Discovery of naldemedine: A potent and orally available opioid receptor antagonist for treatment of opioid-induced adverse effects

Article abstract of DOI:10.1016/j.bmcl.2018.11.007

Structure-activity relationship studies of several morphinan derivatives were conducted to obtain dual antagonists for μ- and δ-opioid receptors. We discovered peripherally restricted dual antagonists for μ/δ-opioid receptors as a new chemotype with a morphinan scaffold, which are orally available and do not easily pass the blood–brain barrier. As we expected, some of these compounds inhibit opioid-induced constipation and emesis/vomiting with limited potential to interfere the analgesic effects of morphine. Among them, naldemedine was selected as a potential drug candidate.

Full text of DOI:10.1016/j.bmcl.2018.11.007

Accepted Manuscript
Discovery of naldemedine: A potent and orally available opioid receptor antag-
onist for treatment of opioid-induced adverse effects
Masanao Inagaki, Masaharu Kume, Yoshinori Tamura, Shinichiro Hara,
Yoshihisa Goto, Haga Nobuhiro, Tsuyoshi Hasegawa, Takashi Nakamura,
Katsumi Koike, Shuuichi Oonishi, Toshiyuki Kanemasa, Hiroyuki Kai
PII:
S0960-894X(18)30863-1
https://doi.org/10.1016/j.bmcl.2018.11.007
BMCL 26118
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 August 2018
22 October 2018
6 November 2018
Please cite this article as: Inagaki, M., Kume, M., Tamura, Y., Hara, S., Goto, Y., Nobuhiro, H., Hasegawa, T.,
Nakamura, T., Koike, K., Oonishi, S., Kanemasa, T., Kai, H., Discovery of naldemedine: A potent and orally
available opioid receptor antagonist for treatment of opioid-induced adverse effects, Bioorganic & Medicinal
Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.11.007
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Discovery of naldemedine: A potent and orally available opioid receptor antagonist
for treatment of opioid-induced adverse effects
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Masanao Inagakia,*, Masaharu Kumea, Yoshinori Tamuraa, Shinichiro Haraa, Yoshihisa Gotob, Haga
Nobuhiroa, Tsuyoshi Hasegawaa, Takashi Nakamurac, Katsumi Koiked, Shuuichi Oonishie, Toshiyuki
Kanemasad, Hiroyuki Kaia.
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a Medicinal Chemistry Research Laboratory, Shionogi Co., Ltd. 3-1-1 Futaba-cho, Toyonaka, Osaka
561-0825, Japan.
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b Production Technology Department, Shionogi Co. & Ltd. 2-1-3 Kuise Terajima, Amagasaki, Hyogo
660-0813, Japan
c Shionogi TechnoAdvance Research Co., Ltd. 1405 Koga-cho Gotanda, Koga, Shiga 520-3423, Japan.
d Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd, 3-1-1 Futaba-cho, Toyonaka,
Osaka 561-0825, Japan.
e Research Laboratory for Development, Shionogi & Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka
561-0825, Japan.
* Corresponding author. Tel.: +81-6-6331-6194; fax: +81-6-6332-6385; E-mail address:
masanao.inagaki@shionogi.co.jp
Key words: μ- and δ-opioid receptor antagonist, peripherally selective, morphinan, opioid-induced
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constipation, opioid-induced emesis/vomiting

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Abbreviation: methanesulfonic acid: MsOH, aqueous: aq., room temperature: rt, saturated: sat.,
N-hydroxybenzotriazole: HOBt, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride:
WSCD·HCl, ethyl acetate: AcOEt, subcutaneous injection: sc, per os: po.
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5

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Abstract: Structure-activity relationship studies of several morphinan derivatives were conducted to
obtain dual antagonists for μ- and δ-opioid receptors. We discovered peripherally restricted dual
antagonists for μ/δ-opioid receptors as a new chemotype with a morphinan scaffold, which are orally
available and do not easily pass the blood–brain barrier. As we expected, some of these compounds
inhibit opioid-induced constipation and emesis/vomiting with limited potential to interfere the analgesic
effects of morphine. Among them, naldemedine was selected as a potential drug candidate.
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Opioid analgesics such as morphine and oxycodone have long played a critical role in chronic and
acute pain control.1 Opioids are potent analgesic agents and, therefore, widely used for pain management
in cancer and non-cancer patients.2 Conversely, opioids are associated with adverse events, such as
analgesic tolerance, physical dependence, addiction, sedation, respiratory depression, constipation, and
nausea/vomiting.3 Among them, the most common adverse effects are constipation and nausea/vomiting.4
These adverse effects of opioids are among the main reasons why patients discontinue their therapeutic
use. Opioid-induced constipation (OIC) is thought to be caused by activation of μ-opioid receptors in the
gastrointestinal tract.5 Additionally, δ-opioid receptor antagonism is reported to decrease opioid-induced
nausea/vomiting (OINV).6 Thus, μ- and δ-opioid dual antagonists would be desirable drugs for alleviation
of certain side-effects of opioids. Indeed, naltrexone and naloxone have been reported to be effective to
reduce the frequency of constipation, but these antagonists also block desirable analgesic effects.7
Therefore, we sought to design peripheral opioid antagonists. Methylnaltrexone8 and naloxegol9 are the
only such drugs currently approved for the treatment of OIC. These drugs were designed to act
peripherally by modification of naltrexone and naloxone. They have characteristic structures, including a
quaternary nitrogen atom and a polyethylene glycol (PEG) side chain. These characteristic moieties
restrict these drugs to act peripherally and limit their ability to penetrate the BBB.
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Figure 1. Known opioid receptor antagonists
Our design strategies were different from these. Our first strategy involved introduction of a highly
polar moiety such as a carboxylic acid moiety to known opioid antagonists, such as naltrindole10
derivatives (Toray’s patent compounds11 ) to confer peripheral selectivity, because compounds with highly
polar functions are known to not easily cross the blood–brain barrier (BBB).12 Our second strategy was to
design new chemotypes with morphinan scaffolds, which were expected to minimize the penetration of
the BBB.
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First, we introduced carboxylic acid moieties to known opioid receptor antagonists. Indole carboxylic
acids 4 were synthesized by Fischer indole synthesis from naltrexone hydrochloride (NTX·HCl; 1) as a
starting material and the corresponding arylhydrazine (2) in acidic conditions and following hydrolysis,
according to the known method11 described in scheme 1.
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Scheme 1. Reagents and conditions for the synthesis of indole carboxylic acids 4: (a) MsOH, EtOH,

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reflux, R1= H 57%, R1= Cl 78%; (b) 2M NaOH, MeOH, rt, R1= H 97%, R1= Cl 98%.
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Next, we designed new chemotypes that could be synthesized starting from naltrexone. We focused
upon 7-acetyl-morphinan, which had been reported previously,13 because: 1) only 7-acetyl-morphinan
was known, and its biological activities have not been studied; 2) β-diketones are easily converted to
various heterocyclic compounds, such as pyrazoles, and pyrimidines. Moreover, these derivatives are
predicted to not easily penetrate the BBB because of their higher polar surface area (PSA) values
compared with naltrexone.
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7
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Indeed, the heterocyclic compounds described above were synthesized from 7-acyl morphinans. The
intermediate 7-acyl morphinans were synthesized using previously reported methods.13 Free naltrexone
(prepared from 1) was treated with acyl anhydride at 130 °C to yield the 3,14-di-O-acyl derivative 5. Next,
compound 5 was treated with aqueous NaOH, and deprotection / acyl rearrangement to the 7-position
proceeded smoothly to yield the 7-acyl derivatives 6 (Scheme 2).
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Scheme 2. Reagents and conditions for the synthesis of the 7-acyl derivatives 6: (a) 1) sat. NaHCO3; 2)
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(R2CO)2O, 100 °C; (b) 2M NaOH, MeOH, rt, R2 = Me 80%, R2 = Et 92% (2 steps).
6,7-Fused heterocyclic compounds were synthesized as follows (Scheme 3). Pyrazole 7 was simply
obtained by treatment with the corresponding hydrazine and compound 6a. Pyrimidine 8 was synthesized
from guanidine and the intermediate (6a).

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Scheme 3. Reagents and conditions for the synthesis of compounds 7 and 8: (a) hydrazine·2HCl, EtOH,
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reflux, 46%; (b) guanidine carbonate, AcOH, EtOH, reflux, 20%.
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The preliminary SAR results are shown in Table 1. The indole carboxylic acid 4a along with the
naltrindole derivatives had dual affinities to opioid receptors, but showed slight δ-receptor selectivity.
Compound 4a was metabolically stable and showed a low brain Kp value but was not orally bioavailable.
This extremely low bioavailability of compound 4a was thought to result from its zwitterion structure.
Introduction of a chlorine substituent onto the indole ring produced no improvement in bioavailability
(4b). The other indole carboxylic acid derivatives were all orally inactive (data not shown). We concluded
that introduction of a carboxylic acid moiety on the morphinan scaffold was an ineffective strategy for
development of opioid antagonists in light of the poor oral bioavailability of this series of compounds.
Next, the 7-acyl derivatives 6 also had dual affinities for opioid receptors but were slightly μ-selective,
unlike the indole carboxylic acids. These derivatives showed extremely high clearance and poor
bioavailability. Additionally, they had high brain Kp values (6a: 1.1, 6b: 1.7).
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The results of the 6,7-fused heterocycles are shown in Table 1. Pyrazole 7 showed moderate
bioavailability and a comparatively low brain Kp value, but its value was not lower than our preriminary
criteria (brain Kp value: <0.1). Pyrimidine 8 showed good bioavailability and a moderately low brain Kp
value. The 6,7-Fused heterocycles were all slightly δ-selective antagonists. The compounds shown in
Table 1 did not achieve both bioavailability and low brain Kp.

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Table 1. SAR study of morphinan derivatives
Conc. in
Comp.No μ (Ki:nM)*1 δ (Ki:nM)*2 MS h, r (%) *3 CL*4 BA *5
brain Kp*6 brain
PSA*8
(ng/mL) *7
0.023
0.032
5.8
18
0.62
1
98, 97
97, 100
95, 80
85, 46
98, 81
92, 58
71.8
18.1
233
313
199
220
0.1
0.2
4
0.03
0.03
1.1
106
106
83
4a
4b
6a
6b
7
19
0.95
1.4
24
31
9.9
1.2
2.1
6.4
26.9
42.5
1.7
6.5
83
0.25
0.31
2.2
82
8.6
4.6
105
8
2
3
*
1, 2 Recombinant human μ-opioid receptors (produced in CHO-K1 cells) and δ-opioid receptors
(produced in HEK-293 cells); the radioligands [3H]- [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO)
(for μ-opioid receptors), [3H]- [D-Ala2, D-Leu5]-enkephalin (DADLE) (for δ-opioid receptors).
*3Metabolic stabilities were evaluated by measuring the remaining % of substrates (0.5uM) after 0.5 hour
incubation with human or rat microsomes. *4, 5, 6Compounds were evaluated in cassette dosing. Usually 2
to 5 compounds (1mg/kg) were orally administered simultaneously and, then evaluated. CL: total
clearance (mL/min/kg); BA: bioavailability (%); brain Kp: ratio of the concentrations in brain tissue and
in the blood. *7Concentrations in brain at Cmax in oral adiministration. *8PSA: polar surface area (Å2)
calculated by MOE. PSA value of NTI is 62.
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6
7
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9
10
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12
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We found that the 7-Acyl derivatives 6a and 6b were chemically unstable and easily converted to a
mixture of the 14-O-acyl form and the 7-acyl form. They were produced from intramolecular
rearrangement (Figure 2). In compound 10, polar hydroxy group on 14 position was masked by acyl
group. So, compound 10 could pass BBB more easily than naltrexone and compound 6. This would
be the reason why 7-acyl derivatives 6a and 6b have much higher brain Kp values than we expected.
Next, we designed chemically stable 7-carboxamide derivatives, 9, because acyl rearrangements are
well-known reactions in some chemistries,14 especially sugar chemistry,14a but carboxamide
rearrangements are uncommon.15 More importantly, carboxamides have larger PSA values than
corresponding acyl derivatives.

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Figure 2. Structure-based design of 7-carboxamide derivatives 9
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The 7-carboxamide derivatives, 9, were synthesized from the 7-ethoxycarbonylnaltrexone 13 derived
from 12,16 and excess amines with microwave irradiation following acidic hydrolysis of intermediates,
enamino-carboxamides (method A). These 7-carboxamide derivatives were revealed to be chemically
stable, as we expected. After 24 hour incubation in plasma at 37 °C, 7-acyl derivatives were unstable
(remaining % values were <20%) but 7-carboxamides were generally stable (remaining % values were
>80%).
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9
10
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Scheme 4. Reagents and conditions for the synthesis of the 7-carboxamide derivatives 9 (method A): (a)
H2, Pd/C, EtOH, rt, 96%; (b) 1) R3NHR4, Et3N, methoxyethanol, 180 °C, microwave irradiation; 2) 2M
HCl, rt, 1h, 9a: 68%, 9b: 34%, 9c: 11%, 9d: 41%.
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15

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The results for the 7-carboxamide derivatives (9a–d) are shown in Table 2. Compounds 9a and 9b
showed high affinities to opioid receptors and good metabolic stabilities, moderate clearances, good
bioavailability, and especially, low brain Kp values. (In both cases, neither compound was detected in
brain tissues.) Lipophilic amines, such as the benzylamine (9c) and the secondary cyclic amine (9d)
showed poorer metabolic stability, slightly higher clearance, and higher brain Kp values than those of 9a
and 9b.
Table 2. Preliminary SAR results of morphinan-7-carboxamide derivatives
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Conc.
Comp. No
R3
R4
μ (Ki:nM) δ (Ki:nM) MS h, r (%) CL
BA
brain Kp in brain
(ng/mL)
PSA
ND*2
ND
12
H
H
H
i-Pr
Ph
5.2
4.1
1.1
4
7.4
20
95, 88
89, 78
94, 14
99, 24
41
50
57
46
18
NC*1
NC
90
90
90
83
9a
9b
9c
9d
36
Bn
16
61
0.17
0.22
3.0
-(CH2)4-
7.4
102
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12
13
14
15
See footnotes of Table 1.
*1 NC: not calculated. *2 ND: not detected.
Exploratory structure-activity relationship studies of the morphinans led to discovery of a new
chemotype, the 7-carboxamide derivatives 9, which showed high affinities for µ- and δ-opioid receptors,
good pharmacokinetics profiles, and most importantly, extremely low brain Kp values.

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Encouraged by these results, we began further optimization of the 7-carboxamide derivatives 9. We
designed compounds which had larger PSA values than those of 9a and 9b. In further modification
studies, another useful synthetic method (method B) for 7-carboxamide derivatives had to be developed,
as described in Scheme 5. The enol OH of 12 was protected with a benzyl group by the Mitsunobu
reaction to give a dibenzyl ether 14. The dibenzyl ether 14 was hydrolyzed to afford the carboxylic acid
15. The acid 15 was treated with amines under general amidation conditions to give protected amides 16.
Finally, the protecting groups were removed by hydrogenation or treatment with BBr3 to give the
7-carboxamide derivatives 9.
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Scheme 5. Reagents and conditions for the synthesis of the 7-carboxamide derivatives 9 (method B): (a)
benzyl alcohol, ADDP, nBu3P, THF, -10 °C, quant; (b) 4M KOH aq., MeOH, 50 °C, 77%; (c) R4-NH2,
WSCD·HCl, HOBt, DMF, rt, 38 to 83%; (d) H2, Pd(OH)2, MeOH, rt, (or BBr3, CH2Cl2, rt to 40 °C); 30 to
86%.
12
13
14
15
16
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The results from the 7-carboxamide derivatives (9e–n) are shown in Table 3. Several compounds with
nanomolar affinity for µ- and δ-opioid receptors were obtained, which showed good to moderate
pharmacokinetics profiles and very low brain Kp values.

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Table 3. Optimizations of 7-carboxamide derivatives
Conc. in
Comp. No
R4
μ (Ki:nM)
δ (Ki:nM) MS h, r (%)
CL
BA
brain Kp brain
PSA
(ng/mL)
5.1
16.5
46.1
1.6
3.99
11.8
9.8
101, 103
NT*1
25
28
30
15
27
29
20
8.5
25
28
68
0.08
0.04
0.06
0.01
0.05
0.04
0.03
0.03
0.05
0.04
119
130
125
157
115
130
130
116
102
105
9e
9f
0.52
11
0.055
1.3
100, 103
104, 99
NT
9g
9h
9i
93.6
19.4
7.3
5.5
0.77
3.4
11
0.018
0.21
0.29
1.3
18
5.8
92, 99
73, 76
103, 92
98, 97
93, 86
9j
1.1
0.91
11.1
6.8
29
9k
9l
5.1
12
1.3
9.8
55
5.6
9m
9n
2.4
18.9
13
0.56
3
4
5
6
See footnotes of Table 1.
*1 NT: not tested.
Among these 7-carboxamide derivatives, four compounds (9a, 9b, 9g, and 9k)17 were selected for

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further evaluation. They were evaluated for in vivo antagonism of opioid-induced emesis/vomiting in the
ferret,18 against opioid-induced constipation in the rat19, and against the analgesic effects of morphine in
the rat20. The results are shown in Table 4. All compounds reversed constipation and reduced emetic
effects. Two compounds produced no antagonism of opioid analgesic activity. Among those examined
further, compound 9k antagonized both emetic effect and constipation effect at 0.03mg/kg (po), and its
safety margin was quite large. These efforts led to the discovery of clinical candidate 9k, naldemedine
(S-297995), for the treatment of opioid-induced adverse effects.
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Table 4. Evaluation studies of selected compounds
MNTX
Compound No.
9a
9b
9g
9k
μ: 3.4
μ: 1.0
μ: 1.6
μ: 1.13
μ: 5.48
Binding affinity (Ki: nM)
δ:
δ: 2.0
μ: 6.2
δ: 3.8
δ: 6.8
μ: 3.2
δ: 3.6
δ: 9.8
μ: 4.1
δ: 7.6
δ: 0.91
μ: 0.05
δ: 0.37
3460
μ: 56
Functional activity (Ke: nM)*1
δ:
1080
0.69
(SC*2)
Anti emetic effect (ED50:
mg/kg)18
0.04
0.57
10.65
266
0.04
0.99
16.54
413
0.026
0.57
0.03
0.03
Anti constipation effect (ED50:
mg/kg)19
4.5 (SC)
Anti analgegic effect (ED50:
mg/kg)20
>100
>3846
>30
NT*3
Margin between anti emetic
and anti analgesic activity
Margin between anti
constipation and anti analgegic
activity
>1000
-
19
17
>175
>500
-
10
11
12
13
*1 Antagonist activities were evaluated by [35S]- guanosine 5'-O-[gamma-thio]triphosphate (GTPγS)
binding assay. *2 SC: subcutaneous injection *3 NT: not tested.

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Acknowledgements
We thank Drs. Tsutomu Suzuki (Hoshi University School of Pharmacy and Pharmaceutical Sciences) and
Koji Kawai (Toray Industries, Inc.) for their helpful advices. Drs. Shozo Takechi, Akira Kato, Gaku
Sakaguchi, Yasuyoshi Iso, Yasunobu Ishihara, and Takuko Sawada are acknowledged for project
management.
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Ishihara, Y. WO 2007/043518. c) Smith, H. S.; Laufer, A. Eur. J. Pharmacology, 2014, 722, 67.
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9a) Movantik (naloxegol) tablets [prescribing information]. Wilmington, DE: AstraZeneca
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N. Engl. J. Med., 2014, 370, 2387.
10) Portogeese, P. S.; Sultana, M.; Takemori, A. E. European J. Pharmacol. 1988, 146, 185
11) Nagase, H.; Mizusuna, A.; Kawai, K.; Nakatani, I. WO09407896
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13) Nagase, H.; Portogheese, P. S. J. Org. Chem. 1990, 55, 366.
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14a) Reese, C. E.; Trentham, D. R. Tetrahedron Lett., 1965, 29, 2467. b) Cockman, S. J.; Joll, C. A.;
Mortimer, B. C.; Redgrave, T. G.; Stick, R. V. Aust. J. Chem., 1990, 43, 2093. c) Skwarczynski, M.; Kiso,
Y. Current Medicinal Chemistry, 2007, 14, 2813. d) Camilleri, P.; Buch, A.; Soldo, B.; Hutt, A. J.
Xenobiotica, 2017, Ahead of Print.
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15) Hayashida, K.; Fujii, H.; Hirayama, S.; Nemoto, T.; Nagase, H. Tetrahedron, 2011, 67, 6682.
16) Fujii, H.; Hirano, N.; Uchiro, H.; Kawamura, K.; Nagase, H. Chem. Pharm. Bull. 2004, 52, 747.
17) NMR data of compound 9a : 1H-NMR (300 MHz, DMSO-d6) δ 0.12-0.15 (m, 2H), 0.44-0.53 (m, 2H),
0.83 (m, 1H), 1.02 (d, J = 6.6 Hz, 3H), 1.08 (d, J = 6.6 Hz, 3H), 1.41 (d, J = 11.4 Hz, 1H), 1.85 (d, J =
15.6 Hz, 1H), 2.04-2.62 (m, 7H), 3.04 (d, J = 18.6 Hz, 1H), 3.24 (m, 1H), 3.96 (m, 1H), 4.71 (s, 1H), 4.74
(s, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 7.40 (br d, J = 7.2 Hz, 1H), 9.16 (s, 1H), 14.50
(s, 1H).
NMR data of compound 9b: 1H-NMR (300 MHz, DMSO-d6) δ 0.10-0.24 (m, 2H), 0.45-0.60 (m, 2H),
0.89 (m, 1H), 1.45 (d, J = 11.1 Hz, 1H), 1.70-3.40 (m, 10H), 4.78 (s, 1H), 4.82 (s, 1H), 6.54 (d, J = 8.4 Hz,
1H), 6.58 (d, J = 8.4 Hz, 1H), 7.05 (m, 1H), 7.29 (t, J = 7.8 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 9.14 (s, 1H),
9.24 (br s, 1H), 13.90 (br s, 1H).
NMR data of compound 9g: 1H-NMR (300 MHz, DMSO-d6) δ 0.12-0.14 (m, 2H), 0.46-0.51 (m, 2H),
0.85 (m, 1H), 1.06-1.09 (m, 2H), 1.35-1.36 (m, 2H), 1.41 (d, J = 11.7 Hz, 1H), 1.86 (d, J = 15.6 Hz, 1H),
2.17-2.61 (m, 7H), 3.03 (d, J = 18.3 Hz, 1H), 3.17 (d, J = 6.0 Hz, 1H), 3.56 (s, 3H), 4.74 (s, 1H), 4.77 (brs,
1H), 6.51 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 9.17 (brs, 1H), 14.1 (brs, 1H). A proton (OH) was

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not observed.
Experimental procedure for preparation of compound 9k: The synthetic method and NMR data are as
follows. Acid 15 (500 mg, 0.884 mmol) was dissolved in CH2Cl2 (5 mL). To this solution, WSCD·HCl
(203 mg, 1.06 mmol), HOBt (143 mg, 1.06 mmol), 2-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-amine
(212 mg, 0.884 mmol), and Et3N (0.308 mL, 2.21 mmol) were added, and the mixture was stirred at rt
overnight. The reaction mixture was poured into cold saturated aqueous NaHCO3. The product was
extracted by AcOEt twice. The combined organic layer was washed with brine. The organic layer was
separated and dried over Na2SO4, filtered and evaporated to give a crude residue. The residue was
purified using silica gel chromatography by eluting with CHCl3: MeOH = 100:1~30:1 to give the
precursor of 9k as a yellow foam (431 mg, 64.9%). The precursor (430 mg, 0.573 mmol) was dissolved in
CH2Cl2 (4 mL). To this solution was added BBr3 (1.0M solution in CH2Cl2; 1.72 mL) at rt. The mixture
was stirred at rt for 2 hours and treated with BBr3 (1.0M solution in CH2Cl2; 1.72 mL) again. The reaction
was stirred at rt for 1 hour, and then at 40 °C for 1 hour. After cooling to rt, the reaction mixture was
poured into cold saturated aqueous NaHCO3. The products were extracted twice with EtOAc. The
combined organic layer was washed with brine. The organic layer was separated and dried over Na2SO4,
filtered and evaporated to give a crude residue. The residue was purified using silica gel chromatography
by eluting with CHCl3: MeOH = 50:1~20:1 to yield compound 9k as a colorless solid (98 mg, 30%).
NMR data of p-TsOH salt of 9k; 1H-NMR (300 MHz, DMSO-d6) δ 0.35-0.55 (2H, m), 0.55-0.80 (2H, m),
0.95-1.15 (1H, m), 1.60-1.75 (1H, m), 1.70 (6H, s), 2.10 (1H, d, J=14.7 Hz), 2.29 (3H, s), 2.40-2.60 (2H,
m), 2.60-2.75 (1H, m), 2.90-3.00 (1H, m), 3.07 (2H, br d, J=12 Hz), 3.25-3.50 (2H, m), 3.95 (1H, d, J=5.1
Hz), 4.94 (1H, s), 6.56 (1H, s), 6.69 (2H, ABq.), 7.11 (2H, d, J=8.4 Hz), 7.45-7.49 (2H, m), 7.53-7.60 (3H,
m), 7.96-7.99 (2H, m), 8.12 (1H, s), 8.95 (1H, br s), 9.44 (1H, s), 13.37 (1H, s).
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18) Evaluation of the test compound antagonism of morphine-induced emesis/vomiting in the ferret.
19) Evaluation of the test compound antagonism of constipation produced by morphine-induced

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inhibition of small intestinal transit in the rat.
20) Evaluation of test compound antagonism of morphine analgesia in the rat tail-flick test.
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We discovered a new chemotype, 7-carboxamide morphinan derivatives as opioid
antagonist.
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This chemotype is suitable for acting on peripherally.
From our results, compounds which have over 100 of PSA values are difficult to
pass BBB.
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Naldemedine showed dual actions in one dose, inhibiting constipation and
nausea/vomiting induced by opioids.

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Discovery of naldemedine: A potent and
orally available opioid receptor antagonist
for treatment of opioid-induced adverse
effects
Masanao Inagaki, Masaharu Kume, Yoshinori Tamura, Shinichiro Hara, Yoshihisa Goto, Haga Nobuhiro,
Tsuyoshi Hasegawa, Takashi Nakamura, Katsumi Koike, Shuuichi Oonishi, Toshiyuki Kanemasa, Hiroyuki Kai