Delta agonist hydroxy bioisosteres: The discovery of 3-((1-benzylpiperidin-4-yl){4-[(diethylamino)carbonyl]phenyl}amino)benzamide with improved delta agonist activity and in vitro metabolic stability

Article abstract of DOI:10.1016/j.bmcl.2009.09.068

We have investigated phenol replacements in a series of diaryl amino piperidine delta opioid agonists. From this study we have demonstrated that the hydroxy functional group can be replaced with a primary amide group, giving enhanced activity at the delta

Full text of DOI:10.1016/j.bmcl.2009.09.068

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5999–6003
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Delta agonist hydroxy bioisosteres: The discovery of 3-((1-benzylpiperidin-4-yl)
{4-[(diethylamino)carbonyl]phenyl}amino)benzamide with improved delta
agonist activity and in vitro metabolic stability
a
a
b
b
Andrew M. Griffin a, , William Brown , Christopher Walpole , Martin Coupal , Lynda Adam ,
*
Mylene Gosselin b, Dominic Salois b, Pierre-Emmanuel Morin b, Marie Roumi b
a Department of Medicinal Chemistry, AstraZeneca R&D Montréal, 7171 Frédérick-Banting, Ville St. Laurent, Québec, Canada H4S 1Z9
b Department of In vitro Biology and DMPK, AstraZeneca R&D Montréal, 7171 Frédérick-Banting, Ville St. Laurent, Québec, Canada H4S 1Z9
a r t i c l e i n f o
a b s t r a c t
Article history:
We have investigated phenol replacements in a series of diaryl amino piperidine delta opioid agonists.
From this study we have demonstrated that the hydroxy functional group can be replaced with a primary
amide group, giving enhanced activity at the delta receptor, increased selectivity versus mu and kappa as
well as improved in vitro metabolic stability.
Received 3 August 2009
Revised 15 September 2009
Accepted 17 September 2009
Available online 22 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Delta agonism
Bioisosteres
Metabolic stability
Three main opioid receptor subtypes have been shown to ex-
ist—mu, delta, and kappa.1 Current analgesics such as morphine
act at the mu receptor and while they produce pronounced analge-
sia they are also associated with undesired side effects such as tol-
erance, addiction, and respiratory depression. Initial investigation
of the delta receptor demonstrated that analgesia was produced
without the unwanted side effects of mu receptor agonists2 and re-
cently Adolor published information on their development delta
agonist, ADL5859, for pain management.2d The delta receptor has
been implicated in additional therapeutic areas. For example, a re-
cent report from Pfizer3 demonstrated that peripheral delta ago-
nists are effective in models of irritable bowel syndrome while a
report from Johnson and Johnson4 showed antidepressant and anx-
iolytic effects in rodent models with a series of 4-phenyl-4-[1H-
imidazol-2-yl]-piperdine delta agonists.
Within our own contributions to the development of non-pep-
tidic delta agonists, the previous Letter5 highlighted the discovery
of N,N-diethyl-4-[(3-hydroxyphenyl)(piperidin-4-yl)amino] benz-
amide derivatives 1 as potent and selective delta agonists (Fig. 1).
One of the most interesting compounds in this series, phenol 2
(Fig. 1), displayed potent agonism at the delta receptor and good
selectivity over the mu and kappa receptors, yet had suboptimal
metabolic stability as measured in human and rat liver micro-
somes. In this Letter, we report our studies aimed at improving
metabolic stability in this scaffold by investigating replacements
for the metabolically labile phenol group. Approaches to replace
the phenol group of several mu opioid ligands have been docu-
mented with varying degrees of success in the literature.6 In this
study, we demonstrate that the hydroxy functional group in our
delta agonists can be replaced with a primary amide group, giving
enhanced activity at the delta receptor, increased selectivity versus
mu and kappa as well as improved in vitro metabolic stability.
Syntheses of analogs where the hydroxy group is replaced with
alternative functional group are shown in Schemes 1–4. For all
derivatives, the diethyl amide and benzyl group were kept con-
stant and much of the chemistry relied on palladium mediated
N-arylation.7
Synthesis of aldehyde 4 was achieved using an acetal as a masked
aldehyde as shown in Scheme 1. Synthesis of acetal 3 was achieved
via arylation of 1-benzylpiperidin-4-amine with 2-(3-bromophe-
nyl)-1,3-dioxolane and BINAP8 as the phosphine ligand followed
by a second arylation using 4-bromo-N,N-diethylbenzamide and
xantphos9 as the ligand. The use of xantphos was essential for a good
conversion to acetal 3 (79% yield) as BINAP afforded poorer yields for
the second arylation (ꢀ30%). Cleavage of the acetal 3 under acidic
conditions afforded aldehyde 4, which was then converted to sec-
ondary alcohol 5 and ketone 6.
Primary amine 8 was synthesized in two steps as shown in
Scheme 2. Arylation of 1-benzylpiperidin-4-amine with 3-bro-
mobenzonitrile followed by a second arylation with 4-bromo-N,N-
diethylbenzamide was performed in a two-step, one pot reaction
* Corresponding author. Tel.: +1 514 832 3200; fax: +1 514 832 3232.
E-mail address: andrew.griffin@astrazeneca.com (A.M. Griffin).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.09.068

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A. M. Griffin et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5999–6003
O
O
N
N
N
X
N
N
OH
N
R
1
X = OH, OMe
R = alkyl, aromatic, heteroaromatic
2
Figure 1.
O
O
Et2N
NH2
N
Et2N
O
HN
N
O
O
N
N
N
N
b
a
O
c
H
O
3
O
4
O
Et2N
Et2N
OH
O
d
N
N
N
N
e
6
5
Scheme 1. Reagents and conditions: (a) 2-(3-bromophenyl)-1,3-dioxolane, Pd2(dba)3, BINAP, NaOtBu, toluene, 80 °C, 91%; (b) 4-bromo-N,N-diethylbenzamide, xantphos,
Pd2(dba)3, NaOtBu, toluene, 110 °C, 79%; (c) HCl, THF, 86%; (d) MeMgBr, THF, À78 °C to rt, 77%; (e) TPAP, NMO, CH2Cl2, 65%.
O
O
Et2N
NH2
N
Et2N
N
N
N
N
CN
a, b
c
NH2
7
8
Scheme 2. Reagents and conditions: (a) 3-bromobenzonitrile, Pd2(dba)3, BINAP, NaOtBu, toluene, 80 °C; (b) 4-bromo-N,N-diethylbenzamide, NaOtBu, toluene, 110 °C, 93%
over two steps; (c) CoCl2, NaBH4, MeOH, 41%.
to afford the bis arylated adduct 7 in 93% overall yield. The success of
BINAP for the double arylation is in contrast to the synthesis de-
scribed above in Scheme 1, which required xantphos as phosphine
ligand for the second arylation. Reduction of the nitrile group was
achieved using CoCl2 and sodium borohydride.10
Alcohol, amine, amide, and ester derivatives were synthesized
from aldehyde 4 as shown in Scheme 3 using standard chemical
transformations. Amino derivatives 19–22 were synthesized as
shown in Scheme 4 and once again made use of N-arylation
chemistry. Arylation of 1-benzylpiperidin-4-amine with 4-bromo-

A. M. Griffin et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5999–6003
6001
O
O
O
Et2N
Et2N
O
Et2N
O
N
N
N
O
OH
N
N
H
a
b
NR1R2
N
4
d
12
e
14, 15, 16
c
O
O
O
Et2N
Et2N
Et2N
N
N
O
N
N
N
N
OH
NR1R2
OMe
9
10, 11
13
Scheme 3. Reagents and conditions: (a) NaOCl2, NaH2PO4, tBuOH, H2O, 27%; (b) R1R2NH, pyBOP, iPr2NEt, DMF, 48–65%; (c) NaBH4, MeOH, 64%; (d) R1R2NH, NaCNBH3, MeOH,
32–44%; (e) TMSCHN2, MeOH, 58%.
O
O
O
NH2
N
Et2N
Et2N
Et2N
N
N
Br
b
N
N
NH2
a
NH
N
c, d
19
18
17
e
g
f
O
O
O
Et2N
Et2N
Et2N
N
N
NH
N
N
N
N
NH
S
NH
O
OMe
O
O
O
20
22
21
Scheme 4. Reagents and conditions: (a) 4-bromo-N,N-diethylbenzamide, Pd2(dba)3, BINAP, NaOtBu, toluene, 80 °C, 77%; (b) 1,3-dibromobenzene, xantphos, Pd2(dba)3,
NaOtBu, toluene, 110 °C, 68%; (c) benzophenone imine, Pd2(dba)3, BINAP, NaOtBu, toluene, 80 °C; (d) HCl, THF, 81% over two steps; (e) methyl carbamate, xantphos, Pd2(dba)3,
NaOtBu, toluene, 110 °C, 23%; (f) MeSO2Cl, NEt3, CH2Cl2, 38%; (g) AcCl, NEt3, CH2Cl2, 66%.

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A. M. Griffin et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5999–6003
N,N-diethylbenzamide and BINAP as the ligand gave mono aryl ad-
duct 17 in 77% yield. Subsequent arylation with 1,3-dibromobenzene
required xantphos as the ligand and gave bromide 18 in 68% yield.
With bromide 18 in hand, arylation with methyl carbamate11 gave
20, while arylation with benzophenone imine12 followed by treat-
ment with acid afforded aniline 19. Synthesis of sulfonamide 21 and
acetate 22 was achieved under standard conditions from aniline 19.
Binding affinities for analogs were determined as described in
the previous Letter5 and data is reported in Table 1. Data for phenol
2 is included for comparison.
Table 2
Binding affinity of primary amide regioisomers
O
N
O
N
O
NH2
N
N
N
C(O)NH2
N
Amines (8, 10, 11), alcohols (5, 9) ester 13, and acid 12 showed a
significant loss in binding affinity at the delta receptor compared to
phenol 2 and were not pursued further. Amino derivatives 19–22,
however, possessed delta agonist potencies in the range 1–7 nM
and demonstrated that replacement of the hydroxy group of 2
was possible. It is of interest to note that a report in the literature
demonstrated the hydroxy group of some mu ligands could not be
replaced by a sulfonamide isostere.6c This is not the case in our ser-
ies of delta agonists, although sulfonamide 21 was eight times less
potent an agonist than phenol 2. Carbamate 20 had a similar profile
to phenol 2 with a slightly enhanced binding affinity at mu.
Primary amide 14 was the most interesting analog synthesized,
showing improved selectivity (972 vs 210 for mu and 2500 vs
1771 for kappa) over phenol 2 and a twofold improvement in delta
14
23
O
O
N
NH2
N
N
agonist potency as determined in the [35S] GTP
cS binding assay.
SAR around 14 showed the primary amide group was optimal for
delta activity as mono-methylation caused a 67-fold drop in delta
binding affinity (compound 15) and dimethylation a 379-fold drop
(compound 16). Regioisomers of amide 14 were synthesized
(schemes not shown) and data shown in Table 2. The meta position
of the primary amide functional group was optimal as both ortho
and meta analogs showed a >100-fold drop in delta binding affinity.
Metabolic stability of amino analogs 20–22 and primary amide
14 was assessed and data shown in Table 3 along with data for phe-
24
Compound
Binding affinities (Ki nM)
Selectivity ratios
/d /d
d
l
j
l
j
12
23
24
0.29 0.02
38.1 4.5
32.0 2.3
282 96
5036 427
486 68
725 86
>10,000
6176 265
972
132
15
2500
262
193
Table 1
Binding affinity and d agonist activity of OH replacements
O
N
N
N
R
Compound
R
Binding affinities (Ki nM)
Selectivity ratios
/d /d
d Agonist activity
EC50 (nM) Emax (%)
d
l
j
l
j
2
4
5
6
8
OH
CHO
CHOHCH3
COCH3
CH2NH2
CH2OH
CH2NH(CH3)
CH2N(CH3)2
CO2H
CO2CH3
CONH2
CONHCH3
CON(CH3)2
NH2
NHCO2CH3
NHSO2CH3
NHCOCH3
0.42 0.03
88 11
1188 212
3750 727
1541 148
831 53
744 127
210
349
47
906
2
1771
1411
59
2671
7
0.56 0.07
17.0 1.7
100
109
2
5
3.40 0.14
80.6 1.9
1.70 0.38
447 56
11.7 0.7
435 70
34.3 3.3
1369 13
60.3 7.6
0.29 0.02
19.4 2.7
110 15
2.01 0.30
0.41 0.02
1.37 0.03
1.79 0.24
4796 534
4742 2954
4542 648
2928 305
6666 733
7.93 0.80
133 38
277 38
116
1
9
3809 377
326
570
103 10
10
11
12
13
14
15
16
19
20
21
22
4162 378
1747 130
121
51
112
5
7104 1592
282 96
4711 1663
5543 1993
725 86
>10,000
118
972
243
92
2500
>515
0.30 0.03
151 53
101
100
4
4
2879 448
75 11
462 79
4249 1201
576 151
3556 412
>10,000
1432
183
337
568
2114
1405
2596
>5587
19.2 3.2
1.08 0.11
4.53 0.87
6.94 0.96
109
102
98
9
1
3
5
1017 246
96

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Table 3
References and notes
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nol 2. Phenol 2 shows a high intrinsic clearance of 286
l
l/min/mg
when incubated with human liver microsomes while all other ana-
logs in Table 3 show improved metabolic stability. Of all the analogs
presented in Table 3, primary amide 14 is not only more metaboli-
cally stable than phenol 2 but is a more potent delta agonist, demon-
strating the primary amide to be a suitable replacement for the
hydroxy group in our series of delta agonists.
To summarize, we have continued our work in the amino piper-
idine series of delta agonists and shown that the hydroxy group
can be successfully replaced with a primary amide functional
group. A similar modification has been successfully reported in a
series of mu ligands6a around the same time as our initial discov-
ery.13 The amide derivative 14 not only shows improved delta po-
tency and selectivity versus mu and kappa but it is also
metabolically more stable as determined in human liver micro-
somes. Further developments in the amide series of delta agonists
will be reported in due course.
10. Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyaji, Y.; Imai, Z. Tetrahedron Lett. 1985, 26,
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Acknowledgment
We thank Sophie Turcotte for assistance with binding
experiments.