Design and discovery of a selective small molecule κ opioid antagonist (2-methyl- n -((2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl) methyl)propan-1-amine, PF-4455242)

Article abstract of DOI:10.1021/jm2006035

By use of parallel chemistry coupled with physicochemical property design, a series of selective κ opioid antagonists have been discovered. The parallel chemistry strategy utilized key monomer building blocks to rapidly expand the desired SAR space. The potency and selectivity of the in vitro κ antagonism were confirmed in the tail-flick analgesia model. This model was used to build an exposure-response relationship between the ? K_i and the free brain drug levels. This strategy identified 2-methyl-N-((2′- (pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242, which entered phase 1 clinical testing and has demonstrated target engagement in healthy volunteers.

Full text of DOI:10.1021/jm2006035

ARTICLE
pubs.acs.org/jmc
Design and Discovery of a Selective Small Molecule j Opioid
Antagonist (2-Methyl-N-((20-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)-
methyl)propan-1-amine, PF-4455242)
Patrick R. Verhoest,* Aarti Sawant Basak, Vinod Parikh, Matthew Hayward, Gregory W. Kauffman,
Vanessa Paradis, Stanton F. McHardy, Stafford McLean, Sarah Grimwood, Anne W. Schmidt,
Michelle Vanase-Frawley, Jodi Freeman, Jeffrey Van Deusen, Loretta Cox, Diane Wong, and Spiros Liras
Neuroscience Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Groton, Connecticut, United States
S Supporting Information
b
ABSTRACT:
By use of parallel chemistry coupled with physicochemical property design, a series of selective k opioid antagonists have been
discovered. The parallel chemistry strategy utilized key monomer building blocks to rapidly expand the desired SAR space. The
potency and selectivity of the in vitro k antagonism were confirmed in the tail-flick analgesia model. This model was used to build an
exposureꢀresponse relationship between the k Ki and the free brain drug levels. This strategy identified 2-methyl-N-
((20-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242, which entered phase 1 clinical testing and has
demonstrated target engagement in healthy volunteers.
’ INTRODUCTION
dopaminergic containing cells that project to the nAcc. Dynor-
phin up-regulation in the nucleus accumbens shell is stimulated
by stress and various drugs of abuse and causes anhedonia-like
effects potentially linking k antagonism as a path to treating
depression.5
The opioid family of G-protein-coupled receptors has long
been a target class of interest to the medicinal chemistry community.
This family consists of three subtypes μ, δ, and k, and all have
expression throughout the central nervous system.1
Clinical evidence provides indirect support that k receptors
may be a viable target for the development of a novel antide-
pressant. Buprenorphine (BUP), a partial μ agonist/k antago-
nist, was reported to be effective as a pharmacological treatment
for affective disorders. A double blind investigation showed BUP
to induce strong antidepressant effects in patients with endo-
genous depression.6 Additionally, depressive symptoms were
found to be significantly decreased with BUP treatment in heroin
addicted patients who were depressed at intake.7
Preclinically it has been reported that k blockade has afforded
antidepressant activity in several animal models and is likely to
dampen the decreased reward associated with excessive stimula-
tion of k receptors. Antidepressant activity has been reported
with k antagonists in the forced swim8 and social defeat assays.9
The μ opioid receptor has been the most characterized and is
the target for many of the analgesic drugs on the market.2 One of
the most famous is morphine which displays effective pain control
but can cause addiction, respiratory depression, and constipation.
The role of the δ receptor is less clear, though it is likely to participate
in processing pain signals as well.3 In the late 1980s, the k receptor
was considered a promising target for pain, potentially lacking
addiction/abuse liability. Clinical trials with spiradoline showed
significant dysphoria, ending most development of agonists as
potential pain therapeutics.4
Dynorphin is the native peptide agonist at the k receptor, and
changes in dynorphin levels in the nucleus accumbens in response
to stress may be noteworthy. Most depressed patients exhibit a
reduced ability to experience pleasure (anhedonia) and loss of
motivation. Reward is mediated by the ventral tegmental area
(VTA) nucleus accumbens (nAcc) dopaminergic pathway which
is modulated (inhibited) by the k receptors located directly on
Received: May 12, 2011
Published: July 11, 2011
r
2011 American Chemical Society
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Figure 1. Structures of nor-BNI (1), 50-GNTI (2), and JDTic (3).
Figure 2. HTS lead structures 4 and 5.
In addition, k blockade has been suggested as a treatment for
addiction with antagonists showing activity in reinstatement of
cocaine condition place preference.10 With the preclinical and
limited clinical information, a program was engaged to identify a
selective k opioid antagonist to potentially take forward into
depression and substance abuse clinical trials.
Scheme 1. Parallel Chemistry Enablement from Diverse
Monomer Sets (X = CH, CR, or N)a
The discovery of selective, nonpeptidic k opioid ligands has
received much attention from the medicinal chemistry commu-
nity. The design of k ligands has been mainly influenced by two
structural motifs, the morphinans and the 4-phenylpiperidines,
which also supplied many of the breakthroughs for the discovery
of selective δ and μ opioid ligands. Structural modifications of the
basic morphine and naltrexone skeletons, which demonstrate
affinity for all opioid receptors and modest selectivity for the μ
receptor, have delivered compounds with appreciable in vitro k
receptor selectivity. Nor-BNI (1)11 and 50-GNTI (2)12 (Figure 1)
are two such compounds that demonstrate this principle of
modulating receptor selectivity by chemical modifications of
the morphinan basic skeleton. As those two molecules suggest,
gains in selectivity were realized concomitant with an overall
increase in molecular volume and weight, relative to the basic
opioid pharmacophore (e.g., morphine or naltrexone).
a Parallel synthesis reagents and conditions: (a) step 1, sulfonyl chloride
A (1 equiv), amine B (1 equiv), triethylamine (2 equiv), CH2Cl2, 30 h,
then boronic acid C, 1,2 dichloroethane, sodium carbonate (aq),
Pd(dppf)Cl2 (20%), 80 °C, 18 h, then amine D (1.2 equiv), sodium
triacetoxyborohydride (3 equiv), 18 h. Followed by acid resin (SCX
SPE) and HPLC.
to the basic μ selective phenylpiperidine scaffold. The physico-
chemical properties and structural complexity of 1ꢀ3 are not in
line with marketed CNS drugs.17 This makes these templates
challenging lead series to develop a safe orally bioavailable compound.
Similarly, the 4-phenylpiperidines have inspired the design of
k opioid receptor selective ligands and have produced selective μ
opioid receptor ligands.13,14 Carrol and co-workers demon-
strated that k selectivity could be delivered from the phenylpi-
peridines by modification of the N-alkyl side chain.15 JDTic (3)
was discovered from these efforts (Figure 1).16 Compound 3
exhibits high selectivity for the k receptor over the μ and δ
receptors and displays antagonist functional activity, thus sug-
gesting that similar conformational aspects influenced functional
activity for this class across both the μ and k receptors. Similar to
1 and 2 the discovery of 3 suggested that selectivity could be
realized with an increase in the molecular size and weight relative
’ RESULTS AND DISCUSSION
With this background knowledge in hand we launched a high
throughput screen (HTS) to enable the discovery of novel and
selective k opioid receptor antagonist with favorable pharma-
ceutical and pharmacokinetic properties. The high throughput
screen yielded two major classes of compounds depicted in
Figure 2, as represented by the phenylpyrrolidines (e.g., com-
pound 4) and the biphenylamines (e.g., compound 5). Phenyl-
pyrrolidine 4 exhibited high affinity for the k receptor and
modest selectivity, exceptional ligand efficiency18 (LE = 0.43),
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Table 1. Biphenyl Opioid SAR and in Vitro ADME Propertiesa
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Table 1. Continued
a Human k and μ Ki: Potency reported in nM as average of n = 3. HLM human liver microsomal clearance in (mL/min)/kg. MDR is the efflux ratio BA/
AB. Data for compound 1 (nor-BNI): k Ki = 0.85; μ Ki = 79.9 nM; δ Ki = 65.2 nM.
and lipophilic efficiency19 (LLE = 6.91) values. The compound
was characterized by extremely low molecular weight but was
determined to be a functional agonist at k in the GTP-γS assay.
The biphenylamine 5 similarly exhibited high affinity for the k
receptor (9 nM) and modest selectivity over μ (2ꢁ). Impor-
tantly, compound 5 was found to be a functional antagonist at
both k and μ. On the basis of our knowledge of opioid medicinal
chemistry, we anticipated that the phenylpyrrolidines 4 would be
limited by a series of issues that characterize the structural motif.
For example, we anticipated that the functional activity would vary
with different N substitutions, and as previous literature suggested,
antagonists would likely require large alkyl substitutions.20
We also anticipated that issues such as CYP2D6 metabolism, P-gp,
and HERG channel interaction would complicate the lead optimi-
zation of the series given the basic tertiary amine moiety.21,22
We anticipated that the solution space, for example, reduction of
lipophilicity and modulation the pKa of the nitrogen, was limited
because of the synthetic chemistry limitations for rapid modification
of the core phenylpyrrolidine. We also anticipated that the
phenol moiety, which was important for pharmacological activ-
ity, would pose a risk for secondary metabolism and that phenol
surrogates would be required to optimize in vivo performance.23
Typically phenol replacements contain acidic hydrogen bond
donors and they also pose increased risk for P-glycoprotein efflux
(P-gp). By applying similar prospective thinking, we rationalized
that the chief issue with the biphenylamines was molecular
weight and lipophilicity reduction. While we anticipated that
issues such as CYP2D6 metabolism, HERG channel interaction,
and P-gp efflux were likely to emerge, we rationalized that we
would more efficiently probe the solution space within this core
because the intrinsic synthetic enablement provided us with the
option to vary polarity, hydrogen bond donor number, and pKa
readily. Consequently we investigated the rapid exploration of
the lead series represented by compound 5.
the undesirable in vitro ADME properties of 5. It displays high
human liver microsomal clearance with an intrinsic clearance of
>300 (mL/min)/kg, suggesting a low projected human
bioavailability.25 In addition, it appears to be a P-gp substrate
with an MDR flux ratio of 2.56.26 The high P450 mediated
clearance and the potential brain penetration liability result in
this molecule requiring very high doses to achieve CNS exposure.
The high projected doses and the poor physicochemical proper-
ties make this molecule a significant attrition risk.27 Selectivity
over μ was another key area to improve, and a selectivity of >20ꢁ
was targeted to allow for 80% k receptor occupancy with less
than 10% μ receptor occupancy.28
While compound 5 was not the ideal lead from a binding
efficiency or a physical chemical property perspective, it did have
a large advantage in that it could be chemically enabled to deliver
diverse analogues in a parallel chemistry format. By focusing the
chemistry strategy on enabling chemistry, we could explore a
variety of binding mode hypotheses and improve the physical
chemical properties in a rapid fashion.29 Toward this end, the
synthetic chemistry was designed to utilize diverse building
blocks that were available commercially or could be readily
synthesized. Monomers A and C were prepared (Scheme 1)
with a variety of substituted phenyl groups and pyridine hetero-
cycles. In addition, there are greater than 500 primary and
secondary amines in our internal file and available externally
for use in library chemistry. By preparation of only five A and C
monomer building blocks, the synthesis of over 6.25 million
compounds was enabled.
With the extraordinary number of compounds that one could
consider making, a design plan was put in place targeting
improved physical chemical properties. The pyridine hetero-
cycles were designed for monomers A and C to lower lipophilicity
to improve safety and clearance with the hope of maintaining
potency and improving selectivity.30 In addition the pyridine C
ring monomers would reduce the pKa of the amine, reducing a
potential HERG and P-gp liability. The large amine monomer set
was reduced by considering the molecular weight of the amine
building block. The biphenylsulfonyl core has a minimum molecular
weight of 230 g/mol; limiting the amines to a molecular weight
of less than 125 g/mol significantly reduced the potential final
compounds under consideration. By use of the reduced mono-
mer sets, the library was enumerated and the final compounds
were filtered based on physical chemical properties. The decision
Although a potent lead was identified, compound 5 is large for
a lead structure with a molecular weight of 462 and is fairly
lipophilic with ClogD = 4.13. Both of these properties fall outside
the ideal range for central nervous system (CNS) drugs which
display an average molecular weight of 305 and an average ClogD
of 1.7.24 Even with a high degree of potency for 5, these unoptimized
physical chemical properties result in a poor ligand efficiency (LE =
0.24) and a low lipophilic ligand efficiency (LLE = 3.82). The high
molecular weight and high lipophilicity significantly contribute to
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Table 2. Heteroaryl Opioid SAR and in Vitro ADME Propertiesa
a Human k and μ Ki: Potency reported in nM as average of n = 3. HLM human liver microsomal clearance in (mL/min)/kg. MDR is the efflux
ratio BA/AB.
was to synthesize the vast majority of the molecules that only
contained 0ꢀ1 hydrogen bond donors, had a molecular weight of
<425 g/mol, and had a ClogD < 3. By reduction of the number
of hydrogen bond donors and lowering of the molecular
weight, it would decrease the probability that molecules would
be P-gp efflux substrates, thereby allowing penetration into the CNS.12
Targeting lower lipophilicity than the HTS hit 5 would increase
our odds of having improved human liver microsomal clearance
and safety.
With the design plan in place the library chemistry was executed
by coupling the sulfonyl chlorides with primary and secondary
amines. This was followed by a Suzuki coupling utilizing Pd-
(dppf)Cl2 as the catalyst in the reaction. Subsequent reductive
amination reducing with sodium triacetoxy borohydride provided
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Figure 3. Exposureꢀeffect relationship of compounds 10, 11, 19, 23, 25, and 29 dosed subcutaneously: (A) Relationship between free plasma
normalized to k binding Ki and antinociception for k antagonists; (B) relationship between free brain normalized to k binding Ki and antinociception for
k antagonists. Symbols represent data from SpragueꢀDawley rats. Lines represent the fit of the PK/PD model to the antinociception serum
concentrations. Data are presented as mean values [serum concentration (n = 3ꢀ4); antinociception (n = 6)].
Figure 4. Compound 11 in the tail flick mouse analgesia model response assay vs k and μ agonists dosed subcutaneously.
the target analogues. This library protocol was successful in
producing over 80% of the molecules that were designed.
The library chemistry provided a wealth of SAR knowledge.
The biphenyl group provided numerous examples with increased
potency and concomitant improvements in physicochemical
properties. Molecular weight was reduced significantly in going
from the initial R1 indanol to simple branched alkyls, substituted
piperidines, and bicyclic amines. The SAR of the sulfonamide
established that 2-substituted piperidines, morpholines, and
pyrrolidines along with unsubstituted pyrolidines provided high
potency with improved selectivity over μ (Table 1). Compound
8 with a monosubstituted sulfonamide significantly lost k potency.
As designed, a general trend for the whole series was seen that as
ClogD was reduced to <2, compounds had low to moderate in
vitro human liver microsomal (HLM) clearance. This repre-
sented a significant improvement over the initial HTS lead 5.
As was also designed, reducing the hydrogen bond donor count
and reducing the molecular weight delivered compounds with
reduced P-gp liability. The vast majority of the compounds had a
MDR efflux ratio of less than 2. Compound 25 nicely highlights
that as two hydrogen bond donors were added, a significant P-gp
liability was seen with a MDR efflux ratio of 14. Multiple compounds
(7, 11, and 17) from this initial library set met the project goals of
having high potency of <10 nM, low to moderate HLM clearance,
and a MDR ratio of <2.5.
potentially maintain the potency and improve the selectivity at μ.
If this was obtained, these analogues may have improved safety
profiles, lower promiscuity, improved lipophilic ligand efficiency,
and improved dose projections. As a general trend the pyridyl
analogues had significantly lower HLM clearance than their
biphenyl counterparts. For example, compound 37 is not turned
over in HLM and compound 11 has a modest clearance of 27
(mL/min)/kg. As expected, the addition of hydrogen bond
acceptors did not increase the MDR P-gp efflux liability unlike
the addition of hydrogen bond donors.31 Unfortunately while the
pyridyl analogues improved the physicochemical properties and
in vitro ADME, a loss in potency and selectivity was seen. When
X1ꢀ5 was nitrogen, a significant loss in k potency resulted. With
X6 as a nitrogen, compounds (37ꢀ39) had reasonable potency
but displayed minimal selectivity (∼3ꢁ) over μ.
To understand the relationship of in vitro potency to in vivo
efficacy, a simplified PK/PD model was sought to understand
rodent free brain and free plasma drug levels normalized to the k
Ki. The tail flick analgesia model provided the opportunity to
understand in vitro potency to in vivo exposureꢀeffect relation-
ship and to increase confidence in k pharmacology of this series
utilizing 40 (2-(3,4-dichlorophenyl)-N-methyl-N-[(1R,2R)-
2-pyrrolidin-1-ylcyclohexyl]acetamide, U50488H) as a selective
k agonist.32
To determine an in vitro potency to in vivo response correla-
tion across compounds from this series, discrete single doses of
compounds (Figure 3) were administered to male SD rats followed
by a single dose of 40 to the same animals 1 h after dose of
The library enablement also allowed for rapid exploration
of heterocyclic replacements of the biphenyl (Table 2). The
heterocycles were designed to reduce the HLM clearance and
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Table 3. Summary of Preclinical Pharmacokinetic Para-
meters of Compound 11a
parameter
rat
dog
monkey human
microsomal CLb b ((mL/min)/kg) 44.6
37.7
29.6
33
3.1
na
in vivo CLb c ((mL/min)/kg)
161
23.8
0.79ꢁ
0.68
ivivc
3.5ꢁ ∼1ꢁ
0.64 0.91
na
microsomal ERh
0.11
a na = not applicable. ivivc = in vitro to in vivo correlation. b Calculated
using the well-stirred model with all binding factors. c CLh determined
from JVC rat, dog, and monkey study, iv dose 1 mg/kg.
of 6.20 and a ligand efficiency (LE) of 0.33. These properties are
all consistent with the marketed CNS drugs.23
Figure 5. Free brain, free plasma, and CSF drug exposure time course of
11. SpragueꢀDawley rats were dosed at 3.2 mg/kg sc.
Further pharmacokinetic profiling showed that 11 has good
solubility (>8.53 mg/mL at pH 5.5 and 0.11 mg/mL at pH 6.6.)
and permeability in PAMPA and RRCK models (∼19 ꢁ
10ꢀ6 cm/s). The in vitro, in vivo, and in silico data generated
preclinically for 11 suggest it will be well absorbed in humans
following oral administration. Compound 11 showed good brain
penetration in rats (AUC0ꢀ4h free brain/free plasma of ∼1,
AUC0ꢀ4h CSF/unbound plasma of 1.2, AUC0ꢀ4h CSF/free
brain of ∼1.4) with no evidence of impairment for the com-
pound to cross the bloodꢀbrain barrier (Figure 5). It showed
moderate in vivo clearance in dog, monkey, and human hepato-
cytes in vitro; in rats this compound was highly metabolized
(Table 3). Overall, 11 was predicted to have moderate human
systemic clearance using preclinical methods of clearance
predictions.36 Further details on preclinical and clinical pharma-
cokinetics and mechanistic studies on phenotyping will be in a
future publication.
administration of the test compounds. Antinociceptive response
(hot-plate method) was determined against vehicle groups 30 min
after dosing of 40. Brain tissue and plasma were collected and
analyzed for drug exposure using LCꢀMS/MS. Protein binding
of each of the compounds33 was determined using equilibrium
dialysis to calculate free drug exposure in plasma and brain. To
understand the concentrationꢀeffect relationship for these ana-
logues, reversal of pain tolerance due to k agonist 40 was plotted
using SigmaPlot and fitted to a sigmoidal Emax model against free
plasma or free brain exposures normalized to k binding Ki as shown
in Figure 3.
As seen in part A, free plasma exposures vs Ki plot, efficacy did
not correlate perfectly with the binding Ki. Compound 25 was
the biggest outlier and is not surprising, since it is a P-gp substrate
and subject to active efflux due to impediment at the bloodꢀ
brain barrier. On the other hand, free brain exposures correlated
strongly with binding of all compounds considered within this
series. This observation is consistent with that made by Kalvass
et al., where free brain concentrations (measured in mice dosed
with clinically relevant opioids) have shown strong correlation with
binding Ki; furthermore, the human EC50 for the same set of
opioids strongly correlated with the free brain EC50 measured in
mice (r2 = 0.95).34 This understanding of the exposure response
relationship demonstrated a functional knowledge that the
primary determinant of in vivo effect across this series is indeed
k mediated.
In addition to the exposure response analysis, the tail flick
assay has the ability to show functional selectivity of k vs μ
(Figure 4). 11 (2-methyl-N-((20-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)-
methyl)propan-1-amine, PF-4455242)35 was tested for its ability
to block the analgesic effects of the k agonist 40 and μ agonist
morphine. The ED50 to block the k agonist was 0.67 mg/kg vs
12.0 mg/kg for the μ agonist. This clearly demonstrated the
translatability of the in vitro selectivity data to an in vivo model.
From analysis of the PK/PD effects and taking into account
the potency, selectivity over μ, physicochemical properties, P-gp
liability, human liver microsomal clearance, and binding efficien-
cies, 11 met our desired criteria for advancement. Compound 11
is a 3 nM antagonist and 1.2 nM in the GTP-γS assay at the k
receptor with over 20-fold selectivity over μ. In addition it possessed
the desired in vitro ADME properties with lowꢀmoderate
human liver microsomal clearance, was not a P-gp substrate with
an efflux ratio less than 2.5 in the MDR cell line, and possessed an
acceptable HERG therapeutic index. The compound has excel-
lent binding efficiencies with a lipophilic ligand efficiency (LLE)
’ CONCLUSION
In summary, parallel chemistry enablement and physicochem-
ical property based design were utilized to identify a series of
biphenylamine compounds with selectivity for the k opioid
receptor and with druglike properties. The antagonist effects of
the molecules were confirmed in testing the ability to block
agonist induced analgesia in the tail flick assay and additionally
showing functional selectivity for k over the μ opioid system. An
exposureꢀresponse analysis was completed in the early stages of
the project, clearly demonstrating that central exposure of the
compounds in relation to the k binding affinity was driving
efficacy. From this effort, 11 was advanced into broad based
pharmacokinetic testing and showed the potential to have
desirable pharmacokinetics in humans. This compound has been
profiled in multiple models that may be predictive of antidepres-
sive activity, and these data will be disclosed in future publica-
tions. With desirable preclinical data, compound 11 has entered
into phase 1 human clinical trial and has demonstrated clear
human target engagement.35,37
’ EXPERIMENTAL SECTION
All reagents and solvents were used as purchased from commercial
sources. Reactions were carried out under a blanket of nitrogen. Silica gel
chromatography was done using the appropriate size Biotage prepacked
silica filled cartridges. Mass spectral data were collected on a Micromass
ADM atmospheric pressure chemical ionization instrument (LRMS
APCI). NMR spectra were generated on a Varian 400 MHz instrument.
Chemical shifts were recorded in ppm relative to tetramethylsilane
(TMS) with multiplicities given as s (singlet), bs (broad singlet), d
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(doublet), t (triplet), dt (doublet of triplets), m (multiplet). Compound
purity is determined by combustion analysis (Quantitative Technologies
Inc.) or high pressure liquid chromatography (HPLC). HPLC condi-
tions utilized are as follows: gradient, 0ꢀ0.25 min 5% A/95% B,
0.25ꢀ6.25 min 5% A/95% B f 90% A/10% B, 6.25ꢀ6.75 min 90%
A/10% B, 6.75ꢀ6.85 min 90% A/10% B f 5% A/ 95% B, 6.85ꢀ9.5 min
95% A/5% B; column temperature of 45 °C; UV detector, 210 nM.
Retention times (tR) are in minutes, and purity is calculated as % total
area. (Column 1: Waters BEH C8 2.1 mm ꢁ 100 mm, 1.7 μm. Mobile
phase A: acetonitrile. B: 0.1% (v/v) H3PO4 + 50 mM NaClO4. Column 2:
Waters BEH C8 2.1 mm ꢁ 100 mm, 1.7 μm. Mobil phase A: acetonitrile. B:
20 mM ammonium bicarbonate, pH 6.8. Column 3: Waters BEH RP
C18 2.1 mm ꢁ 100 mm, 1.7 μm. Mobile phase A: acetonitrile. B: 0.1%
methanesulfonic acid. Column 4: Waters HSS T3 2.1 mm ꢁ 100mm, 1.8
μm. Mobile phase A: acetonitrile. B: 0.1% methanesulfonic acid. Column 5:
Waters BEH C8 2.1 mm ꢁ 100 mm, 1.7 μm. Mobile phase A: acetonitrile.
B: 20 mM ammonium bicarbonate, pH 8.0. All final compounds either
met combustion analysis within (0.4% or were >95% pure by HPLC by
the methods above.
General Parallel Procedure for the Preparation of Com-
pounds 6ꢀ39. Step 1. Sulfonamide Formation. Sulfonyl chloride A
(0.1 mmol, 1 equiv) and triethylamine (0.2 mmol, 2 equiv) were
combined in 0.6 mL of dry methylene chloride, and the amine B (0.1
mmol, 1 equiv) in 0.2 mL of dry dichloromethane was added. The
mixture was shaken at room temperature for 30 h. Dichloromethane
(3 mL) and water (2 mL) were added. The organic layer was washed and
transferred to a collection vial. The solvent was removed, and the crude
was taken on to next step without further purification.
Step 2. Suzuki Reaction. N2 was bubbled through a 2 M solution of
sodium carbonated and 1,2-dimethoxyethane to deoxygenate. The
boronic acids C (0.2 mmol, 2 equiv) and the crude bromosulfonamides
(0.1 mmol, 1 equiv) were added to 0.6 mL of 1,2-dimethoxyethane.
Pd(dppf)Cl2 (0.02 mmol, 0.2 equiv) was added with solid dispenser
followed by the addition of 0.6 mL of the 2 M sodium carbonate solution
(0.3 mmol, 3 equiv). The mixtures were shaken and heated at 80 °C
overnight. Then 2.5 mL of ethyl acetate and 0.5 mL of water were added
to the reaction mixture and the organic layer was transferred to a
collection vial. The solvent was removed and the crude taken on to next
step without purification.
Step 3. Reductive Amination. To the amine D (0.12 mmol, 1.2 equiv)
was added crude aldehyde (0.1 mmol, 1 equiv) dissolved in 0.5 mL of dry
dichloromethane. Sodium triacetoxyborohydride (∼0.3 mmol, 3 equiv)
was added neat with a solid dispenser. The mixtures were shaken at room
temperature overnight. The reaction mixtures were partitioned between
2 mL of 10% ammonium hydroxide and 2.5 mL of dichloromethane.
The organic layer was loaded onto a SCX SPE (6 mL, 1 g, SiliCycle)
column. The resin was washed with 5 mL of methanol. The compounds
were eluted from the resin with 7.5 mL of 10% triethylamine in
methanol. The solvent was evaporated and the crude purified via HPLC
to provide the library compounds in >95% purity and confirmed by MS.
Singleton Resynthesis for in Vivo Tail Flick Experiments.
1-(2-Bromophenylsulfonyl)pyrrolidine. Triethylamine (2.0 g, 23.5 mmol)
was added to a solution of pyrrolidine (1.67 g, 23.5 mmol) in anhydrous
dichloromethane (100 mL, 0.2M). This was followed by dropwise addi-
tion of 2-bromobenzenesulfonyl chloride (5.0 g, 20.0 mmol), and the reac-
tion mixture was stirred overnight at room temperature. The reaction mixture
was washed with 1 N HCl (2 ꢁ 20 mL), and the organic layer was
extracted with dichloromethane and dried over MgSO4. The solution
was filtered, concentrated, and flash-chromatographed on silica gel, eluting
with 30% ethyl acetate/heptane to provide the title compound as an
oil (4.0 g, 70%). 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (dd, J = 7.8,
1.8 Hz, 1H), 7.75 (dd, J = 7.8, 1.3 Hz, 1H), 7.36 (m, 2H), 3.37 (m, 4H),
1.87 (m, 4H); GC/MS (M+ m/z = 290).
20-(Pyrrolidin-1-ylsulfonyl)biphenyl-4-carbaldehyde. To a solution
of 1-(2-bromophenylsulfonyl)pyrrolidine (20 g, 69 mmol) and 4-for-
mylphenylboronic acid (12.90 g, 86.20 mmol) in DME (200 mL) was
added 2 M Na2CO3 (40 mL) and Pd(dppf)2Cl2 (563 mg, 0.689 mmol).
The mixture was refluxed for 4 h. The reaction mixture was cooled to
room temperature and diluted with ethyl acetate (600 mL). It was then
washed with 2 M Na2CO3 solution (1 ꢁ 100 mL), brine (1 ꢁ 100 mL),
dried over Na2SO4, filtered, and concentrated in vacuo. Flash chroma-
tography eluting with 40% ethyl acetate/heptanes provided the title
compound (22 g, 69%) as a white solid. 1H NMR (400 MHz, CDCl3) δ
ppm 10.06 (s, 1 H), 8.12 (dd, J = 7.9, 1.3 Hz, 1 H), 7.92 (d, J = 7.8 Hz, 2 H),
7.59 (d, J = 7.8 Hz, 2 H), 7.56 (m, 2 H), 7.29 (dd, J = 7.3, 1.3 Hz, 1 H),
2.94 (m, 4 H), 1.40 (m, 4 H); LC/MS (M+ m/z = 315).
2-Methyl-N-((20-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-
1-amine (11). 20-(Pyrrolidin-1-ylsulfonyl)biphenyl-4-carbaldehyde (19.5 g,
61.80 mmol) was dissolved in dichloromethane (200 mL, 0.3 M) followed
by the addition of 2-methylpropan-1-amine (5.40 g, 73.80 mmol), and
the resulting mixture was stirred for 30 min. Sodium triacetoxyborohydride
(19.6 g, 92.30 mmol) was added, and the reaction mixture was stirred
overnight. The reaction was quenched with water (50 mL), and the mixture
was allowed to stir for 10 min after which the aqueous layer was made basic
by adding 10% ammonium hydroxide solution. The solution was extracted
with ethyl acetate (3 ꢁ 100 mL). The organic layer was dried over sodium
sulfate, filtered, and concentrated. The crude product was chromatographed
on silica gel using 5ꢀ20% methanol/dichloromethane gradient and to
provide the title compound (18.28 g, 79%) as an oil. The oil was dissolved in
150 mL of ether, and 15 mL of 2 M HClꢀether solution was added to form
a precipitate. The solid was filtered to provide the hydrochloride salt of the
title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.92
(S, 1 H), 8.11 (dd, J = 7.8, 1.6 Hz, 1 H), 7.72 (d, J = 7.8 Hz, 2 H), 7.61 (m,
1 H), 7.52 (dd, J = 7.80, 1.6 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 2 H), 7.25 (dd, J =
7.4, 1.6 Hz, 1 H), 4.25 (s, 2 H), 2.90 (m, 4 H), 2.64 (s, 2 H), 2.28 (spt, J =
6.70 Hz, 1 H), 1.77 (m, 4 H), 1.09 (d, J = 6.6 Hz, 6 H); MS (M+H m/z =
373). Anal. Calcd for C21H29N2O2SCl: C, 61.67%; H, 7.51%; N, 6.85%.
Found C, 61.40%; H, 7.34%; N, 6.75%.
N-Isopropyl-N-methyl-40-(piperidin-1-ylmethyl)biphenyl-2-sulf-
onamide (10). Following the procedure for the preparation of 2-methyl-
N-((20-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine
(11) but substituting piperidine and 40-formyl-N-isopropyl-N-methyl-
biphenyl-2-sulfonamide (commercial ASDI) provided the title com-
pound (70%). 1H NMR (400 MHz, methanol-d4) δ ppm 8.07 (d, J = 7.9,
2 H), 7.68 (t, J = 6.2 Hz, 1 H), 7.54 (m, 5 H), 7.34 (d, J = 7.2 Hz, 1 H),
4.34 (s, 2 H), 3.69 (m, 1 H), 3.49 (m, 2 H), 3.03 (dt, J = 12.5, 2.1 Hz, 2 H),
2.31 (s, 3 H), 1.98 (m, 2 H), 1.77 (m, 3 H), 1.53 (m, 1 H), 0.93 (d, J = 6.7,
6 H); MS (M+H m/z = 386). HPLC purity, >95%.
N,N-Dimethyl-N-((20-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl-methyl)-
ethane-1,2-diamine (19). Following the procedure for the preparation
of 2-methyl-N-((20-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-
1-amine (11) but substituting N,N-dimethylehtane-1,2-diamine pro-
vided the title compound (75%). 1H NMR (400 MHz, methanol-d4) δ
ppm 8.03 (dd, J = 7.9, 1.3 1 H), 7.67 (dt, J = 7.5, 1.3 Hz, 1 H), 7.58 (dd,
J = 7.9, 1.3 1 H), 7.53 (m, 2 H), 7.44 (m, 2 H), 7.32 (dd, J = 7.9, 1.6 1 H),
4.16 (s, 2 H), 3.21 (m, 2 H), 3.13 (m, 2 H), 2.87 (m, 4 H), 2.70 (s, 6 H),
1.70 (m, 4 H); MS (M+H m/z = 387). HPLC purity, >95%.
(()-6-((20-(Pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)-6-azabicyclo-
[3.2.1]octane (23). Following the procedure for the preparation of
2-methyl-N-((20-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-
1-amine (11) but substituting 7-azabicyclo[4.2.1]nonane provided the
title compound (83%). 1H NMR (400 MHz, methanol-d4) δ ppm 8.04
(dd, J=7.9, 1.3Hz, 1 H), 7.54(m,3H),7.50(d,J= 8.3 Hz, 2 H), 7.34 (dd, J=
7.5, 1.3 Hz, 1 H), 4.52 (m, 2 H), 3.88 (m, 1 H), 3.71 (m, 1 H), 3.36 (m, 1
H), 3.33 (s, 1 H), 2.88 (m, 4 H), 2.70 (s, 1 H), 2.37 (m, 1 H), 2.11 (d, J =
14.1 Hz, 1 H), 1.62 (m, 9 H); MS (M+H m/z = 411). HPLC purity, >95%.
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Journal of Medicinal Chemistry
ARTICLE
(S)-2-(1-((20-(3-(Hydroxymethyl)piperidin-1-ylsulfonyl)biphenyl-4-
yl)methyl)piperidin-4-yl)ethanol (25). Following the procedure for the
preparation of 2-methyl-N-((20-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)-
methyl)propan-1-amine (11) but substituting 2-(piperidin-4-yl)ethanol
and 20-(2-(hydroxymethyl)piperidin-1-ylsulfonyl)biphenyl-4-carbalde-
hyde (commercial ASDI) provided the title compound (83% yield).
This compound was separated on a preparative Chiralpack AD column
using heptane/ethanol/1% TFA, 80:20, as eluant to afford (R)-enatio-
mer (41% yield, first eluting product, retention time of 21 min) and
hydrochloride salts as a white solid. [R] ꢀ14.92° (c 1, CHCl3). 1H NMR
(400 MHz, CDCl3) δ ppm 8.17 (dd, J = 7.9, 1.3 Hz, 1 H), 7.52 (m, 1 H),
7.41 (m, 3 H), 7.33 (m, 2 H), 7.30 (d, J = 7.5 Hz, 1 H), 3.64 (m, 2 H), 3.61
(d, J = 16.6 Hz, 2 H), 3.59 (s, 2H), 3.35 (m, 2 H), 2.88 (m, 2 H), 2.61 (m, 2
H), 2.06 (s, 2 H), 1.69 (d, J = 12.9 Hz, 2 H), 1.51 (q, J = 6.4 Hz, 4 H), 1.30
(m, 4 H), 1.03 (m, 2 H); MS (M+H m/z = 473). HPLC purity, >95%.
1-(2-Bromopheylsulfonyl)piperidine. Following the procedure for
the preparation of 1-(2-bromophenylsulfonyl)pyrrolidine but substitut-
ing piperidine provided the title compound (89%). 1H NMR (400 MHz,
CDCl3) δ ppm 8.07 (dd, J = 7.9, 2.1 Hz, 1H), 7.73 (dd, J = 7.9, 1.3 Hz,
1H), 7.42 (m, 2H), 3.24 (m, 4H), 1.60 (m, 4H) 1.53 (m, 2H); MS
(M+ m/z = 305).
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1
compound (45%). H NMR (400 MHz, methanol-d4) δ ppm 8.07
(dd, J = 7.9, 1.3 Hz, 1 H), 7.74 (dt, J = 7.5, 1.3 Hz, 1 H), 7.62 (m, 3 H),
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures for
b
the pharmacokinetic experiments, tail flick assay, and binding
assays. This material is available free of charge via the Internet at
http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
*Phone: 860-686-2288. Fax: 860-686-0013. E-mail: patrick.r.
verhoest@pfizer.com.
’ ABBREVIATIONS USED
SAR, structureꢀactivity relationship; VTA, ventral tegmental area; nAcc,
nucleus accumbens; BUP, buprenorphine; ADME, absorption,
distribution, metabolism, and elimination; LE, ligand efficiency;
LLE, lipophilic ligand efficiency; P-gp, P-glycoprotein; MDR,
multiple drug resistance; HTS, high throughput screen; HLM,
human liver microsomal; PK/PD, pharmacokinetic/pharmaco-
dynamic; PAMPA, parallel artificial membrane permeation assay; AUC,
area under the curve; hERG, human ether-a-go-go related gene; RRCK,
Russ Ralph canine kidney cells
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