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

Article abstract of DOI:10.1021/jm900255t

We report the design, synthesis, and structure-activity relationships of novel bicyclic lactam-based cannabinoid type 1 (CB₁) receptor antagonists. Members of these series are potent, selective antagonists in in vitro/in vivo efficacy models of CB1 antagonism and exhibit robust oral activity in rodent models of food intake. These efforts led to the identification of 19d, which has been advanced to human clinical trials for weight management.

Full text of DOI:10.1021/jm900255t

2652
J. Med. Chem. 2009, 52, 2652–2655
Letters
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
Robert L. Dow,* Philip A. Carpino, John R. Hadcock,
Shawn C. Black,† Philip A. Iredale, Paul DaSilva-Jardine,
Steven R. Schneider, Ernest S. Paight, David A. Griffith,
Dennis O. Scott, Rebecca E. O’Connor, and
Chudy I. Nduaka
Departments of CardioVascular, Metabolic and Endocrine Diseases,
Neuroscience, and Drug Safety, Pfizer Global Research and
DeVelopment, Groton, Connecticut 06340
Figure 1. Structures of 1, 2, and bicyclic pyrazoles.
ReceiVed February 28, 2009
preclinical safety studies, this side effect profile and narrow TI
appear to be a class effect associated with the pyrazolopyrimi-
dinone core structure. Herein we describe efforts to overcome
these issues, resulting in the identification of 19d (PF-514273)
which has been advanced to human clinical trials for weight
management.
On the basis of the promising in vitro profile of members of
bicyclic series such as 3, follow-on efforts focused on ap-
proaches toward improving the solubility properties within this
class. One of several tacks pursued toward improving solubility
was disruption of the planar nature of the bicyclic core of these
systems. We reasoned that fused six-/seven-membered lactam
systems such as 4 and 5 would have the potential to provide
improved oral bioavailability, relative to the pyrazolopyrimi-
dinone core, via disruption of crystal packing forces.15 In
addition, it was hoped that this significant alteration of the core
chemotype of 3 would afford a greater preclinical safety window
while retaining a desirable CB1 antagonist profile.
When the overlays of low energy conformations are com-
pared, a better overlap of the lactam nitrogen substituent (R)
with the piperdinyl side chain of 1 is predicted for 4 relative to
regioisomeric lactam 5. However, previous results from our
laboratory (unpublished) with a series of N-acylated 3-ami-
nopyrazoles had revealed positive in vitro micronucleus activity
associated with this chemotype. Not surprisingly, initial ana-
logues from series 4 were also found to possess this genetoxic
liability. This finding led us to direct our efforts on regioisomeric
lactams 5.
Synthesis of the six-membered lactam series 5 (X ) bond)
is detailed in Scheme 1. Bromopyrazole 616 is homologated via
Stille vinylation to afford 7. Hydrolysis and amidation afford
amides 9a-i. Hydroboration of the olefin and conversion of
the hydroxyl group to mesylates 11a-i set the stage for
cyclization via intramolecular alkylation employing lithium
bis(trimethylsilyl)amide to afford lactams 12a-i. The corre-
sponding amine-based bicyclic 13 is prepared from 12i by
reduction with lithium aluminum hydride (Figure 2).
Abstract: We report the design, synthesis, and structure-activity
relationships of novel bicyclic lactam-based cannabinoid type 1 (CB1)
receptor antagonists. Members of these series are potent, selective
antagonists in in vitro/in vivo efficacy models of CB1 antagonism and
exhibit robust oral activity in rodent models of food intake. These efforts
led to the identification of 19d, which has been advanced to human
clinical trials for weight management.
The endocannabinoid system, and specifically the cannabinoid
a
type 1 (CB1 ) receptor, plays a pivotal role in energy
homeostasis.1-3 As such, stimulation of the ECS promotes food
intake and energy storage and may be chronically overactive
in obese subjects.4-7 In contrast, blockade of the CB1 receptor
decreases food intake and increases energy expenditure, leading
to a reduction in body weight.8-11
CB1 receptor antagonists may provide effective therapy
options for the management of metabolic disorders, such as
obesity. It was hoped that CB1 receptor antagonists might
provide effective therapy options for the management of
metabolic disorders, such as obesity. Unfortunately, several CB1
receptor inverse agonists/antagonists were recently withdrawn
from clinical development including the diarylpyrazole rimona-
bant12 1 (SR141716A) and the acyclic amide taranabant13
2
(MK-0364) (Figure 1).
Our group recently reported the discovery of a series of potent
pyrazolopyrimidinone-based (e.g., 3) CB1 receptor antagonists.14
While members of this series possess potent CB1 antagonism
in vitro and in vivo, there are issues that have impeded their
further development. These consist of impaired absorption
(solubility-limited) for certain members of the series and more
importantly a very narrow therapeutic index (TI) in preclinical
safety models (vide infra). On the basis of a number of
* To whom correspondence should be addressed. Phone: 860-441-4423.
Fax: 860-441-1128. E-mail: robert.l.dow@pfizer.com.
†
Present address: Johnson & Johnson Pharmaceutical Research and
Development, Welsh & McKean Roads, Spring House, PA 19477-0776.
a Abbreviations: AUC, area under curve; CB, cannabinoid; GTP,
guanosine triphosphate; PK, pharmacokinetic; CNS, central nervous system;
TI, therapeutic index.
Scheme 2 details the preparation of the ether-based lactams
19a-e, starting from the known ketoester 14.17 Insertion of the
diazo species generated from 2-chloroaniline followed by
10.1021/jm900255t CCC: $40.75
2009 American Chemical Society
Published on Web 04/07/2009

Letters
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 2653
Table 1. Biochemical Properties of Lactams 12a-i and 13
Scheme 1. Synthesis of Bicyclic Lactams 12a-ia
CB-1 Ki
CB-2 Ki
GTPγ[35S]
compd
R
(nM)a
(nM)a
(nM)b
1
3
1.8 ( 1.4 1569 ( 845 1.6 ( 0.7
0.6 ( 0.1 >10000
1.0
12a
12b
12c
12d
12e
12f
12g
12h
12i
13
H
61
CH2CH3
4.7
23440
25
CH(CH3)2
CH2CH(CH3)2
C(CH3)3
2.5 ( 0.8 >10000
5.5 ( 0.8
2.5
4.7
24
1780
6810
9.8
11
c-pentyl
CH2C(CH3)2(OCH3) 11
162
>10000
13
3.1 ( 1.4
0.8 ( 0.2
CH2CF3
CH2CF2CH3
1.7 ( 1
0.7 ( 0.2 >10000
30
a Ki determinations (mean ( SD of g3 runs in triplicate or single
a (a) Tributylvinyltin, Pd(Ph3P)4, DMF, 110 °C; (b) KOH, H2O, EtOH,
50 °C; (c) (iPr)2NEt, RNH2, 1-propanephosphonic anhydride; (d) 9-BBN,
THF, 70 °C; (e) MeSO2Cl, TEA, CH2Cl2; (f) LiN(TMS)2, THF.
determination run in triplicate). b CP-55,940 (10 µM) utilized as agonist.
selectivity versus CB2 receptor binding. Incorporation of cy-
cloalkyl (12f) or heteroatoms (12g) into the lactam substituent
had negative effects on CB1 binding and in the latter example
greatly reduced selectivity versus the CB2 receptor.
These early results confirmed that the bicyclic lactam motif
could serve as a replacement for the pyrazolopyrimidinone core.
While structure-activity trends for lactams 12 generally follow
those observed for the pyrazolopyrimidinone series, the one
exception was a lack of translation upon incorporation of small
fluorine containing substituents (12h-i). In the case of the
pyrazolopyrimidinone series incorporation of the trifluoroethyl
or 2,2-difluoropropyl groups provide a >10-fold improvement
in CB1 binding affinity relative to the parent alkyl substituents.14
However, for the lactam series 12 this modification does not
produce a dramatic improvement in affinity or functional
response. While the difference in projected trajectories for the
N-substituents of these two series is subtle, there is clearly a
significant impact on binding affinity for certain pairs of
compounds. These results are consistent with the rather tight
constraints14 on CB1 receptor space in the vicinity of the
N-substituent for these series (e.g., 12f ) 24 nM), which
contrasts with the fairly broad tolerance for substituents in the
vector occupied by the amide functionality of 1.19 This idea is
further supported by the finding that eliminating the in-plane
projection of the difluoropropyl substituent through reduction
to the amine (13) dramatically lowers binding affinity, though
the concomitant production of a basic center could also be
contributing to this resultant loss in potency.
Figure 2. Preparation of amino analogue 13.
Scheme 2. Synthesis of Bicyclic Lactams 19a-ea
a (a) 2-Chloroaniline, NaNO2, AcOH, H2O, 0 °C; (b) CuBr2, EtOAc,
CHCl3, 60 °C; (c) NaOAc, MeOH, reflux; (d) RNHCH2CH2OH, 125 °C;
(e) triphenylphosphine, 1,1′-(azodicarbonyl)dipiperidine, toluene.
Compound 12i was selected for profiling in efficacy and
preclinical safety models based on its in vitro profile. Pharma-
cokinetic analysis in the rat revealed a good profile for 12i (1
mg/kg iv, 5 mg/kg po, F ) 99%, T1/2 ) 3.6 h, Vss ) 2.6 L/kg).
As expected from its structure, this compound penetrates the
brain via passive diffusion and is not excluded by active
transport processes, achieving a steady-state total brain to plasma
ratio of 3.2 (unbound ratio ) 1). Functional antagonism of
central-mediated CB1 pharmacology was confirmed by complete
reversal of four cannabinoid agonist-mediated (CP-55,940)
behaviors (locomotor activity, hypothermia, analgesia, and
catalepsy) at doses of 1 mg/kg, sc, of 12i. Compound 12i
exhibited dose-dependent anorectic activity in a model of acute
bromination and cyclization under mild conditions affords
hydroxypyrazole 17.18 Amide formation with the requisite
N-hydroxyethylamine followed by Mitsunobu cyclization affords
the ether-based lactams 19a-e.
Incorporation of small N-alkyl substituents into the six-
membered bicyclic lactam core (12b-e) provides single-digit
nanomolar CB1 antagonists (Table 1). Comparable levels of
functional CB1 receptor antagonism (GTPγ[32S], CP-55,940
utilized as agonist) are observed, as well as high levels of

2654 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
Letters
Table 2. Biochemical Properties of Lactams 19a-e
CB-1 Ki
CB-2 Ki
GTPγ[35S]
compd
R
(nM)a
(nM)a
(nM)b
1
1.8 ( 1.4
83
1.3
1.9
1.0 ( 0.7
1.4
1569 ( 845
1.6 ( 0.7
19a
19b
19c
19d
19e
H
CH(CH3)2
CH2CF3
CH2CF2CH3
CH2CF2CH2CH3
>10000
>10000
>10000
>10000
4.8
1.5
0.82 ( 0.2
0.7
a Ki determinations (mean ( SD of g3 runs in triplicate or singe
determination run in triplicate). b CP-55,940 (10 µM) utilized as agonist.
component of the binding affinity of 1.21 Given the orientation
of the carbonyl oxygen of lactams 12 and 19 are directed ∼120°
relative to that of 1, it is unlikely that the carbonyl functionality
in the former is interacting with Lys192 of the CB1 receptor.
Table 2 details the CB pharmacology profile of a core set of
ether-based lactams. The ring expanded analogues 19a-e have
CB1 binding affinities that are comparable to the six-membered
lactams and 3. The parallel structure-activity trends between
12 and 19 suggest that the respective lactam substituents are
occupying similar CB1 receptor space.
On the basis of its in vitro biochemical profile, 19d was
selected for further evaluation. Pharmacokinetic analysis in the
rat revealed a good profile (1 mg/kg iv, 5 mg/kg po, F ) 42%,
T1/2 3.5 h, Vss ) 2.6 L/kg). In analogy to 12i, this ether-based
homologue penetrates the brain via passive diffusion and is not
excluded by active transport processes, achieving a total steady-
state brain to plasma ratio of 3.1 (unbound ratio ) 1). Compound
19d was able to completely reverse the four CB1 agonist-
mediated (CP-55,940) effects induced in the rat at doses of g1
mg/kg, sc. On the basis of confirmation of in vivo antagonism
of the CB1 pathway, 19d was evaluated in two models of feeding
behavior. Acute analysis in a fast-induced refeeding rat model
produced a dose-responsive reduction (2 h measurement after
food introduction) in food intake over a 2 h test period. An
oral dose (methyl cellulose vehicle) of 1 mg/kg 19d produced
a 40 ( 11% reduction in food intake, while the positive control
1 was 43 ( 9% at 3 mg/kg. In a chronic setting, 7 days of oral
dosing in diet-induced obese mice, 19d produced a cumulative
23% reduction in food intake at 1 mg/kg relative to a control
group (21% for 3 mg/kg 1). A statistically significant reduction
in weight gain of 5.9 ( 0.8% was observed at the 1 mg/kg
dose over the 7 days, which was comparable to 5.2 ( 0.8%
produced by 1 at 3 mg/kg.
Figure 3. Overlay of crystal structures of 12i (green)/19d (yellow)
and the minimized structure21 of 1.
food intake in rodents and increased energy expenditure and
fat oxidation.
Pyrazolopyrimidinone 3 and close-in analogues exhibited
substantial adverse behavioral effects in preclinical efficacy and
early safety studies in rats. From these studies with 3, a TI of
at most 10-fold (based on plasma concentrations) is projected
for this class of compounds.20 Broad receptor profiling failed
to identify any specific pharmacological end points that might
be associated with these behavioral side effects. In contrast,
efficacy studies with 12i and related analogues appeared to be
devoid of the frank toxicities observed in similar studies with
3. Evaluation of 12i in a 4-day, rat in vivo toleration assay
reveals this compound to possess a relatively clean safety profile.
On the basis of plasma exposures, it is estimated that 12i
possesses a TI in the 40- to 200-fold range, a significant
improvement relative to the pyrazolopyrimidinone class of
agents.
Regarding the expectation that the bicyclic lactam motif
would aid in disruption of the planar nature of the pyrazolopy-
rimidinone ring present in 3 (mp ) 225 °C), crystalline 12i has
a relatively low melting point (103 °C). While the aqueous
solubility of 12i is very low (0.2 µg A/mL), crystalline material
exhibits high oral bioavailability at doses up to 50 mg/kg in rat
(50% at 500 mg/kg). The greater than expected fraction
absorbed, based on experimentally determined aqueous solubil-
ity, suggests enhanced solubilization of 12i in the intestinal tract.
This is supported by solubility measurements in media intended
to replicate the mixed micelles (sodium taurocholate/phosphati-
dyl choline salts) found in intestines that provide a nearly 100-
fold increase in solubility (18.5 µg A/mL) for 12i.
The hypothesis that disruption of the planar nature of 3 was
responsible for the improved safety profile and improved
physical properties associated with series 12 led to the design
of seven-membered lactams 5 (X ) O). These ether-based
lactam structures were hypothesized to possess improved
physical properties due to increased polar surface area and
greater disruption of crystal packing forces relative to the six-
membered lactam series. Also, from overlays of the modeled
structures (confirmed by crystal structures, see Figure 3), the
amide substituent vector of the seven-membered lactams is
predicted to be directed closer to that of the amide functionality
of 1, allowing for interactions of the lactam substituent with
CB1 binding domains not accessible from 12. Previous work
has hypothesized that a hydrogen bond between the carbonyl
oxygen of 1 and Lys192 of the CB1 receptor is a significant
No clinical signs or histological changes were observed for
19d in a 4 day in vivo safety assessment of 19d in rats ((3/
sex)/dose) at oral doses of 5, 50, and 500 mg/kg. Pharmacoki-
netic analysis of this study revealed good dose proportional
plasma exposures up to 50 mg/kg and with oral bioavailability
of crystalline material (methylcellulose vehicle) ranging from
51 to 74%. At the top dose of 500 mg/kg, the average plasma
AUC was >170 mg ·h/mL for both sexes. These results
combined with the plasma concentrations required for efficacy
in the feed intake studies provide a minimum safety TI of 200-
fold in the rat. Further details on the efficacy, pharmacokinetic,
and safety profiles of 19d will be the subject of future
publications.
In summary, we have discovered a novel series of bicyclic
lactams that are potent, selective CB1 receptor antagonists.

Letters
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Improved solubility through disruption of crystal packing forces
has led to improved oral efficacy in models of feeding behavior
relative to lead 3. In addition, these agents show substantially
improved safety profiles relative to the initial lead 3. On the
basis of its pharmacological, pharmacokinetic, and early safety
profile, compound 19d was advanced to human clinical studies
for weight management.
Acknowledgment. We thank Robert Day, Darrin Dutcher,
Denise Gautreau, Jeffrey Lizano, Mark Niosi, Dawn Kelly-
Sullivan, Andrew Swick, and Karen Ward for their contributions
to this study.
Supporting Information Available: Experimental details, X-ray
crystallographic data, and elemental analysis results. This material
is available free of charge via the Internet at http://pubs.acs.org.
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