Discovery of N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol and -phenyl carboxamide series of μ-opioid receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2017.04.092

Gastrointestinal dysfunction as a consequence of the use of opioid analgesics is of significant clinical concern. First generation drugs to treat these opioid-induced side-effects were limited by their negative impact on opioid receptor agonist-induced analgesia. Second generation therapies target a localized, peripherally-restricted, non-CNS penetrant drug distribution of opioid receptor antagonists. Herein we describe the discovery of the N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol and -phenyl carboxamide series of μ-opioid receptor antagonists. This report highlights the discovery of the key μ-opioid receptor antagonist pharmacophore and the optimization of in vitro metabolic stability through the application of a phenol bioisostere. The compounds 27a and 31a with the most attractive in vitro profile, formed the basis for the application of Theravance Biopharma's multivalent approach to drug discovery to afford the clinical compound axelopran (TD-1211), targeted for the treatment of opioid-induced constipation.

Full text of DOI:10.1016/j.bmcl.2017.04.092

Accepted Manuscript
Discovery of N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol and -
phenyl carboxamide series of μ-Opioid Receptor Antagonists
Lan Jiang, David T. Beattie, John R. Jacobsen, Samuel Kintz, Glenmar P.
Obedencio, Daisuke Saito, Ioanna Stergiades, Ross G. Vickery, Daniel D. Long
PII:
S0960-894X(17)30481-X
http://dx.doi.org/10.1016/j.bmcl.2017.04.092
BMCL 24945
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 March 2017
29 April 2017
30 April 2017
Please cite this article as: Jiang, L., Beattie, D.T., Jacobsen, J.R., Kintz, S., Obedencio, G.P., Saito, D., Stergiades,
I., Vickery, R.G., Long, D.D., Discovery of N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol and -phenyl
carboxamide series of μ-Opioid Receptor Antagonists, Bioorganic & Medicinal Chemistry Letters (2017), doi:
http://dx.doi.org/10.1016/j.bmcl.2017.04.092
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Bioorganic & Medicinal Chemistry Letters
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Discovery of N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol and -
phenyl carboxamide series of µ-Opioid Receptor Antagonists
Lan Jiang, David T. Beattie, John R. Jacobsen, Samuel Kintz, Glenmar P. Obedencio, Daisuke Saito,
Ioanna Stergiades, Ross G. Vickery, Daniel D. Long*
Theravance Biopharma US, Inc., 901 Gateway Blvd, South San Francisco, CA 94080
ARTICLE INFO
ABSTRACT
Article history:
Received
Gastrointestinal dysfunction as a consequence of the use of opioid analgesics is of significant
clinical concern. First generation drugs to treat these opioid-induced side-effects were limited by
their negative impact on opioid receptor agonist-induced analgesia. Second generation therapies
target a localized, peripherally-restricted, non-CNS penetrant drug distribution of opioid receptor
antagonists. Herein we describe the discovery of the novel N-substituted-endo-3-(8-aza-
bicyclo[3.2.1]oct-3-yl)-phenol and -phenyl carboxamide series of µ-opioid receptor antagonists.
This report highlights the discovery of the key µ-opioid receptor antagonist pharmacophore and
the optimization of in vitro metabolic stability through the application of a phenol bioisostere.
The compounds 27a and 31a, with the most attractive in vitro profile formed the basis for the
application of Theravance Biopharma’s multivalent approach to drug discovery to afford the
clinical compound axelopran (TD-1211), targeted for the treatment of opioid-induced
constipation.
Revised
Accepted
Available online
Keywords:
µ-Opioid receptor antagonist;
Multivalent approach;
Peripherally-restricted;
Opioid-induced constipation.
2017 Elsevier Ltd. All rights reserved.
The family of G-protein-coupled opioid receptors, µ, δ and κ
mediate a range of behavioral and homeostatic functions
throughout the human body. Small molecule opioid receptor
modulators have thus received considerable attention as potential
therapeutics to treat disorders of nociception, food intake,
respiration, reward, and gastrointestinal (GI) motility.1 In
particular, µ-opioid receptor agonists such as morphine continue
to play a critical role in the treatment of chronic malignant and
non-malignant pain principally as a result of their activity within
the central nervous system (CNS).2 However, despite their
effectiveness, opioid receptor agonists are associated with a
number of undesirable, predominantly centrally-mediated side
effects, including the development of analgesic tolerance and
physical dependence, sedation, and respiratory depression.3
Significant GI dysfunction due to opioids is largely peripherally
mediated and is categorized as opioid bowel dysfunction (OBD).4
The most recognized feature of OBD is opioid-induced
constipation (OIC) which is a result of opioid receptor agonist
mediated inhibition of rhythmic contractions associated with both
GI transit and secretion. OIC is not prone to tolerance and often
leads to a range of debilitating symptoms (reported to impact up
to 60% of chronic opioid users) which can be so severe as to
compromise compliance in maintaining therapeutic pain control.5
Until recently, OIC patients were inadequately treated with a
combination of laxatives and dietary changes. The strategy of
blocking peripheral enteric opioid receptors with first generation
antagonists such as naloxone (1) and naltrexone (2), Figure 1, has
demonstrated clinical effects on OIC. However, these readily
CNS penetrant compounds attenuate opioid-induced analgesia
and provoke opioid behavioral withdrawal syndrome.6
Figure 1. Opioid receptor antagonists: 1-2 CNS penetrant; 3-5 peripherally
restricted.
Second generation approaches have therefore focused on a
localized drug distribution targeting non-CNS penetrant,
peripherally-restricted opioid receptor antagonists which have no
impact on beneficial agonist analgesia, but which selectively
alleviate the GI dysfunction.7 Three peripherally-selective opioid
receptor antagonists have been approved by the FDA for the
treatment of opioid-related bowel dysfunction, Figure 1.
Alvimopan (Entereg®) (3) was approved in the US in 2008 as an
oral treatment to accelerate upper and lower gastrointestinal
recovery following partial large or small bowel resection surgery
with primary anastomosis in
a
hospital setting.8 Methyl
___________
* Corresponding author.
E-mail address: dlong@theravance.com (D.D. Long).

naltrexone (Relistor®) (4), approved for subcutaneous dosing
(2008)9 and as an oral formulation (2016),10 and naloxegol
(Movantik®) (5),11 approved in 2014 as an oral formulation, are
both indicated for the treatment of OIC for adult patients with
chronic non-cancer pain. In addition, the non-opioid ligand,
Amitiza® (lubiprostone), a Cl-channel activator, was approved in
2013 for the treatment of constipation caused by opioids in
patients with chronic, non-cancer pain.12
pharmacophore (B) as highlighted. However, when the
predominant isomer of core mixture 11a,b was separated by
crystallization, subsequent single crystal x-ray diffraction
analysis16 revealed it to be the phenyl-endocyclic compound 11a,
Figure 3.17
Our own approach to identify second generation, peripherally-
restricted opioid receptor antagonists began with our initial
discovery
of
novel
N-substituted-endo-3-(8-aza-
bicyclo[3.2.1]oct-3-yl)-phenol and -phenyl carboxamide series of
µ-opioid receptor antagonists which are described herein.
Alvimopan (3) is derived from the trans-3,4-dimethyl-4-(3-
hydroxyphenyl)piperidine class of opioid receptor antagonists in
which the described pharmacophore is proposed to be due to the
lowest energy phenyl-equatorial conformation of the core
structure (A), Figure 2; the R-group N-substituent is reported to
principally affect the magnitude of receptor binding of the
ligand.13 Our design considered novel exo-3-(8-aza-
bicyclo[3.2.1]oct-3-yl)-phenol core (B) as an overlapping opioid
receptor antagonist pharmacophore.
Figure 3. X-ray crystal structure of the hydrobromide salt of compound 11a.
To further explore this structural insight as well as expand
upon the discovery of the potent opioid antagonist profile, a
series of both endo- and exo-N-substituted-3-(8-aza-
bicyclo[3.2.1]oct-3-yl)-phenol compounds were prepared
according to an alternative synthetic route as detailed in Schemes
2 and 3, Table 1. The separation of the isomers of core 11a,b was
achieved by reverse phase preparative HPLC and reaction with a
set of alkyl bromides afforded pure endo isomers 12a, 17-23a as
well as pure exo isomers 12b, 17-23b.
Figure 2. Opioid receptor antagonist pharmacophore.
Scheme 1 details the first synthesis towards the desired core
and a representative N-substituted compound.14 Interestingly,
reduction of styrene 9 resulted in a 4:1 mixture of isomers 10a,b
which upon O-demethylation and subsequent alkylation of the
crude material 11a,b afforded the isomeric 4:1 mixture 12a,b,
which excitingly, exhibited high binding affinity (pKi = 9.8) and
weak intrinsic activity (IA) consistent with an antagonist effect
(IA = 22% of the maximum response achieved by DAMGO in a
GTP binding assay) at the human recombinant µ-opioid receptor,
Table 1.15
Scheme 2. Reagents and conditions: (i) (a) H2, Pd/C, Boc2O, EtOAc, 99%,
(b) NaHMDS, PhN(OTf)2, THF, -78°C, 82%; (ii) 3-benzyloxyphenyl-boronic
acid, PdCl2(PPh3)2, 2M aq. Na2CO3, THF, 80°C, 85%; (iii) (a) H2, Pd(OH)2,
EtOH, (b) TFA, DCM, (c) separation by RP-HPLC; (iv) 3-carbamoylphenyl-
boronic acid, PdCl2(PPh3)2, 2M aq. Na2CO3, THF, 80°C, 55%.
Scheme 3. Reagents and conditions: (i) RBr, DIPEA, EtOH, 65°C.
Scheme 1. Reagents and conditions: (i) aq. HCl, BnNH2, 1,3-
acetonedicarboxylic acid, Na2HPO4, 47%; (ii) CeCl3, 3-methoxyphenyl
magnesium bromide, THF, 0°C, 93%; (iii) 6N aq. HCl, 70°C, 91%; (iv) H2,
Pd(OH)2, EtOH, 66%, ≤ 4:1 mixture by 1H NMR; (v) BBr3, DCM, -78°C to
0°C, 69%; (vi) 1-bromo-3-phenylpropane, DIPEA, EtOH, 60°C, 29%.
In addition to binding affinity and functional IA at the µ-
opioid receptor the binding profile at both the human δ- and
guinea pig κ-opioid receptors was also determined along with an
in vitro measure of metabolic stability upon incubation with rat,
dog and human liver microsomes (RLM, DLM and HLM). The
high binding affinity and weak IA profile at the µ-opioid receptor
was confirmed for the single N-(CH2)3Ph endo isomer 12a (pKi =
It was assumed that the favorable activity was due to the
major component of the mixture, which was thus expected to be
the exo isomer 12b, consistent with the opioid antagonist

10.0, IA = 22%); interestingly, the corresponding exo isomer 12b
displayed a significantly lower affinity and higher IA consistent
with a partial agonist profile (pKi = 8.3, IA = 60%). In addition, it
was determined that the endo compound 12a had approximately
equal µ-opioid receptor affinity as for the κ-receptor (pKi = 10.0)
and approximately 10x greater affinity compared with the δ-
receptor (pKi = 9.1). For all the examples highlighted, the general
trend was that the endo isomers 12a, 17-23a displayed a 1.3-1.9
log higher binding affinity for the µ-, δ- and κ-opioid receptors
(with a similar µ-, δ- and κ-selectivity as described for 12a)
relative to the corresponding exo isomers 12b, 17-23b. In
addition, the IA was consistently higher for the exo isomers. For
the matched pairs 19a, 19b (N-(CH2)3OPh) and 23a, 23b (N-
(CH2CH(OH)CH2Ph), the endo isomers 19a and 23a were close
to pure neutral antagonists (IA = 9% and 1%, respectively) whilst
the exo isomers 19b and 23b were characterized as almost a full
agonist and partial agonist (IA = 85% and 36%, respectively).
The exception to this IA trend were the endo, exo isomers 20a
and 20b with the N-4-tert-butyl-benzyl substituent which were
both full agonists (IA = 100% and 97%, respectively), in contrast
with the closely related N-2,6-difluoro-benzyl isomers 18a and
18b (IA = 36% and 48%, respectively). With regards to
metabolic stability, all of the phenol compounds 12a, 17-23a and
12b, 17-23b had a short half-life (t1/2 < 20 min) in both RLM and
DLM. This general instability was also evident in HLM with the
exception of the exo isomers 18b, 20b and 23b which exhibited
acceptable half-lives (t1/2 = 75, 67 and 90 min, respectively). The
poor metabolic stability of the µ-opioid receptor antagonist endo
phenol isomers precluded their further development. At this time,
a patent application from Pfizer indicated a similar liability with
the related trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine
class of compounds, and it was ascribed to CYP2D6 metabolism
of the electron-rich phenol core.18 With this in mind, we explored
phenyl primary carboxamides as phenol isosteres.19 The synthesis
of the equivalent endo and exo N-substituted 3-(8-aza-
bicyclo[3.2.1]oct-3-yl)-carboxamide compounds is described in
Schemes 2 and 3. The metabolic stability across all species was,
in general, significantly improved for both the endo and exo
carboxamide isomers relative to their equivalent phenol
compounds. For the endo isomers 24a-31a, which were of most
interest, the t1/2 in HLM was >90 min in all examples with the
exception of 25a (t1/2 = 40 min). Additionally, there was minimal
change in either the binding affinities at µ-, δ- and κ-opioid
receptors, or the IA at the µ-opioid receptor comparing the
carboxamide to phenol endo isomers, 12a versus 24a, and 17-23a
versus 25-31a, thus confirming the success of the bioisosteric
replacement of phenol to phenyl-carboxamide for this class of
opioid-receptor antagonist.20 The most interesting compounds
were those with the N-(CH2)3OPh and (N-(CH2CH(OH)CH2Ph)
substituent, 27a and 31a, respectively, which were both high
affinity µ-opioid receptor antagonists with a close to neutral IA
and acceptable HLM stability (pKi = 9.7 and 9.6, IA = 0 and 3%,
HLM t1/2 >90 and >90 min, respectively). These compounds and
the core endo phenyl-carboxamide scaffold 16a from which they
are derived formed the basis for the application of Theravance
Biopharma’s multivalent approach to drug discovery21 to afford
the peripherally-restricted µ-opioid receptor antagonist,
axelopran (TD-1211) 32,22 Figure 3, which will be described in
detail in a future publication. Axelopran has successfully
completed three Phase 2, proof-of-concept clinical trials in
patients with OIC and is currently classified as Phase 3 ready. It
was generally well tolerated and demonstrated a clinically
meaningful response to therapy.23
Figure 4. Compound 27a and Axelopran (TD-1211) 32.
In summary, a de novo design of a µ-opioid receptor
antagonist scaffold based on the reported trans-3,4-dimethyl-4-
(3-hydroxyphenyl)piperidine phenyl equatorial pharmacophore
of alvimopan 3, afforded the novel N-substituted-endo-3-(8-aza-
bicyclo[3.2.1]oct-3-yl)-phenol series of compounds 12a and 17-
23a which as exemplified by the defining crystal structure of the
core 11a, adopt a phenyl axial conformation. This endo series in
general, displayed a high affinity for the µ-, δ- and κ-opioid
receptors and a functional activity at the µ-opioid receptor
consistent with an antagonist profile, in contrast to the related
series of novel exo isomers 12b and 17-23b which are less potent
and have a higher IA. Whilst all of the endo phenol compounds
have poor overall metabolic stability across RLM, DLM and
HLM, bioisosteric replacement to the novel N-substituted-endo-
3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenyl carboxamide series of
compounds 24-31a afforded comparable binding affinities and
functional activity coupled with improved metabolic stability,
particularly in HLM. Compounds 27a and 31a are key highlights
as high affinity µ-opioid receptor antagonists exhibiting a close
to neutral IA and acceptable HLM stability. This novel series of
N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenyl
carboxamide µ-opioid receptor antagonists formed the basis for
the subsequent discovery of the clinical compound axelopran,
targeted for the treatment of OIC.
Acknowledgments
The authors would like to thank Dr. Adam Hughes and Dr.
Tom Lam from Theravance Biopharma US, Inc. for their
assistance in reviewing this article; and Dr. Sean Dalziel and Dr.
Venkat Thalladi for work related to crystal structure
determination.

Stereo-
chemistry
RLM
t1/2 (min)
DLM
t1/2 (min)
HLM
t1/2 (min)
µ
pKi a
δ
κ
pKi
µ
IAb
Compound
Series
R
a
pK a
i
Alvimopan
-
-
-
-
9.5
8.1
9.8
10
8.3
6.3
8.9
9.1
7.2
8.9
6.7
8.6
6.6
8.5
6.3
6.8
5.6
6.5
5.3
8.8
7.2
8.4
7
8.3
7.7
-
-6
24
22
22
64
24
48
26
62
28
38
36
48
26
19
9
>90
>90
-
>90
>90
-
>90
>90
-
Methyl naltrexone
-
-
12a,bc
12a
12b
24a
24b
17a
17b
25a
25b
18a
18b
26a
26b
19a
19b
27a
27b
phenol
-
(CH2)3Ph
endo
exo
endo
exo
endo
exo
endo
exo
endo
exo
endo
exo
endo
exo
endo
exo
10
8.1
9.8
-
2
2
15
phenol
8.3
9.9
7.8
9.6
7.7
9.4
7.5
7.8
6.2
7.5
5.9
10
2
2
27
(CH2)3Ph
>90
11
3
>90
18
2
>90
>90
10
phenyl-
carboxamide
9.6
7.6
9.4
phenol
2
9
2
(CH2)6CH3
>90
7
20
2
40
phenyl-
carboxamide
10
8.3
6.9
7.8
6.4
9.6
7.7
9.1
7.5
2
20
13
>90
>90
9
29
phenol
2
75
(CH2)-2,6-diF-Ph
26
74
2
>90
>90
25
phenyl-
carboxamide
phenol
8.5
9.7
8.2
85
0
2
2
20
(CH2)3OPh
2
7
>90
>90
phenyl-
carboxamide
95
2
6
20a
20b
28a
28b
21a
21b
29a
29b
22a
22b
30a
30b
23a
23b
31a
31b
endo
exo
10
8.7
10
9.3
7.5
8.8
6.7
7.6
6.1
7.1
6.7
9.3
7.7
8.7
6.4
8.2
6.6
8.4
6.3
10
8.5
10
7.5
9.1
7.1
8.5
-
100
97
92
73
26
97
0
2
2
5
7
16
67
phenol
(CH2)-4-tBu-Ph
(CH2)4-N-phthalimide
CH2(CO)cyclohexyl
CH2C(OH)CH2Ph
endo
exo
>90
>90
18
21
>90
>90
2
>90
>90
11
12
18
11
2
>90
>90
33
phenyl-
carboxamide
8
endo
exo
9.1
7.4
8.8
7.5
10
phenol
38
endo
exo
>90
>90
12
phenyl-
carboxamide
75
33
57
41
93
1
endo
exo
11
9.1
10
7.7
-
phenol
8.7
9.8
7.8
9.6
8
2
2
13
endo
exo
70
81
2
21
9
>90
>90
32
phenyl-
carboxamide
endo
exo
2
phenol
7.7
9.5
7.1
36
3
2
2
>90
>90
>90
endo
exo
9.6
7.5
31
14
>90
59
phenyl-
carboxamide
39
Table 1. aµ-, δ- and κ-opioid receptor binding pK values were determined using a [3H]-DPN radioligand binding assay with membranes prepared from CHO-K1
i
cells stably-transfected with human recombinant µ- and δ-opioid receptor and guinea pig κ-opioid receptor; bfunctional activities were determined using GTP
binding assays with [35S]-GTPγS in membranes prepared from CHO-K1 cells stably-transfected with the human recombinant µ-opioid receptor: the maximum
c
compound-evoked response (minus basal) is expressed as a percentage of the maximum response evoked by DAMGO; 12a,b is an approximate 4:1 mixture of
endo:exo isomers 12a and 12b, respectively.
Portenoy, R. K.; Rich, B. A.; Roberts, R. G.; Todd, K. H.; Miaskowski, C. J.
Pain 2009, 10, 113.
3 (a) Walsh, T. D. J. Pain. Symptom Manag. 1990, 5, 362; (b) Vanegas, G.;
Ripamonti, C.; Sbanotto, A.; De Conno, F. Cancer Nursing 1998, 21, 289.
References and notes
4 Brock, C.; Olesen, S. S.; Olesen, A. E.; Frokjaer, J. B.; Andresen, T.;
Drewes, A. M. Drugs 2012, 72, 1847.
5 Walters, J. B.; Montagnini, M. J. Opioid Management 2010, 66, 435.
6 (a) Culpepper-Morgan, J. A.; Inurrisi, C. E.; Portenoy, R. K.; Foley, K.;
Houde, R. W.; Marsh, F.; Kreek, M. J. Clin. Pharmacol.
1 Stein, C. Ann. Rev. Med. 2016, 67, 433.
2 (a) Walsh, T. D. Seminars in Oncology 2000, 27, 45; (b) Chou, R.;
Fanciullo; G. J.; Fine, P. G.; Adler, J. A.; Ballantyne, J. C.; Davies, P.;
Donovan, M. I.; Fishbain, D.A.; Foley, K.M.; Fudin, J.; Gilson, A. M.;
Kelter, A.; Mauskop, A.; O’Connor, P. G.; Passik, S. D.; Pasternak, G. W.;
Therap. 1992, 52, 90; (b) Pappagallo, M. Am. J. Surgery 2001, 182, 11S.

7 Diego, L.; Atayee, R.; Helmons, P.; Hsiao, G.; von Gunten, C. F. Expert
Opin. Investig. Drugs 2011, 20, 1047.
8 Beattie, D. T. Clin. Med.: Ther. 2009, 1, 199.
9 Rauck, R. L. Drugs 2013, 73, 1297.
10 https://shared.salix.com/shared/pi/relistor-pi.pdf
11 Garnock-Jones, K. P. Drugs 2015, 75, 419.
12 Jamal, M. M.; Adams, A. B.; Jansen, J.-P.; Webster, L. R. Am. J.
Gastroenterol. 2015, 110, 725.
13 (a) Le Bourdonnec, B.; Goodman, A. J.; Michaut, M.; Ye, H.-F.; Graczyk,
T. M.; Belanger, S.; Herbertz, T.; Yap, G. P. A.; DeHaven, R. N.; Dolle, R. E.
J. Med. Chem. 2006, 49, 7278; (b) Carroll, F. I.; Dolle, R. E. Chem. Med.
Chem. 2014, 9, 1638.
14 Long, D. D.; Jacobsen, J. R.; Jiang, L.; Saito, D. R.; Stergiades, I. US 2015
9,206,172 B2.
15 Compounds are classified: -5<IA<25 as antagonists, 25<IA<80 as partial
agonists, 80<IA<120 as full agonists
16 CCDC 1546551 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
17 The N-Boc derivative of mixture 11a,b was also selectively crystallized and
x-ray crystal structure analysis confirmed the major isomer to be the Ph-
endocyclic compound.
18 McHardy, S.; Liras, S.; Guediche, S.; Coe, J. W. US 2004/0204453 A1.
19 Wentland, M. P.; Lou, R.; Ye, Y.; Cohen, D. J.; Richardson, G. P.; Bidlack,
J. M. Bioorg. Med. Chem. Lett. 2001, 11, 623. Whilst an effective isostere for
cyclazocine, the primary carboxamide was at the time not deemed generally
applicable as it was ineffective when applied to morphine - Wentland, M. P.;
Lou, R.; Denhardt, C. M.; Duan, W.; Cohen, D. J.; Bidlack, J. M. Bioorg.
Med. Chem. Lett. 2001, 11, 1717. However subsequent examples of the
successful use of this isostere have been reported - Le Bourdonnec, B.;
Belanger, S.; Cassel, J. A.; Stabley, G.; DeHaven, R. N.; Dolle, R. E. Bioorg.
Med. Chem. Lett. 2003, 13, 4459.
20 The binding affinity for the phenyl carboxamide exo isomers is
approximately 0.5 log lower as compared to the phenol exo isomers.
21 (a) Long, D. D.; Aggen, J. B.; Christensen, B. G.; Judice, J. K.; Hegde, S.
S.; Kaniga, K.; Krause, K. M.; Linsell, M. S.; Moran, E. J.; Pace, J. L. J.
Antibiot. 2008, 61, 595; (b) Choi, S.-K.; Green, D.; Ho, A.; Klein, U.;
Marquess, D.; Taylor, R.; Turner, S. D. J. Med. Chem. 2008, 51, 3609; (c)
McKinnell, R. M.; Armstrong, S. R.; Beattie, D. T.; Choi S.-K.; Fatheree, P.
R.; Gendron, R. A. L.; Goldblum, A.; Humphrey, P. P.; Long, D. D.;
Marquess, D. G.; Shaw, J. P.; Smith, J. A. M.; Turner, S. D.; Vickery, R. G.
J. Med. Chem. 2009, 52, 5330; (d) Hughes, A. D.; Chin, K. H.; Dunham, S.
L.; Jasper, J. R.; King, K. E.; Lee, T. -W.; Mammen, M.; Martin, J.; Steinfeld,
T. Bioorg. Med. Chem. Lett. 2011, 21, 1354; (e) Jacobsen, J. R.; Choi, S.-K.;
Combs, J.; Fournier, E. J. L.; Klein, U.; Pfeiffer, J. W.; Thomas, G. R.; Yu,
C.; Moran, E. J. Bioorg. Med. Chem. Lett. 2012, 22, 1213; (f) Long, D. D.;
Armstrong, S. R.; Beattie, D. T.; Choi S.-K.; Fatheree, P. R.; Gendron, R. A.
L.; Goldblum, A. A.; Humphrey, P. P..; Marquess, D. G.; Shaw, J. P.; Smith,
J. A. M.; Turner, S. D.; Vickery, R. G. Bioorg. Med. Chem. Lett. 2012, 22,
4849; (g) Long, D. D.; Armstrong, S. R.; Beattie, D. T.; Choi, S.-K.;
Fatheree, P. R.; Gendron, R. A. L.; Genov, D.; Goldblum, A. A.; Humphrey,
P. P.; Jiang, L.; Marquess, D. G.; Shaw, J. P.; Smith, J. A. M.; Turner, S. D.;
Vickery, R. G. Bioorg. Med. Chem. Lett. 2012, 22, 6048; (h) Long, D. D.;
Frieman, B.; Hegde, S. S.; Hill, C. M.; Jiang, L.; Kintz, S,; Marquess, D. G.;
Purkey, H.; Shaw, J. P.; Steinfeld, T.; Wilson, M. S.; Wrench, K. Bioorg.
Med. Chem. Lett. 2013, 23, 939; (i) McKinnell, R. M.; Armstrong, S. R.;
Beattie, D. T.; Fatheree, P. R.; Long, D. D.; Marquess, D. G.; Shaw, J. P.;
Vickery, R. G. Bioorg. Med. Chem. Lett. 2013, 23, 4210; (j) Jacobsen, J. R.;
Aggen, J. B.; Church, T. J.; Klein, U.; Pfeiffer, J. W.; Pulido-Rios, T. M.;
Thomas, G. R.; Yu, C.; Moran, E. J. Bioorg. Med. Chem. Lett. 2014, 24,
2625; (k) McKinnell, R. M.; Klein, U.; Linsell, M. S.; Moran, E. J.; Nodwell,
M. B.; Pfeiffer, J. W.; Thomas, G. R.; Yu, C.; Jacobsen, J. R. Bioorg. Med.
Chem. Lett. 2014, 24, 2871; (l) Hughes, A. D.; Chen, Y.; Hegde, S. S.;
Jasper, J. R.; Jaw-Tsai, S.; Lee, T.-W.; McNamara, A.; Pulido-Rios, M. T.;
Steinfeld, T.; Mammen, M. J. Med. Chem. 2015, 58, 2609.
22 (a) Armstrong, S. R.; Campbell, C. B.; Richardson, C. L.; Vickery, R. G.;
Tsuruda, P. R.; Long, D. D.; Hegde, S. S.; Beattie, D. T. Naun. Schmi. Arch.
Pharmacol. 2013, 386, 471; (b) Tsuruda, P. R.; Vickery, R. G.; Long, D. D.;
Armstrong, Beattie, D. T. Naun. Schmi. Arch. Pharmacol. 2013, 386, 479.
23 (a) Vickery, R.; Schwertschlag, U.; Singla, N.; Webster, L.; Canafax, D. J.
Pain 2013, 14, S78; (b) Holder, R. M.; Rhee, D. Pharmacother. 2016, 36,
287.

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Discovery of N-substituted-endo-3-(8-aza-
bicyclo[3.2.1]oct-3-yl)-phenol and -phenyl
carboxamide series of µ-Opioid Receptor
Antagonists
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Lan Jiang, David T. Beattie, John R. Jacobsen, Samuel Kintz, Glenmar Obedencio, Daisuke Saito, Ioanna
Stergiades, Ross G. Vickery, Daniel D. Long*