Discovery of 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4- ethylamino-piperidine-4-carboxylic Acid Amide Hydrochloride (CP-945,598), a novel, potent, and selective cannabinoid type 1 receptor antagonist

Article abstract of DOI:10.1021/jm8012932

We report the structure-activity relationships, design, and synthesis of the novel cannabinoid type 1 (CB₁) receptor antagonist 3a (CP-945,598). Compound 3a showed subnanomolar potency at human CB₁ receptors in binding (K_i= 0.7 nM) and functional assays (K _i = 0.12 nM). In vivo, compound 3a reversed cannabinoid agonist-mediated responses, reduced food intake, and increased energy expenditure and fat oxidation in rodents. The endocannabinoid system (ECS ^a), and speci?cally the cannabinoid 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 CB ₁ receptor decreases food intake and increases energy expenditure, leading to a reduction in body weight.^8-11 It was hoped that CB ₁ ceptor 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 Unfortunately, several CB₁ receptor inverse agonists/antagonists were recently withdrawn from clinical development including the diarylpyrazole rimonabant¹² 1 (SR141716A) and the acyclic amide taranabant¹³2 (MK-0364). Herein, we describe the design strategies that led to the identi?cation of a series of purine derivatives as CB₁ receptor antagonists, and the optimization of PK properties that resulted in the discovery of the orally active 3a (CP-945,598), a novel, potent, and selective CB₁ receptor antagonist, recently evaluated in phase 3 clinical trials for weight management.

Full text of DOI:10.1021/jm8012932

234
J. Med. Chem. 2009, 52, 234–237
Letters
Discovery of 1-[9-(4-Chlorophenyl)-8-
(2-chlorophenyl)-9H-purin-6-yl]-4-ethylamino-
piperidine-4-carboxylic Acid Amide
Hydrochloride (CP-945,598), a Novel, Potent,
and Selective Cannabinoid Type 1 Receptor
Antagonist
Figure 1. Medchem strategy.
David A. Griffith,* John R. Hadcock, Shawn C. Black,†
Philip A. Iredale, Philip A. Carpino, Paul DaSilva-Jardine,
Robert Day,‡ Joseph DiBrino, Robert L. Dow,
Margaret S. Landis, Rebecca E. O’Connor, and
Dennis O. Scott
Department of CardioVascular, Metabolic, and Endocrine Diseases
and Department of Neuroscience, Pfizer Global Research and
DeVelopment, Groton, Connecticut 06340
Figure 2. Lowest energy conformation of 1 where the carbonyl is
adjacent to the methyl, constrained purine analogue (3b), and an overlay
of the two structures (A).22
ReceiVed October 14, 2008
Abstract: We report the structure-activity relationships, design, and
synthesis of the novel cannabinoid type 1 (CB1) receptor antagonist
3a (CP-945,598). Compound 3a showed subnanomolar potency at
human CB1 receptors in binding (Ki ) 0.7 nM) and functional assays
(Ki ) 0.12 nM). In vivo, compound 3a reversed cannabinoid agonist-
mediated responses, reduced food intake, and increased energy
expenditure and fat oxidation in rodents.
We hypothesized that conformationally restricted analogues
of 1 that adopt its bioactive conformation would have improved
potency.14 In designing our targets, we looked to minimize
lipophilicity to achieve low metabolic clearance and good
solubility. To achieve good central nervous system (CNS)
penetration, we sought compounds with low molecular weight
(MW < 450), moderate topological polar surface area (TPSA
< 90), and less than two hydrogen-bond donors (HBD).15,16
Finally, we wanted to remove the hydrazine functionality and
the corresponding potential to generate reactive metabolites.17-20
A reasonable low-energy conformation of 1, depicted in
Figure 1, minimizes the dipole interaction between the pyrazole
and the amide carbonyl and allows for a hydrogen bond to form
to the pyrazole N1 atom. We hypothesized that purine analogues
would mimic this low energy conformation, locking the bio-
active conformation of 1 while also providing a hydrogen bond
acceptor to mimic the amide carbonyl.21 There is excellent
overlap of the minimized conformations22 of 1 (lowest energy
conformation where the carbonyl is adjacent to the methyl) and
the corresponding purine analogue as depicted in Figure 2.
The synthesis of these compounds is illustrated in Scheme
1.23 Reaction of 4-chloroaniline with 4,6-dichloro-5-aminopy-
rimidine (4) in refluxing aqueous hydrochloric acid24 provided
diaminopyrimidine 5. Acylation with the appropriate benzoyl
chlorides gave amides 6a,b, which were then cyclized to
purinones 7a,b by heating under acidic conditions. The key
chloropurines 8a,b, obtained by heating 7a,b in the presence
of phosphorus oxychloride, were useful for preparing a variety
of nitrogen, oxygen, and carbon-linked analogues.25 In the
present case, primary and secondary amines readily react with
chloropurines 8a,b to give the desired 6-alkylaminopurine
analogues 3a-g.
The endocannabinoid system (ECSa), and specifically the
cannabinoid 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 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 rimonabant12 1 (SR141716A) and the acyclic
amide taranabant13 2 (MK-0364).
Herein, we describe the design strategies that led to the
identification of a series of purine derivatives as CB1 receptor
antagonists, and the optimization of PK properties that resulted
in the discovery of the orally active 3a (CP-945,598), a novel,
potent, and selective CB1 receptor antagonist, recently evaluated
in phase 3 clinical trials for weight management.
* To whom correspondence should be addressed. Phone: 860-441-6215.
Fax: 860-715-8324. E-mail: david.a.griffith@pfizer.com.
†
Current address: Johnson & Johnson Pharmaceutical Research &
Development, Welsh and McKean Roads, Spring House, PA 19477-0776.
‡
Current address: Novartis Institutes for Biomedical Research, Inc., 100
Technology Square, Cambridge, MA 02139.
a Abbreviations: ECS, endocannabinoid system; CB1, cannabinoid type
1; CNS, central nervous system; eLLE, ligand-lipophilicity efficiency using
measured ElogD; MW, molecular weight; TPSA, topological polar surface
area; HBD, hydrogen-bond donors; SAR, structure-activity relationship;
FIRF; fast-induced refeeding; P-gp, P-glycoprotein; MDCK, Madin-Darby
canine kidney.
Compound 3b, the corresponding conformationally con-
strained analogue of 1, exhibited good in vitro binding and
functional affinity, confirming the feasibility of our approach
(Table 1). The intrinsic microsomal clearance of this compound
was high, attributed to its lipophilicity (ElogD ) 5.3).26 The
10.1021/jm8012932 CCC: $40.75
2009 American Chemical Society
Published on Web 12/22/2008

Letters
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 2 235
Scheme 1. Synthesis of Purines 3a-ga
nM) assays. In vivo, 3a reversed four cannabinoid agonist-
mediated behaviors (locomotor activity, hypothermia, analgesia,
and catalepsy) following administration of the synthetic CB1
receptor agonist 5-(1,1-dimethylheptyl)-2-[(1S,2S,5S)-5-hydroxy-
2-(3-hydroxypropyl)cyclohexyl]phenol, 9 (CP-55,940).29 Com-
pound 3a exhibited dose-dependent anorectic activity in a model
of acute food intake in rodents and increased energy expenditure
and fat oxidation.30
Comparison of brain to plasma concentration ratios in
P-glycoprotein (P-gp) knockout (mdr1a/1b-/-) vs wild-type
mice31 with 3a indicated P-gp-mediated efflux (data not shown).
Furthermore, the brain to plasma unbound concentration ratio
of 3a in rats measured in the FIRF assay was ∼0.1 (Table 2).
Despite these data indicating active efflux from the CNS in
rodents, preclinical efficacy of 3a was demonstrated in a number
of animal models.30 Human dose predictions assumed impaired
CNS penetration as observed in rats. Good plasma/brain
concentration-effect relationships have been observed wherein
reductions in food intake correlate with compound potency and
free CNS drug levels.32 Studies in Caco-2 cells and Madin-Darby
canine kidney (MDCK) cells expressing human MDR133
indicated moderate permeability of 3a but suggested no active
efflux from the CNS in humans. This was confirmed in an in
vitro ATPase assay34 in human cells where no or low ATP
turnover was observed at 1.25-25 mM 3a (data not shown).
By use of a calcein-AM assay35 in human cell lines, 3a was
shown to be a weak P-gp inhibitor, with IC50 ranging from 15
to 30 mM, indicating it is unlikely that 3a will inhibit P-gp in
the CNS. Further details of the pharmacology of 3a will be
reported in future publications.
a (a) HCl, EtOH/H2O, reflux; (b) pyridine or dimethylacetamide; (c)
AcOH, reflux; or H2SO4, iPrOH, reflux; (d) POCl3, reflux; or POCl3, Et3N,
toluene, reflux; (e) HNRR′.
structure-activity relationships (SAR) of the amine headgroup
were readily explored using small libraries, though the high MW
of the purine core limited the size of amines employed.
Replacement of the 1-aminopiperidinyl moiety with various
small, lipophilic head groups did not lead to any loss of affinity.
However, the compounds still showed rapid clearances in
microsomal preparations. The lipophilicity of the series was
reduced by removing one of the chloro atoms on the N1 phenyl
group, leading to improved metabolic stability. For example,
3e exhibited a 9-fold decrease in intrinsic microsomal clearance
relative to 3d.
Compound 3d was shown to be biologically active in
reversing two of the cannabinoid agonist-induced tetrad of
behaviors following subcutaneous injection, but it was not orally
active in an animal model of feeding behavior (Table 2) because
of poor exposure of this compound. Peripheral and central
unbound drug concentrations were 2 orders of magnitude below
the rat Ki (rKi). Poor oral exposure was not surprising given its
high lipophilicity, which resulted in high unbound intrinsic
clearance and poor solubility.27
Incorporation of heteroatoms (e.g., polar headgroups, het-
erocyclic replacements for the chlorophenyls) improved the
solubility of compounds (e.g., 3f and 3g; Table 2). Compound
3f was the first orally active analogue in the series as
demonstrated by its efficacy in inhibiting fast-induced refeeding
(FIRF, Table 2). Central exposure was ∼17% rKi 2 h postdosing.
Compound 3f exhibited potent activity in the hERG potassium
ion channel assay, suggesting possible issues with QTc pro-
longation. We therefore sought to introduce an electron-
withdrawing substituent adjacent to the amine to increase the
polarity of the molecule and decrease the basicity of the adjacent
amine, with the aim of attenuating the microsomal clearance
and hERG affinity.28 Library and singleton chemistries were
used to prepare analogues containing polar basic amines, taking
care not to increase PSA too high and impair CNS permeability.
The 4-alkylamino-4-aminocarbonylpiperidine headgroup proved
ideal and balanced the properties of 3a, resulting in a potent
cannabinoid CB1 receptor antagonist (Table 1) with moderate
unbound microsomal clearance, low hERG affinity, and adequate
CNS penetration. While the rat binding affinity of 3a is similar
to that of 3f, 3a was more potent in the human binding and
functional assays (Table 1). Furthermore, 3a also displayed
anorectic properties in the FIRF assay (Table 2) with unbound
exposure similar to 3f at 2 h. Compound 3a has similar in
vitro potency but ∼6-fold lower intrinsic microsomal clear-
ance than 1.
Despite our best intentions, 3a exceeded several physio-
chemical criteria we had set at the outset of the project (MW,
510; TPSA, 102; HBD, 3). The moderately impaired CNS
penetration observed in rodents was unsurprising given the
physiochemical properties of 3a that lie outside the typical CNS
property space.36,37 The geminal arrangement of the aminoamide
functionality was critical to achieving reasonable CNS penetra-
tion. It is apparent from the crystal structure (data not shown)
that a hydrogen bond between the amide NH and the amine
lone pair may reduce the effective polarity and allow for
reasonable CNS penetration. Further details of this SAR will
be reported in future publications.
Ligand efficiency38 (Table 1) remained fairly constant,
ranging from 0.36 to 0.41, for the compounds described above.
During our designs we were careful to use lipophilicity as
efficiently as possible. Significant gains were made in the
binding energy achieved by nonlipophilic interactions, as
reflected in the ligand-lipophilicity39 (eLLE, ligand-lipophilicity
efficiency using measured ElogD) increases observed during
the course of our work. Compound 3d, which lacked oral
efficacy, had an eLLE of 2.3. Judicious introduction of polarity
provided orally efficacious 3f with an eLLE of 3.3. Further
optimization gave candidate 3a with an eLLE of 5.2.
In summary, a novel purine derivative 3a was discovered with
good CB1 receptor binding and functional activity and good in
vivo activity in rodent models of feeding. Judicious introduction
of polar functionality to reduce lipophilicity led to reductions
in intrinsic clearance and hERG activity. Compound 3a falls
outside the normal property space for a CNS agent, yet still
exhibits good efficacy. Clinical development of 3a was recently
discontinued on the basis of changing regulatory perspectives
on the risk/benefit profile of the CB1 class and likely new
regulatory requirements for approval.
Compound 3a showed subnanomolar potency at human CB1
receptors in binding (hKi ) 0.7 nM) and functional (Ki ) 0.12

236 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 2
Letters
Table 1. Biochemical Properties of Purine CB1 Antagonists 1 and 3a-ga
a MW, molecular weight; h, human; r, rat; LE, ligand efficiency; eLLE, ligand-lipophilicity efficiency using measured ElogD; µsome, liver microsome.
Table 2. Biological Characteristics of Purine CB1 Antagonists 3a-ga
a FIRF, fast-induced refeeding; po, oral administration; sc, subcutaneous; /, P < 0.05 vs vehicle; †, P < 0.05 vs the cannabinoid CB1 receptor agonist
9; a, 20 mg/kg.
Acknowledgment. We thank D. Gautreau, J. Lizano, D.
Kelly-Sullivan, K. Ward, A. Swick, D. Dutcher, K. Dernberger,
A. Rosado, M. Niosi, and M. Hammond for their contributions
to this study. This study was sponsored by Pfizer, Inc. Editorial
support was provided by C. S. Lee, Ph.D., at Envision Pharma
and was funded by Pfizer, Inc.
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