Biaryl piperidines as potent and selective delta opioid receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2009.11.113

The design and synthesis of novel opiates are reported. Based on the message-address principle a novel class of 4,4- and 3,3-biaryl piperidines was designed and synthesized. Biological evaluation confirmed that these compounds exhibit high affinity and se

Full text of DOI:10.1016/j.bmcl.2009.11.113

Bioorganic & Medicinal Chemistry Letters 20 (2010) 503–507
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Biaryl piperidines as potent and selective delta opioid receptor ligands
a,
Spiros Liras a, , Stanton F. McHardy , Martin P. Allen a, Barb E. Segelstein a, Steven D. Heck a,
*
Dianne K. Bryce b, Anne W. Schmidt b, Michelle Vanase-Frawley b, Ernesto Callegari c, Stafford McLean b
a Neuroscience Medicinal Chemistry, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA
b Neuroscience Biology, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA
c Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The design and synthesis of novel opiates are reported. Based on the message-address principle a novel
class of 4,4- and 3,3-biaryl piperidines was designed and synthesized. Biological evaluation confirmed
that these compounds exhibit high affinity and selectivity for the delta opioid receptor. Key structure–
activity relationships that influence affinity, selectivity, functional activity and clearance are reported.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 15 September 2009
Revised 18 November 2009
Accepted 20 November 2009
Available online 26 November 2009
Keywords:
Delta
Receptor
Ligands
Opioid ligands of the three receptor subtypes mu, delta, and
kappa have been implicated in the modulation of several disease
states of the central nervous system spanning from addiction and
pain, to depression and bipolar disorder.1 Thus, the quest for novel
and selective tools that would aid the pharmacological character-
ization of these receptor subtypes is an active research area for
medicinal chemistry. Our initial interest in the opioid family fo-
cused on the delta receptor. There is an emerging body of knowl-
edge which suggests that agonists of the receptor could be
effective pain therapeutics.2 Antagonists of the receptor have been
implicated as suppressors of ethanol addiction.3 Our research
aimed to probe the latter hypothesis. Hence, at the start of the
investigation we set as key project objectives the discovery of no-
vel, potent, and selective delta receptor antagonists with sufficient
exposure in the CSF relative to in vitro receptor affinity. Subse-
quently, our goal was to characterize these compounds in preclin-
ical models with disease relevance.
delta opiates with phenyl groups as the address component. The
hypothesis that the address portion of delta opiates may not be
strictly limited to aromatic moieties has been postulated. For
example, computational studies have suggested that the pipera-
zine delta receptor agonist SNC-808 (Fig. 1) shares receptor binding
elements with molecules derived from the application of the mes-
sage-address principle.9 This recognition led to the discovery of no-
vel molecules that contain polar functionality, such as the diethyl
amide, as the address component responsible for selectivity.
Based on molecular modeling, we were compelled to investi-
gate whether biaryl piperidines (Fig. 2) would furnish potent and
selective delta opiates. As a structural class, biaryl piperidines offer
many design advantages. The biaryl piperidines represent an evo-
N
O
OH
The design of selective delta opioid receptor ligands has been
largely influenced by the message-address principle which de-
Et2N
scribes essential structural features for affinity and selectivity.4
A
OMe
O
N
HO
N
N
H
powerful application of the message-address principle, which led
to the identification of naltrindole is represented by the work of
Portoghese et al.5,6 Additional delta selective ligands such as
TAN-67 (Fig. 1) have emerged from the application of the mes-
sage-address principle.7 Both naltrindole and TAN-67 represent
naltrindole (NTI)
OH
N
SNC-80
N
H
* Corresponding author.
TAN-67
E-mail address: spiros.liras@pfizer.com (S. Liras).
Current address: Synthesis and Process Chemistry, Southwest Research Institute,
6220 Culebra Rd, San Antonio, TX 78238, USA.
Figure 1. Naltrindole (NTI), TAN-67 and SNC-80.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.11.113

504
S. Liras et al. / Bioorg. Med. Chem. Lett. 20 (2010) 503–507
R2
R2
OMe
O
OMe
OH
OMe
a
R3
R3
1
N
N
R
R1
N
Ph
11
N
Ph
12
1
1:
5:
R alkyl,
R
1 alkyl,
R2 CONR'R",
R3 OH
R2 CONR'R",
R3 OH
OH
2: R1 alkyl,
R2 C(OH)R'R",
R3 OH
6: R1 alkyl,
OH
R2 C(OH)R'R",
R3 OH
R alkyl,
b, c, d
1
3:
7:
R
1 alkyl,
N
R2 CONR'R
R3 CONH2
R2 CONR'R
R3 CONH2
R1
2
4: R1 alkyl,
8: R1 alkyl,
R2 C(OH)R'R",
R3 CONH2
R2 C(OH)R'R",
R3 CONH2
Scheme 2. Synthesis of diethyl carbinols as amide replacements. Reagents and
conditions: (a) EtMgBr, THF, 0–50 °C, 91%; (b) EtSH, NaH, DMF, 130 °C, 68%; (c) H2,
Pd(OH)2–C, EtOH, 84%; (d) various aldehydes, NaBH(OAc)3, (CH2)2Cl2, 60–89%.
Figure 2. Biaryl piperidine targets.
CN
OH
OH
lution of phenyl piperidines, compounds with significant presence
in the literature as opioid agonists and antagonists.10 The signifi-
cant body of knowledge regarding phenyl piperidines aids the de-
sign of biaryl piperidine compounds with desired CNS disposition
and appropriate pharmacokinetic characteristics. The structure
provides the opportunity for the parallel SAR investigation of key
functionality at the aromatic rings and at the piperidine nitrogen.
Thus, we aimed to probe the effect of amine substitutions (R1) on
binding and functional activity. Additionally, we sought to identify
address moieties beyond amides (R2) and examine the impact on
affinity and selectivity. Finally, we intended to probe the signifi-
cance of the phenol moiety (R3) and to identify low molecular
weight phenol replacements which would mitigate the potential
risk posed by zwitterions on brain penetration.
The reduction to practice of the plan for the synthesis of 4,4-
biaryl piperidines (compounds 1–4) is shown below (Schemes 1–
3). We devised a common strategy for the synthesis of the corre-
sponding 3,3-biaryl piperidines which afforded compounds 5–8.
Our work commenced with the addition of m-methoxy phenyl
magnesium bromide, generated in situ, to N-benzyl-4-piperidi-
a, b
OH
N
N
Bn
Bn
14
13
CONH2
d
CONH2
OH
OH
c
+
N
N
O-
Bn
Bn
16
15
e, f
CONH2
OH
N
OMe
OMe
R1
OH
c, d
4
OH
b
a
Scheme 3. Synthesis of primary amides replacing the phenol. Reagents and
conditions: (a) triflic anhydride, ET3N, DMAP, CH2Cl2, 79%; (b) Zn(CN)2, Pd(PPh3)4,
DMF, 120 °C, 93%; (c) H2O2, H2O, EtOH, Na2CO3, rt; (d) Raney-nickel, DME, 70%
overall for steps c and d; (e) H2, Pd(OH)2–C, EtOH, 84%; (f) various aldehydes,
NaBH(OAc)3, (CH2)2Cl2 62–91%.
N
Ph
10
N
O
Ph
9
N
Ph
none. The resulting tertiary alcohol 9 was treated with AlCl3 and
phenol in refluxing dichloromethane to furnish phenol 10. Phenol
10 was converted readily to the ester 11 by treatment with triflic
anhydride/pyridine and subsequent elaboration under standard
carbonylation conditions with Pd(OAc)2, DPPP, carbon monoxide
in methanol and triethylamine in DMSO at 70 °C.11 Elaboration to
the final products of general structure 1 was accomplished via
the following sequence: (a) conversion of the ester to the amides
under the influence of trimethyl aluminum and various secondary
amines, (b) dealkylation of the methyl ether with HBr/AcOH, (c)
hydrogenolysis of the benzyl group with palladium hydroxide in
acetic acid, and (d) reductive alkylation under standard conditions
with various aldehydes.
O
OMe
OH
O
OMe
e, f, g, h
NR'R"
N
N
Ph
11
R1
1
Scheme 1. Synthesis of 4,4-biaryl piperidine 1. Reagents and conditions: (a) 3-
bromoanisole, Mg, I2, THF, 95%; (b) phenol AlCl3, (CH2)2Cl2, 73%; (c) triflic
anhydride, Et3N, DMAP, 75%; (d) Pd(OAc)2, DPPP, CO, MeOH, TEA, DMSO, 70 °C,
84%; (e) R’R”NH2, AlMe3, toluene, rt to reflux, 72–84%; (f) HBr, AcOH, 120 °C, 88%;
(g) H2, Pd(OH)2–C, AcOH, rt, 83%; (h) various aldehydes, NaBH(OAc)3, (CH2)2Cl2, 62–
91%.

S. Liras et al. / Bioorg. Med. Chem. Lett. 20 (2010) 503–507
505
As intended, the flexibility of the synthetic route allowed us
to quickly probe the potential for replacing the amide moiety
with other functionalities, such as tertiary carbinols. The approach
to these compounds is described in Scheme 2. Ester 11 was
converted to the diethyl carbinol 12 via exhaustive addition of
ethyl magnesium bromide. The targeted phenols 2 were obtained
following a three step sequence which involved methyl ether
deprotection employing sodium hydride and ethanethiol in DMF,
debenzylation with palladium hydroxide–carbon in ethanol, and
reductive alkylation with conditions as reported in Scheme 1
above.
through Whatman GF/B filters and rinsed with ice-cold 50 mM Tris
buffer (pH 7.4). Membrane bound [3H]diprenorphine levels were
determined by liquid scintillation counting of the filters in Beta-
Scint. The IC50 value (concentration at which 50% inhibition of spe-
cific binding occurs) was calculated by linear regression of the
concentration–response data. Ki values were calculated according
to the Cheng–Prusoff equation, Ki = IC50/(1 + (L/Kd)), where L is
the concentration of the radioligand used in the experiment and
the Kd value is the dissociation constant for the radioligand (deter-
mined previously by saturation analysis).
The receptor affinity values included in Tables 1 and 2 represent
averages of 2–6 screening runs. Results from the in vitro biological
studies of the 4,4 biaryl piperidine series are included in Table 1.
The results yielded several useful conclusions and also revealed
certain consistent limitations regarding the structural class. From
the affinity standpoint the design generally succeeded in its objec-
tives. Most compounds exhibited significant affinity for the delta
receptor. A variety of nitrogen tethers which included aliphatic
chains of variable lengths delivered compounds with high affinity
for the delta receptor. In vitro selectivity for the delta receptor
was high with a variety of nitrogen substitutions; especially over
the mu receptor (e.g., compounds 1a–1d). Amide alkyl group vari-
ations were broadly tolerated. Our studies revealed that larger
amide alkyl groups offered no advantage with respect to molecular
properties, affinity and ligand efficiency. Therefore, we focused our
emphasis on low molecular weight amide groups (e.g., 1e).
Replacement of the amides with tertiary carbinols16 produced
compounds that retained high affinity and selectivity. Finally, the
impact of phenol substitutions on binding was probed. We ob-
served that primary carboxamides were well tolerated and deliv-
ered compounds with high affinity and appreciable selectivity
(e.g., 4a and 4b). The major limitation of the class appeared to be
high clearance measured in vitro by human and rat liver micro-
somes. In vitro clearance for key compounds measured by human
liver microsomes is included in Table 1. A body of data suggested
that for the 4,4-biaryl piperidines increased microsomal stability
could be achieved by decreasing lipophilicity as measured by
Clog P.17
Replacement of the phenol moiety with low molecular weight
isosteres such as primary carboxamides proceeded in a straightfor-
ward manner as described in Scheme 3. Phenol 13 was readily con-
verted to the corresponding triflate with triflic anhydride and
triethylamine/DMAP and the resulting aryl triflate was subse-
quently transformed to the nitrile with Zn(CN)2 and palladium
catalysis.12 Treatment of the nitrile moiety in compound 14 with
aqueous hydrogen peroxide13 under controlled conditions pro-
ceeded to afford a mixture of the desired amine/amide product
15 and the N-oxide/amide 16 as the predominant side product.
The N-oxide side product 16 was formed almost exclusively with
prolonged reaction times but could be readily reduced to the de-
sired amine/amide by treatment with Raney-nickel in DME in
nearly quantitative yield. Debenzylation of the amine with
Pd(OH)2–carbon in ethanol followed by reductive alkylation with
various aldehydes yielded the desired compounds of general struc-
ture 4. The preparation of related compounds covered by the gen-
eral structures 3, 7, and 8 was accomplished by similar routes.
Analogs14 from both structural motifs were tested in radioli-
gand assays measuring binding affinity. Binding assays on mem-
branes from CHO cells expressing human kappa, mu, and delta
opioid receptors were performed according to standard proce-
dures.15 Briefly, frozen cell paste (70–80 mg per 96 well plate)
was homogenized in 50 mM Tris–HCl buffer (pH 7.4 at 4 °C) con-
taining 2.0 mM MgCl2 using a Polytron and spun in a centrifuge
at 40,000g for 10 min. The final pellet was re-suspended in assay
buffer (50 mM Tris–HCl buffer (pH 7.4) containing 1 mM EDTA,
5 mM MgCl2). Incubations were initiated by the addition of tissue
to 96-well plates containing test drugs and 0.6 nM [3H]diprenor-
Regarding the 3,3-biaryl piperidines, affinity for the delta recep-
tor was consistently high for this class as well. A variety of substi-
tutions at the piperidine nitrogen yielded compounds with high
delta receptor affinity. Selectivity was modest for some small alkyl
chains (e.g., 5a, 5c, and 5d) but was generally high with most other
substitutions (e.g., 5b and 5f). Reductive alkylations with small
phine in a final volume of 250
mined by radioligand binding in the presence of a saturating
concentration of naltrexone (10 M). After a one hour incubation
lL). Non-specific binding was deter-
l
period at room temperature, assay samples were rapidly filtered
Table 1
Binding affinities for delta, mu and kappa receptors and in vitro (HLM) clearance activity of select 4,4-biaryl-piperidines
Compound
R1
R2
R3
d Ki (nM)
l
Ki (nM)
j
Ki (nM)
Clog P
Clint (ml/min/kg)
62.9
1a
CONEt2
OH
9.0
>890
440
4.1
1b
1c
CONEt2
CONEt2
OH
OH
1.9
0.9
>890
66.5
347
3.8
5.1
34.6
239
95.0
1d
1e
4a
4b
CONEt2
OH
1.8
11.0
2.3
2.0
>890
>890
>890
380
>890
150
5.7
4.7
4.4
6.1
NA
CONMe2
C(OH)Et2
C(OH)Et2
OH
80
CONH2
CONH2
79.0
45.0
26.1
108

506
S. Liras et al. / Bioorg. Med. Chem. Lett. 20 (2010) 503–507
Table 2
Binding affinities for delta, mu and kappa receptors and in vitro clearance (HLM) of select 3,3-biaryl-piperidines
Compound
R1
R2
R3
d Ki (nM)
l
Ki (nM)
j
Ki (nM)
Clog P
Clint (ml/min/kg)
89
5a
CONEt2
OH
0.8
35.0
>890
52.0
24.0
>890
66.0
4.1
5b
5c
CONEt2
OH
OH
6.2
2.2
4.9
3.6
113
70
CON(Me)Et
5d
5e
CONEt2
CONEt2
OH
OH
2.9
3.5
>890
>890
24.0
163
3.98
3.48
>300
>300
CF3
S
N
H
N
5f
CONEt2
OH
1.2
>890
>890
2.97
230
N
N
6a
7a
C(OH)Me2
CONEt2
OH
39.0
7
110
41.0
4.30
2.15
22
S
CONH2
>890
>890
NA
heterocyclic aldehydes yielded compounds with high affinity and
excellent selectivity. Trends with amide alkyl substitutions were
similar to those observed for the 4,4 class and consequently we fo-
cused on small amide replacements (e.g., 5c). Tertiary carbinols
replacing the amide moiety delivered compounds with appreciable
affinity for the delta receptor; although the delta receptor affinity
for dimethyl carbinols specifically was lower (e.g., 6a). Replace-
ment of the phenol moiety with a primary carboxamide delivered
compounds which retained similar affinity and selectivity profiles
with the corresponding phenols (e.g., 7a). Clearance, as measured
in vitro by human liver microsomes (HLM) was generally high.
Compounds with small alkyl piperidine nitrogen substitutions
and small amide groups exhibited the better clearance profiles.
Nitrogen substitutions containing heterocyclic moieties did not
improve clearance (e.g., 5e and 5f).
containing heterocyclic moieties (compounds 5e and 7a). Replac-
ing the diethyl amide with carbinols or the phenol with carboxam-
ides in 4,4- and 3,3-biaryl piperidines did not impact the functional
activity.
In conclusion, we have demonstrated that biaryl piperidines are
potent and selective ligands for the delta opioid receptor. We have
been able to identify selective antagonists of the delta opiate
receptor which will aid the pharmacological characterization of
the receptor. While receptor affinity and selectivity can be ratio-
nalized on the basis of the message-address principle, the struc-
tural and conformational requirements that deliver delta receptor
antagonists are subject to additional investigation. Lead com-
pounds from this investigation are generally characterized by high
in vitro clearance. Further progress towards delivering pharmaco-
logical tools with desirable pharmacokinetic properties and char-
acterization of these probes in disease relevant models of ethanol
intake reduction will be disclosed in subsequent reports.
Based on a balance of properties, which included delta receptor
affinity, selectivity and microsomal stability a number of key com-
pounds were characterized for functional activity at the delta
receptor by a GTP-c S assay. Results from the investigation are de-
References and notes
picted in Table 3. Functional activity values included represent the
average of minimally two screening runs. IC50 values are reported
for antagonists. Within the 4,4-biaryl piperidine class good antag-
onists were identified with long aliphatic and branched alkyl
chains (e.g., compounds 1e and 4b). Compounds 1a and 4a with
small aliphatic chains showed significantly reduced functional
activity relative to their binding affinity and this is a phenomenon
we are studying further. Within the 3,3-biaryl piperidine class
good antagonists were identified with small and medium size alkyl
chains (e.g., compounds 5a and 5b) and with larger substitutions
1. (a) Capasso, A. Med. Chem. 2007, 3, 480; (b) Bodnar, R. J. Peptides (Amsterdam,
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Table 3
Delta receptor functional activity for representative biaryl piperidines
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14. All compounds were characterized by 1H NMR and mass spectroscopy and
gave satisfactory spectral data. For example, Compound 4a: 1H NMR (400 MHz,
CDCl3) d 7.71 (t, J = 1.8 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.38–7.22 (m, 6H), 6.09
(br, 1H), 5.83 (br, 1H), 2.61–2.40 (m, 7H), 2.15–2.13 (m, 2H), 1.94 (br, 1H),
1.81–1.73 (m, 5H), 0.82–0.78 (m, 1H), 0.71 (t, J = 7.5 Hz, 6H), 0.48–0.40 (m, 2H),
0.04–0.01 (m, 2H); MS (M+1) 421.2.Compound 4b: 1H NMR (400 MHz, CDCl3) d
7.76 (t, J = 1.66 Hz, 1H), 7.50 (ddd, J = 7.76, 1.41, 1.17 Hz, 1H), 7.39–7.16 (m,
6H), 6.00 (br, 1H), 5.71 (br, 1H), 3.45 (s, 1H), 2.44 (br, 7H), 1.99 (dd, J = 19.42,
Compound
d IC50 (nM)
1a
1e
4a
4b
5a
5b
5e
7a
155
72
282
4.7
7.1
55
16
12

S. Liras et al. / Bioorg. Med. Chem. Lett. 20 (2010) 503–507
507
7.32 Hz, 2H), 1.82–1.52 (m, 7H), 1.38–1.29 (m, 3H), 1.01–0.96 (m, 1H), 0.84 (t,
J = 7.03, 2H), 0.82 (d, J = 6.64, 3H), 0.71 (t, J = 7.42 Hz, 6H); MS (M+1) 451.3. For
complete experimental conditions describing the preparation of final
compounds and intermediates please see: Liras, S. PCT Int. Patent Appl. WO
2000/14066.
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