduce an F atom
in the alkyl region to reduce imidazole basicity resulted in moder-
ate compounds 39–42. ORL1 binding affinity was observed to de-
crease with an increase in the number of F atoms.
Microsomal stabilities and rat pharmacokinetic property for compound 26
Microsomal stability (% remaining)
Rat PKa
Human
Rat
82
Cl (ml/min/kg)
114
T1/2 (h)
F (%)
85
0.5
10
a
Oral dose 3 mg/kg and IV dose 1 mg/kg.
hERG K+ channel, we also prepared (1S,3R)-3-fluorocyclopentyl-
amine23 derivatives (25, 26, and 28). As expected, the intrinsic po-
tency improved appreciably and this modification led to
threefold increase in potency (24 vs 25 and 27 vs 28). In addition,
F-containing derivatives had even less affinity for the hERG K+
channel than parent compounds due to a reduction in basicity. It
is a general trend that more basic substances tend to have an
a
Table 4
Effect of alkyl substituent on imidazole ring
R
NH
N
N
Cl
Cl
Cl
a
Compound
R
ORL1 IC50 (nM)
7
30
31
32
Me
Et
520
160
33
iPr
tBu
>1000 (26%)
33
34
35
36
37
38
39
40
41
190
Successive lead optimization efforts were employed in confor-
mity with a similar strategy to affect replacement of the aryl group
with an alkyl side chain. Scheme 2 depicts the preparation of 2-
methoxyethyl analog 54 as a typical example. Isopropyl aldimine
44, prepared from 4-chlorobenzaldehyde 43 and isopropylamine,
was converted to 5-(4-chlorophenyl)-1-isopropylimidazole 45 uti-
lizing tosylmethyl isocyanine (TosMIC). Formylation at C-2 posi-
tion as aldehyde 46 followed by bromination provided fully
substituted imidazole 47. Stille cross-coupling of bromide 47 with
tributyl(vinyl)tin gave the corresponding vinyl intermediate 48.
Reductive amination, as mentioned in Scheme 1, generated the
secondary amine 49, which was protected as tert-butyl carbamate
50. Imidazolylethanol 51 was then prepared from 50 by hydrobo-
ration and oxidation with alkaline H2O2. Alkylation with MeI pro-
duced methylether, which upon deprotection of the Boc group
with TFA, afforded the desired amine 54.
530
>1000 (43%)
>1000 (48%)
160
540
As observed in the previous imidazole series (Table 2), incor-
poration of small alkyl groups into this imidazole series is also
acceptable in terms of their potency. Introduction of (1S,3R)-3-
fluorocyclopentylamine resulted in compound 54 which was five
times weaker in affinity than 53 in the hERG assay with de-
creased basicity and lipophilicity.25 Both compounds revealed
good permeability (Papp = 18 and 29, respectively) and P-gp
efflux susceptibility (B–A/A–B ratio = 1.0 and 1.4, respectively)
(Table 5).
F
F
160
F
500
F
F
F
>1000 (32%)
96
In conclusion, based on the former pharmacophore model,1 we
designed novel ORL1 receptor antagonists by replacing a pyrazole
ring with the imidazole motif. Two different types of imidazole
scaffold showed excellent antagonistic activity toward ORL1. In
particular, compounds 28 and 54 displayed high affinity (ORL1
F
F
42
a
Binding affinities for the ORL1 receptor. Numbers in parentheses indicate %
M.
inhibition at 1
l

Y. Sugimoto et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4611–4616
4615
CHO
CHO
N
a
b
c
N
N
N
N
Cl
Cl
Cl
Cl
44
45
43
46
F
CHO
CHO
NH
N
N
g
N
e
f
d
N
N
N
Cl
Cl
Cl
Br
F
47
49
48
F
F
NBoc
NBoc
NBoc
N
N
N
j
h
N
i
N
N
54
Cl
Cl
Cl
OH
OMe
50
52
51
i
i
Scheme 2. Reagents: (a) PrNH2, MgSO4; (b) TosMIC, PrNH2, 68% (2 steps); (c) nBuLi then DMF, 87%; (d) NBS, 97%; (e) tributyl(vinyl)tin, Pd(PPhh3)4, 55%; (f) (1S, 3R)-3-
fluorocyclopentanamine hydrochloride, Et3N, NaBH3CN-1/2ZnCl2, 74%; (g) Boc2O, 1 N NaOH, 91%; (h) NaBH4, BF3OEt2 then 30% H2O2, 5 N NaOH, 24%; (i) MeI, NaH, 72%; (j)
TFA, 48%.
Table 5
Profiles of 5-arylimidazole compounds
R2
NH
N
N
Cl
R1
R1
R2
Binding IC50 (nM)
GTP
c
S IC50 (nM)
hERG IC50 (nM)
Human P-gp
Log Pf
pKa
a
b
c
g
Compound
d
e
B–A/A–B
Papp
53
54
Me–
MeO(CH2)2–
H
F
11
7.6
NTh
5.6
3200
16,000
1.0
1.4
18.2
28.6
5.46
4.32
8.98
8.13
a–h
See footnotes of Table 2.
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l
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Bioorg. Med. Chem. Lett. 2006, 16, 3569.
18. Synthesized from (1R,4S)-(+)-2-cyclopentene-1,4-diol 1-acetate. For details,
see the following patent: Okamoto, O.; Kobayashi, K.; Ito, H.; Tsujita, T.; Ozaki,
S.; Ohta, H. WO 2007/037513 A1, 2007.
19.
[ cS binding assay was conducted as described previously Ozaki, S.;
35S]GTP
Kawamoto, H.; Itoh, Y.; Miyaji, M.; Azuma, T.; Ichikawa, D.; Nambu, H.; Iguchi,
T.; Iwasawa, Y.; Ohta, H. Eur. J. Pharmacol. 2000, 402, 45.
20. Butcher, J. W.; Claremon, D. A.; Connolly, T. M.; Dean, D. C.; Karczewski, J.;
Koblan, K. S.; Kostura, M. J.; Liverton, N. J.; Melillo, D. G. WO 02/05860 A1, 2002.
21. The synthesis of [35S]MK-499 has been reported by C. E. Raab et al. Raab, C. E.;
Butcher, J. W.; Connolly, T. M.; Karczewski, J.; Yu, N. X.; Staskiewicz, S. J.;
Liverton, N.; Dean, D. C.; Melillo, D. G. Bioorg. Med. Chem. Lett. 2006, 16, 1692.
22. P-gp efflux is determined by a transcellular transport study using MDR1 cells.
For details, see the following literatures: (a) Hochman, J. H.; Pudvah, Q.;
Yamazaki, M.; Tang, C.; Lin, J. H.; Prueksaritanont, T. Pharm. Res. 2004, 21, 1686;
(b) Hochman, J. H.; Yamazaki, M.; Ohe, T.; Lin, J. H. Curr. Drug Metab. 2002, 3,
257; (c) Yamazaki, M.; Neway, W. E.; Ohe, T.; Chen, I.-W.; Rowe, J. F.; Hochman,
J. H.; Chiba, M.; Lin, J. H. Pharmacol. Exp. Ther. 2001, 296, 723.
23. The preferable effect of F atom on cyclopentylamine has been already reported.
For details, see Ref. 1.
24. Human and rat microsomal stabilities were determined by percentage parent
compound (1 lM) remaining after 30 min incubation at 37 °C with human/rat
liver microsomes (0.25 mg protein/ml).
25. Recently, AstraZeneca’s researchers have been reported that lipophilicity is a
significant contributor to hERG potency and is of similar importance to
ionization class by conducting in-house dataset analysis: Waring, M. J.;
Johnstone, C. Bioorg. Med. Chem. Lett. 2007, 17, 1759.
15. (a) Zaratin, P. F.; Petrone, G.; Sbacchi, M.; Garnier, M.; Fossati, C.; Petrillo, P.;
Ronzoni, S.; Giardina, G. A. M.; Scheideler, M. A. J. Pharmacol. Exp. Ther. 2004,
308, 454; (b) Yoshizumi, T.; 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. J. Med. Chem. 2008, 51, 4021.
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2000, 43, 4667; (b) Sestili, I.; Borioni, A.; Mustazza, C.; Rodomonte, A.;