Design of a potent CB1 receptor antagonist series: Potential scaffold for peripherally-targeted agents

Article abstract of DOI:10.1021/ml3000325

Antagonism of cannabinoid-1 (CB₁) receptor signaling has been demonstrated to inhibit feeding behaviors in humans, but CB₁-mediated central nervous system (CNS) side effects have halted the marketing and further development of the le

Full text of DOI:10.1021/ml3000325

Letter
pubs.acs.org/acsmedchemlett
Design of a Potent CB1 Receptor Antagonist Series: Potential Scaffold
for Peripherally-Targeted Agents
Robert L. Dow,* Philip A. Carpino, Denise Gautreau, John R. Hadcock, Philip A. Iredale,
Dawn Kelly-Sullivan, Jeffrey S. Lizano, Rebecca E. O’Connor, Steven R. Schneider, Dennis O. Scott,
and Karen M. Ward
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: Antagonism of cannabinoid-1 (CB1) receptor
signaling has been demonstrated to inhibit feeding behaviors
in humans, but CB1-mediated central nervous system (CNS)
side effects have halted the marketing and further development
of the lead drugs against this target. However, peripherally
restricted CB1 receptor antagonists may hold potential for
providing the desired efficacy with reduced CNS side effect
profiles. In this report we detail the discovery and structure−activity-relationship analysis of a novel bicyclic scaffold (3) that
exhibits potent CB1 receptor antagonism and oral activity in preclinical feeding models. Optimization of physical properties has
led to the identification of analogues which are predicted to have reduced CNS exposure and could serve as a starting point for
the design of peripherally targeted CB1 receptor antagonists.
KEYWORDS: Obesity, cannabinoid receptor, antagonist, clearance, polar surface area, multidrug resistance protein 1, ligand efficiency,
ligand-lipophilicity efficiency
pidemiological studies have underscored the high
incidence of obesity in developed countries, exemplified
taranabant, and ibipinabant) were also advanced to late stage
clinical testing and were found to have similar CNS side effect
profiles.5,8 Though these findings were a significant setback,
there may still be a path forward for this mechanism in the
treatment of obesity. Recent genomic data suggests that certain
polymorphisms of the CB1 receptor gene alone or in
combination with variants in the serotonin transporter gene
are linked to the development of anxiety and depression.9 On
the basis of these findings, genetic screening could pave the way
for the selection of a patient population in which CB1
antagonist treatment would have a much improved safety
profile. Alternatively, since these side effects are centrally
mediated, it has been proposed that peripherally targeted CB1
receptor antagonists would possess an improved therapeutic
index.10,11 This strategy has been pursued through increasing
the polar surface area12−14 of lead CB1 receptor antagonist
chemotypes and through the recognition by CNS efflux
transporters (i.e., multidrug resistant protein 1 (MDR1)),15
as a means of reducing central exposure.
E
by a prevalence of one in three U.S. adults.1 Obesity is a
contributing factor to a number of chronic disease states,
including diabetes, heart disease, hypertension, stroke, and
arthritis.2 Because of its impact on this broad array of diseases,
obesity has recently displaced smoking as the leading cause of
preventable death.3 In general, the failure of obese patients to
adhere to the preferred treatment strategy of diet and exercise
has led to intensive research efforts to identify pharmacological
agents that reverse this disease state. Weight gain/loss involves
a balance of both satiety and the metabolic state of the
individual. Therefore, modulation of the mechanisms involved
in controlling either or both of these end points has been
targeted for pharmacotherapy. The only chronic weight loss
treatment currently approved for human use is orlistat, which
disrupts fat absorption through intestinal lipase inhibition.
Since the side effect profile of orlistat limits its widespread use,
additional treatment options for obesity are warranted.
Disruption of endocannabinoid signaling via blockade of
cannabinoid (CB) receptors has been shown to significantly
inhibit food intake and increase energy expenditure in both
preclinical models and humans.4,5 The CB1 receptor subtype,
which is distributed both centrally and peripherally, is
responsible for controlling satiety and energy expenditure.6
While the selective CB1 receptor antagonist rimonabant (1)
was approved for the treatment of obesity in European markets,
it was later withdrawn due to CNS derived side effects
including depression, anxiety, and suicide-ideation.7 In addition,
a number of structurally distinct antagonists (otenabant,
Our group recently disclosed the potent, orally active CB1
receptor antagonist 2 (PF-0514273), which was advanced to
human clinical trials for the treatment of obesity.16 The bicyclic
lactam core of 2 arose through conformational-restriction of the
C-3/C-4 positions of the pyrrole core of 1. Besides locking in a
favorable vector for the N-substituent, this antagonist maintains
Received: February 3, 2012
Accepted: March 21, 2012
Published: March 21, 2012
© 2012 American Chemical Society
397
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ACS Medicinal Chemistry Letters
Letter
highly potent, orally active CB1 antagonists with the potential
to serve as a structural platform for the discovery of peripherally
targeted agents.
Target compounds based on 3 were synthesized as described
in Scheme 1 or 2. Alkylation of the potassium salt of
hydroxypyrazole 416 with tert-butyl 4-bromobutanoate afforded
ether 5 in 82% yield following recrystallization from cyclo-
hexane. Dieckmann cyclization of diester 5 afforded bicyclic β-
ketoester 6 in 90% yield. Removal of the ester functionality
with trifluoroacetic acid, followed by thermal decarboxylation of
the resulting acid provided ketone 7 in 84% overall yield.
Conversion to amines 8 and 9 was achieved in 55−60% overall
yield by reductive amination utilizing the requisite amine and
sodium cyanoborohydride. The enantiomers of 8 were
separated by utilizing chiral phase high-pressure liquid
chromatography, and the absolute stereochemistry of each
was assigned via single crystal X-ray analysis of the
corresponding p-bromobenzamide derivative. These crystal
structures were consistent with the predicted conformation
(Figure 1), in which the acylamino substituent is planar with
the bicyclic core. Conversion of amines 8 and 9 to the targeted
amide, carbamate, and urea derivatives was accomplished in
high yields by employing standard protocols. Cyclic amide 12
was prepared through acylation of 8 with 4-chlorobutyryl
chloride and intramolecular alkylation by employing potassium
tert-butoxide in 38% overall yield (Scheme 2).
While primary amine 8 is a modestly potent inhibitor of the
human CB1 receptor, acetylation led to a substantial increase in
affinity (10a, Table 1). Binding activity translated well into
functional inhibition of the human CB1 receptor, with a Ki for
10a that is comparable to those observed for 1 and 2. Analysis
of CB2 receptor binding affinity revealed 10a to be a highly
selective inhibitor (CB2/CB1 > 20,000). In line with the goal of
identifying chemical space which is more compatible with
designing in CNS exclusion, 10a possesses improved ligand-
lipophilicity efficiency (LLE)20 relative to those of 1 and 2 (5.6
vs 4.1 and 5.0 for 1 and 2, respectively). On the basis of human
liver microsomal (HLM)21 analysis (CLintapp < 8 mL/min/kg),
this acetamide is predicted to have low oxidative clearance in
vivo. Extending the methyl group of 10a to an ethyl or
isopropyl substituent led to improvements in CB1 receptor
inhibitory activity, with 10c being a 40 pM functional
antagonist. This highly potent isobutyramide possesses a LLE
of 6.7, which is well within the targeted space of marketed oral
drugs.20 Incorporation of additional hydrophobic bulk (e.g.,
10f) does not provide significant improvements in CB1
receptor binding affinity, while negatively impacting micro-
somal clearance.
a molecular weight and lipophilicity profile which is similar to
that of 1 (log D7.4 of 1 = 4.7; 2 = 4.1).17 This latter point is
particularly important, since 1, as well as a majority of CB1
antagonists, are on the edge of acceptable property space18 and
previous efforts directed toward peripheral-restriction have
typically resulted in significantly increased molecular
weight.12−14 Thus, improving the physiochemical profile of
the core structure arising from our follow-on efforts related to 2
became a design goal. This driver, along with pharmacophore
overlap analyses, led to the prioritization of the design
represented by 3. Conformational analysis of representative
analogues of 3 predicts the acylamino substituent to be nearly
coplanar with the pyrazole ring, similar to that observed for the
hydrazide group of 1 (Figure 1; R enantiomer shown).19
Figure 1. Overlay of minimized conformations of 1 (cyan) and 10d
(green).
Modeling also reveals a high degree of overlap between the
amide substituents of 1 and 3, which represents a considerable
improvement relative to that observed for the amide substituent
in 2.16 While 2 demonstrates that direct overlap of this portion
of the pharmacophore is not critical for potent CB1 antagonism,
it may still be of value to have an enhanced overlap with the
hydrazide substituent of 1. One potential advantage may lie in
the finding that polar functionality is well tolerated in the
terminus of the piperidine ring of 1, which has led to agents
with high peripheral/CNS partitioning ratios.12−15 In addition,
3 possesses a slightly increased polar surface area (PSA) relative
to those of both 1 and 2 (PSA = 50.4, 47.4, and 56.2 for 1, 2,
and 3 (e.g., R = alkyl), respectively, which could be an
advantage as a starting point for reduced brain penetration.
Herein, we describe our efforts in developing series 3 into
With modeling and X-ray analysis supporting a low energy
conformation of 3 in which the amide functionality is nearly
planar with the pyrazole ring, we evaluated the importance of
this conformation via preparation of tertiary amide derivatives.
N-Methylation (11) of 10c or incorporation of a cyclic amide
(12) resulted in a >150-fold reduction in CB1 receptor
functional activity, while increasing HLM clearance. Increased
steric interaction of the tertiary amide substituent with the
bicyclic core in these cases would be expected to rotate the
amide out of plane and is supported by the observation of
amide rotamers in NMR experiments with 11. These results are
consistent with an in-plane amide requirement and support
conformation models proposing the predicted binding of 1 to
the CB1 receptor involving an in-plane relationship between the
central pyrazole core and the amide side chain.19
398
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ACS Medicinal Chemistry Letters
Letter
a
Scheme 1. Syntheses of Acylaminobicyclics 10a−q and 11
a
Reagents and conditions: (a) tert-butyl 4-bromobutanoate, potassium tert-butoxide, DMF, 0−25 °C; (b) potassium bis(trimethylsilyl)amide, THF,
−78−25 °C; (c) 2:1 CH2Cl2/TFA, RT, then 1:1 toluene/p-dioxane, reflux; (d) ammonium acetate or methylamine hydrochloride, sodium cyano-
borohydride, MeOH/CH2Cl2, RT, then 4 N HCl in p-dioxane; (e) acid chloride, chloroformate or isocyanate, triethylamine, CH2Cl2, RT.
a
Scheme 2. Syntheses of 12
induced by CP-55940 in these mice. These effects were
comparable to that observed for rimonabant (1) at 3 mg/kg.
On the basis of these results, 10d was advanced to a rodent
model of food intake inhibition. Following an overnight fast,
Sprague−Dawley rats were dosed orally with 10d, 1, or vehicle,
and food intake was continuously monitored for 2 h post food
reintroduction (Figure 3). All three doses (0.3, 1, and 3 mg/kg)
of 10d produced a statistically significant reduction in
cumulative food intake relative to the vehicle control at both
0.5 and 2 h. At both time points, a dose of 0.3 mg/kg of 10d
produced an effect comparable to that observed for rimonabant
at 3 mg/kg.
a
Reagents and conditions: (a) 4-chlorobutyryl chloride, triethylamine,
CH2Cl2, RT; (b) KOt-Bu, THF, RT.
Having demonstrated that this bicyclic scaffold displays
potent in vitro and in vivo CB1 antagonism, our attention turned
to evaluating the impact of the introduction of polar
functionality into the acylamino substituent of 3. These
modifications, through either direct impact on PSA12−14 or
potential recognition by MDR1,15,23 could serve to reduce CNS
exposure. While single heteroatom incorporations into larger
acylamino substituents (e.g., 10f to 10g) had a modestly
favorable impact on PSA and microsomal clearance, while
retaining potent primary pharmacology, these changes did not
improve recognition by the MDR1 efflux system. This
modification applied to smaller acylamino substituents also
did not appear to be a viable approach. For example, 10h has
greatly diminished CB1 receptor functional activity, and in the
case of the ethoxyacetamido derivative 10i, high microsomal
clearance was observed. An alternative approach pursued to
minimizing molecular weight and maximizing polarity was
replacement of the acylamino functionality of 10d with a
carbamate or urea (10j−l). All three of these analogues retained
potent CB1 receptor pharmacology and have potential to serve
as starting points for further optimization. As part of a broader
profiling of acylamino substituents, cyanocyclopropyl derivative
10m was found to be a subnanomolar antagonist of the CB1
At the outset of this work, it was unclear what impact the
chiral center in this series would have on CB1 receptor
antagonism. Single crystal X-ray structures of the p-
bromobenzamide derivatives of the enantiomers of 8 confirmed
our initial modeling analysis showing the amide substituent
would occupy nearly identical space for both isomers. Analysis
of the individual enantiomers of 10c revealed that essentially all
the CB1 receptor inhibitory activity resides in the R-enantiomer
(10d), with it being 250-fold more potent than the S-
enantiomer (10e). The three carbon atoms bridging the
oxygen atom and the chiral center of the fused 7-membered
ring occupy significant steric space on opposite faces of the
bicyclic core for the enantiomers of 10 (Figure 1). It is
therefore likely that these bridging atoms are responsible for
driving the differential CB1 receptor affinity observed for the
enantiomers of 10.
To confirm that this series possessed functional CB1 receptor
antagonism in vivo, 10d was screened in two legs of the tetrad
assay.22 A 3 mg/kg, subcutaneous dose of 10d in mice
produced a 72% reversal of the analgesia induced by the
cannabinoid agonist CP-55940 in the hot plate model (Figure
2). This dose also fully reversed the hypothermic response
399
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ACS Medicinal Chemistry Letters
Letter
Table 1. In Vitro Pharmacology and Microsomal Stability Data for 1, 2, 8, 9, 10a−q, 11, and 12
hCB1 K
ai
hCB2 K
ai
hCB1 GTPγ[35S] Ki
HLM CLintapp
(mL/min/kg)
MDR1 Papp A:B (×10−6
MDR1
B:A/A:B
a
R′
(nM)
(nM)
(nM)
cm/s)
MW
PSA
1
1.8
1.0
522
1.6
46
<8
N.D.
7.1
N.D.
1.0
464
452
374
388
416
430
444
444
444
484
486
50.4
47.4
53.1
39.1
56.1
56.1
56.1
56.1
56.1
56.1
65.4
2
>10,000
0.82
b
8
57
N.D.
21
N.D.
N.D.
14.1
12.1
6.9
N.D.
N.D.
1.7
9
46
N.D.
54
10a
10b
10c
10d
10e
10f
10g
methyl
ethyl
0.75
0.41
0.16
0.14
5.1
20,600
16,600
5,400
3,290
11,000
953
0.87
0.11
0.04
0.03
7.5
<8
28
1.5
iso-propyl
50
2.2
iso-propyl (R-ent)
iso-propyl (S-ent)
cyclohexyl
25
8.4
1.3
42
N.D.
N.D.
6.8
N.D.
N.D.
1.1
0.59
0.09
0.05
0.07
>250
41
4-
15,200
tetrahydropyranyl
10h
10i
10j
10k
10l
methoxymethyl
ethoxymethyl
methoxy
1.4
15,400
6,540
5.6
42
206
<8
15
9.1
6.5
1.9
2.0
446
460
432
460
445
467
469
469
470
494
458
442
65.4
65.4
65.4
65.4
68.2
79.9
82.2
82.2
95.1
98.7
47.4
47.4
0.56
0.25
0.26
0.12
0.13
1.6
1.2
>30,000
N.D.
0.72
0.12
0.11
0.08
0.26
0.23
0.08
0.82
4.3
9.1
1.9
iso-propoxy
N-ethylamino
N.D.
6.3
N.D.
2.7
14,700
21,200
16,900
12,100
>30,000
59,000
8,700
34
10m 1-cyanocyclopropyl
<8
<8
36
1.0
1.5
10n
10o
10p
10q
11
isoxazol-3-yl
isoxazol-5-yl
1,2,5-oxadiazol-3-yl
MeSO2CH2-
iso-propyl
6.6
1.5
0.55
1.7
3.2
2.1
<8
16
3.0
3.5
0.54
4.5
2.7
2.9
134
N.D.
11.2
N.D.
1.7
12
1.0
75,600
6.5
149
a
b
These data were obtained from one to three determinations run in triplicate. Value not determined.
and 10o retain subnanomolar potency against the CB1 receptor
and low predicted microsomal clearances. Oxadiazole 10p, with
a PSA of 95, which is near the upper limit of that observed for
CNS drugs,25 retains excellent CB1 receptor functional
antagonism (80 pM) and is predicted to be a low clearance
compound on the basis of HLM analysis. Assessment in
MDR1-MDCK revealed 10p to possess a B/A:A/B ratio of 3.5,
which is consistent with it being an efflux substrate. This data,
along with a low to moderate passive permeability (3 × 10−6
cm/s), is suggestive that the CNS exposure of 10p would be
significantly restricted in humans.22 CB1 receptor pharmacology
was found to tolerate the β-ketone sulfone functionality of 10q,
which is in similar PSA space to 10p. MDR1 mediated efflux
(B/A:A/B = 2.9) and moderate permeability (2.7 × 10−6 cm/s)
were also observed for 10q, suggesting the potential for
reduced brain exposure.
Figure 2. Reversal of CP-55940-induced analgesia and hypothermia in
mice by 1 or 10d.
In summary, the acylamino substituted bicyclic design 3 has
been shown to possess potent and selective CB1 antagonism.
Resolution of the enantiomeric acylamino derivatives revealed
that CB1 receptor binding and antagonism resides mostly in the
R-isomer. A prototypical member (10d) of this series has
demonstrated in vivo functional antagonism of CB1-mediated
behaviors and oral activity in a rodent model of feeding.
Toward a goal of peripheral-restriction, structure−activity
studies revealed that introduction of polar functionality into
the acylamino substituent is tolerated. The profiles observed for
both 10p and 10q suggest that they may hold potential as
peripherally targeted agents or serve as starting points for
further optimization toward this goal.
Figure 3. Inhibition of cumulative food intake in rats following an oral
dose of 1 or 10d.
receptor and to exhibit low microsomal clearance and enhanced
PSA. Evaluation of the above compounds in the Madin−Darby
canine kidney cell line transfected with the MDR1 gene
(MDR1-MDCK)24 suggests that they are unlikely to be
substrates for the MDR1 transporter.
Incorporation of small polar heteroaromatics (10n−p)
resulted in a more promising profile, with PSA values up to
40 units higher than that of 10d. Regioisomeric isoxazoles 10n
400
dx.doi.org/10.1021/ml3000325 | ACS Med. Chem. Lett. 2012, 3, 397−401

ACS Medicinal Chemistry Letters
Letter
receptor blockade improves cardiometabolic risk in mouse models of
obesity. J. Clin. Invest. 2010, 120, 2953−2966.
ASSOCIATED CONTENT
■
S
* Supporting Information
(16) Dow, R. L.; Carpino, P. A.; Hadcock, J. R.; Black, S. C.; Iredale,
P. A.; DaSilva-Jardine, P.; Schneider, S. R.; Paight, E. S.; Griffith, D. A.;
Scott, D. O.; O’Connor, R. E.; Nduaka, C. I. Discovery of 2-(2-
chlorophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropyl)-6,7-dihydro-
2H-pyrazolo[3,4-f][1,4]oxazepin-8-(5H)-one (PF-514273), a novel,
bicyclic lactam-based cannabinoid-1 receptor antagonist for the
treatment of obesity. J. Med. Chem. 2009, 52, 2652−2655.
(17) Log D measurements were determined by shake flask method
partitioning between 1-octanol:0.1 aqueous sodium phosphate (pH
7.4) for 24 h.
Experimental details for the syntheses and the spectroscopic
and pharmacological characterizations of the compounds in this
paper. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: (860) 441-4423. E-mail: robert.l.dow@pfizer.com.
(18) Hanus, L. O.; Mechoulam, R. Novel natural and synthetic
ligands of the endocannabinoid system. Curr. Med. Chem. 2010, 17,
1341−1359.
Notes
The authors declare no competing financial interest.
(19) Shim, J.-Y.; Welsh, W. J.; Cartier, E.; Edwards, J. L.; Howlett, A.
C. Molecular interaction of the antagonist N-(Piperidin-1-yl)-5-(4-
chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox-
amide with the CB1 cannabinoid receptor. J. Med. Chem. 2002, 45,
1447−1459.
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