Discovery of 1-{2-[(1S)-(3-dimethylamino-propionyl)amino-2-methylpropyl]-4- methyl-phenyl}-4-[(2R)-methyl-3-(4-chlorophenyl)-propionyl]piperazine as an orally active antagonist of the melanocortin-4 receptor for the potential treatment of cachexia

Article abstract of DOI:10.1021/jm070806a

A potent and selective antagonist of the melanocortin-4 receptor, 1-{2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-6-methylphenyl} -4-[(2R)-methyl-3-(4-chlorophenyl)propionyl]piperazine (10d), was identified from a series piperazinebenzylamine a

Full text of DOI:10.1021/jm070806a

J. Med. Chem. 2007, 50, 5249-5252
5249
Discovery of 1-{2-[(1S)-(3-Dimethylamino-
propionyl)amino-2-methylpropyl]-4-methyl-
phenyl}-4-[(2R)-methyl-3-(4-chlorophenyl)-
propionyl]piperazine as an Orally Active
Antagonist of the Melanocortin-4 Receptor for
the Potential Treatment of Cachexia
Chen Chen,* Wanlong Jiang, Fabio Tucci,† Joe A. Tran,
Beth A. Fleck, Sam R. Hoare, Margaret Joppa,
Stacy Markison, Jenny Wen, Yang Sai, Michael Johns,
Ajay Madan, Takung Chen, Caroline W. Chen,
Dragan Marinkovic, Melissa Arellano, John Saunders,‡ and
Alan C. Foster
Department of Medicinal Chemistry, Department of Pharmacology,
Department of Neuroscience and Department of Preclinical
DeVelopment, Neurocrine Biosciences, Inc., 12790 El Camino Real,
San Diego, California 92130
ReceiVed July 5, 2007
Abstract: A potent and selective antagonist of the melanocortin-4
receptor, 1-{2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpro-
pyl]-6-methylphenyl}-4-[(2R)-methyl-3-(4-chlorophenyl)propionyl]pip-
erazine (10d), was identified from a series piperazinebenzylamine
attached with a N,N-dimethyl-â-alanine side chain. This compound
possessed high water solubility and exhibited good metabolic profiles.
In animals, 10d showed moderate to good oral bioavailability and
promoted food intake in tumor-bearing mice after oral administration.
Figure 1. Chemical structures of MC4R antagonists 1-5 and agonist
6 (THIQ).
phenylalanine dipeptide derivative 2 is a potent functional
MC4R antagonist with negligible affinity at MC3R.16 Intrap-
eritoneal (i.p.) administration of 2 effectively stimulates daytime
(satiated) food intake as well as decreases basal metabolic rate
in normal animals. Furthermore, this compound attenuates
cachexia and preserves lean body mass in a murine cancer
cachexia model.17
In addition, a series of bispiperazine derivatives exemplified
by 3 have been reported as potent MC4R antagonists with in
vivo effects in rodents.18-20 These data provide evidence for
the potential clinical utility of small molecule MC4R antagonists,
particularly in the treatment of cachexia.21
We have previously reported the discovery of a series of
piperazinebenzylamines such as 4 (Ki ) 19 nM) and 5 (Ki )
6.5 nM) as MC4R antagonists.22,23 Based on these leads, we
started a research effort to improve their properties in several
categories including potency and pharmacokinetics. Here we
report the identification and characterization of 1-{2-[(1S)-(3-
dimethylaminopropionyl)amino-2-methylpropyl]-6-methylphe-
nyl}-4-[(2R)-methyl-3-(4-chlorophenyl)propionyl]piperazine (10d)
as an orally active MC4R antagonist for the potential treatment
of cancer cachexia.
The target compounds were synthesized from the protected
piperazinebenzylamine 624 as shown in Scheme 1. After a
treatment of 6 with TFA, the resultant amine was coupled with
(2R)-methyl-3-(2-Y-4-chlorophenyl)propionic acids to give the
amides 7, which was deprotected with HCl in methanol to afford
the benzylamines 8. Reductive alkylation of 8a with methyl-
(2-oxoethyl)carbamic acid tert-butyl ester provided the diamine
9 after Boc-deprotection. Alternatively, coupling reactions of 8
with N,N-dimethylamino-â-alanine gave the amides 10b-d or,
with N-Boc-amino acid, afforded 10a and 10e-f after TFA
treatment.
Cancer cachexia significantly impairs quality of life and
response to antineoplastic therapies and increases morbidity and
mortality of cancer patients. Unfortunately, currently available
drugs do not provide very effective treatment.1,2
The melanocortin-4 receptor (MC4R), a member of the class
A G-protein-coupled receptor superfamily, plays a very impor-
tant role in feeding behavior and energy homeostasis in animals
and humans.3 Human MC4R mutations are associated with binge
eating and juvenile-onset obesity.4,5 MC4R agonists have been
demonstrated to suppress food intake and reduce body weight
in animals and could potentially be used for the treatment of
obesity.6 In contrast, MC4R antagonists have been shown to
promote food intake and increase weight gain.7 Recent studies
have also demonstrated that cachexia brought about by a variety
of illnesses can be attenuated or reversed by blocking activation
of the melanocortin-4 receptor within the central nervous
system.8 Centrally-administered peptide MC4R antagonists
attenuate tumor-induced cachexia in animal models.9-12
Recently, small molecule MC4R antagonists have been
identified that are suitable for peripheral administration.12
A
2-phenylimidazoline 1 (ML00253764, Figure 1) is reported to
be a functional MC4R antagonist (IC50 ) 103 nM) and to
improve cachexia symptoms in C57BL6 mice bearing Lewis
lung carcinoma tumors.13,14 However, this compound also has
relatively weak affinity for MC4R and poor selectivity versus
the MC3R, a subtype that is also believed to have a role in
feeding regulation.15 We have shown that a â-alanine-(2,4-Cl)-
* To whom correspondence should be addressed. Phone: 858-617-7634.
Fax: 858-617-7602. E-mail: cchen@neurocrine.com.
Compounds 8-10 were tested for their binding affinity at
the human melanocortin-4 receptor using a binding assay as
previously described,25 and results are summarized in Table 1.
For the primary benzylamines 8, the 2-methyl derivative 8b had
† Current address: Department of Medicinal Chemistry, Tanabe Research
Laboratories, U.S.A., Inc., 4540 Towne Centre Ct., San Diego, CA 92121.
‡ Current address: Vertex Pharmaceuticals Inc., 11010 Torreyana Road,
San Diego, CA 92121.
10.1021/jm070806a CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/05/2007

5250 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22
Letters
Scheme 1a
Table 2. Selectivity Profiles (Ki, nM) of MC4R Antagonists at Human
Melanocortin Receptorsa
cmpd
MC1Rb
MC3R
MC4R
MC5R
10a
10d
10e
10f
n.d.c
(50%)
(43%)
(42%)
230d
420
710
270
2.8
2.8
5.7
5.9
180d
340
360
320
a Data are average of 2-3 independent measurements of binding affinity
using [125I]-NDP-MSH as the radiolabeled ligand. The affinity measure-
ments for each compound differed by 2-fold at most, and the resulting
coefficient of variance averaged 20%. b For results where a Ki value could
not be determined (<50% inhibition at highest compound concentration
tested), percentage inhibition at 10 µM concentration in parenthesis. c Not
determined. d Single measurement.
Table 3. In Vitro Metabolism Data of 8c-10f
CYP3A4a
IC50 (µM)
HLM Clsys
Papp
ratiod,e
(b to a/a to b)
b
c,e
cmpd
(mL/min‚kg)
(×10-6 cm/s)
8c
9
8.3
9.0
6.9
6.4
6.8
9.2
6.0
10
13.4
n.d.f
12.4
16.0
16.6
12.2
4.8
5.0
0.3
0.8
3.7
1.9
6.2
1.2
0.3
3.7
26
10a
10b
10c
10d
10e
10f
7.3
3.0
2.7
1.9
7.2
26
9.2
a Reagents and conditions: (a) TFA/CH2Cl2/rt, 1 h; (b) (R)-2-Y-4-
ClC6H3CH2CH(Me)COOH/EDC/HOBt/(i-Pr)2NEt/CH2Cl2/rt, 8 h, 37% for
7c; (c) HCl/MeOH/rt, 1 h, 50-60%; (d) N-Boc-NMeCH2CHO/NaB-
H(OAc)3/CH2Cl2/rt, 2 h, 21%; (e) RCOOH/EDC/HOBt/CH2Cl2/rt, 8 h, 68%
for 10a and 78% for 10d.
a Binding affinity at the cytochrome P450 3A4 enzyme. b Scaled systemic
clearance in human liver microsomes. c Permeability in Caco-2 cell mono-
layer. d Ratio of Papp of basolateral to apical direction versus that of apical
to basolateral direction. e Digoxin was used as a control in this assay, and
its Papp was about 1.0, with a ratio of 10-30. f Not determined.
Table 1. SAR of MC4R Antagonists at the Human Melanocortin-4
Receptora
fold better affinity than its parent 8a. Similar results were also
obtained for 8b/10c and 8c/10d modifications. The N,N-
dimethylamino-â-alanine derivatives 10b-d were optimal,
because the N-monomethyl compound 10e and the primary
amine 10f showed no improvement in affinity compared with
10d. These compounds were distinguished by their functional
activity reflected by their IC50 values in the inhibition of
R-MSH-stimulated cAMP release (Table 1). Thus, 10d (IC50
) 35 nM) was 8-fold better than the primary amine 10f (IC50
) 280 nM), while the functional inhibition produced by the
secondary amine 10e (IC50 ) 87 nM) was between that of 10d
and 10f. In parallel to binding affinity, 10d was 70-fold better
than its parent 8c (IC50 ) 2400 nM) in functional antagonist
activity. The N,N-dimethyl-â-alanine derivative 10b was also
slightly better than the methylaminoethyl 9 and the sarcosine
10a in terms of functional inhibition. None of these compounds
significantly stimulated cAMP production at 10 µM concentra-
tion (Emax e 16%).
cmpd
R
Y
Kib (nM) cAMP (%) IC50d (nM)
8a
8b
8c
9
10a
10b
10c
10d
10e
10f
F
Me
H
F
F
F
Me
H
H
H
35e
9.7
69e
6.0
2.8
2.2
0.6
2.8
5.7
5.9
5
2
16
7
12
0
5
n.d.f
n.d.f
2400
660
410
190
92
CH2NHMe
CH2CH2NMe2
CH2CH2NMe2
CH2CH2NMe2
CH2CH2NHMe
CH2CH2NH2
7
35
8
87
5
280
a Data are average of 2-9 independent measurements. The affinity
measurements for each compound differed by less than 4-fold, and the
resulting coefficient of variance averaged 37% for the binding assay Ki
values and 46% for the functional assay IC50 values. b Binding affinity using
[
125I]-NDP-MSH as the radiolabeled ligand. c Stimulation of cAMP release
at 10 µM concentration in comparison to R-MSH (100%). d Dose-dependent
inhibition of R-MSH-stimulated cAMP release. e Single measurement. f Not
determined.
improved affinity over 8c, which was similar to the 2-fluoro
analog 8a in the binding assay. The X-ray crystal structure of
7c was obtained (data not shown). In the solid state, this
precursor of the antagonist 8c possessed a very similar
conformation to that of the MC4R agonist 6 (THIQ).26 Thus,
the 4-chlorophenyl ring of 7c was almost parallel to the
piperazine ring, suggesting that the framework of an antagonist
structure is not much different from that of an agonist. This
result indicates that the Tic-group of 6, which is missing from
the antagonist 8c, is the primary contributor to its ability to
activate the receptor.27
Incorporating a methylaminoethyl side chain to the benzy-
lamine 8a (Ki ) 35 nM) increased its affinity by about 6-fold
(9, Ki ) 6.0 nM), while the amide derivative displayed further
improvement (10a, Ki ) 2.8 nM), suggesting the additional
amino group in 9 and 10a was able to function as the
benzylamine of 8a and further increase the affinity. The N,N-
dimethylamino-â-alanine derivative 10b (Ki ) 2.2 nM) had 16-
Compounds 10a and 10d-f were also tested for their
selectivity at the other melanocortin receptor subtypes (Table
2). In general, these compounds had little interaction with the
MC1 receptor and displayed much lower affinity at the MC3R
and MC5R than at MC4R. For example, 10d had over 100-
fold selectivity at MC4R over MC3R and MC5R.
These potent antagonists were also tested in several in vitro
assays measuring metabolism-related parameters, and the results
are summarized in Table 3. A common liability for large and
basic molecules is their inhibitory activity at the CYP3A4
enzyme.28 In an in vitro binding assay, all of these compounds
displayed IC50 values above 5 µM, and 10d had an IC50 of 9.2
µM.29
When incubated with human liver microsomes in an in vitro
assay, all compounds exhibited moderate metabolic stability,
which might be associated with their high lipophilicity and high
molecular weight. In a Caco-2 assay, which measures the cell
permeability of a compound, the benzylamine 8c showed good

Letters
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22 5251
Table 4. Pharmacokinetic Profiles of 9 and 10b-e in Ratsa
CL
Vd
t1/2
Tmax
Cmax
oral AUC
Cb (ng/g)
b/p ratio
cmpd
(mL/min‚kg)
(L/kg)
(h)
(h)
(ng/mL)
(ng/mL‚h)
F%
at 1, 4 h
at 1, 4 h
c
c
9
60b
22
3.7
53
95
4.2
4.3
13
17
2.2
13
2.9
8.1
6
4.7
4
4.7
3.3
22
134
208
110
57
299
1469
1947
1398
563
13
13
5.6
43
15
10b
10c
10db
10e
8, 31
9, 42
0.2, 0.3
0.1, 0.3
20, 33
0.2, 0.4
c
c
39
20
a Three animals were dosed intravenously at 2.5 mg/kg, and orally (p.o.) at 10 mg/kg; brain concentrations were taken from p.o. dose. b Intravenous dose
at 5 mg/kg. c Below detection limit (5 ng/mL).
Table 5. Pharmacokinetic Properties of 10d in Animalsa
permeability (Papp ) 5.0 × 10-6 cm/s) and showed evidence
CD-1
mouse
Sprague-Dawley beagle
rat dog
rhesus
monkey
of efflux transport (basolateral to apical direction versus its
reverse direction (b to a/a to b ) 3.7)), suggesting that this
compound may be a substrate for the P-glycoprotein. In
comparison, incorporating a methylaminoethyl (9) or sarcosine
(10a) group into 8c resulted in lower permeability (Table 3).
The N,N-dimethylamino-â-alanine side chain (10b), however,
did not significantly affect the permeability, and among the three
analogs 10b-d, 10d displayed the best profile in this assay.
The monomethylamine 10e and the primary amine 10f also had
lower permeability than 10d. The better permeability of 10d
might be associated with its high logD values (measured using
a shake-flask method, 3.4) and its lower polar surface area
(calculated using ACD software, 56 Å2) compared to the
secondary and primary amines 10a and 10e,f.
species
i.v. dose (mg/kg)
CL (mL/min‚kg)
Vd (L/kg)
2.5
29.6
4.1
5
10.3
5.9
5
8.1
2.0
2.9
t
1/2 (h)
1.6
6.7
AUC (ng/mL‚h)
1410
8200
10 300
p.o. dose (mg/kg)
10
10
10
10
761
1.8
C
max (ng/mL)
946
0.5
2530
32
279
2.7
1520
n/a
41
6.0
262
1.7
2860
Tmax (h)
AUC (ng/mL‚h)
F%
brain Cmax (ng/g)
brain Tmax (h)
brain AUC (ng/g‚h)
brain/plasma ratio
3860
19
19
b
b
91
0.3
367
0.15
254
0.17
a Data are the average of three animals. b Brain concentration was not
determined.
Compounds 9 and 10b-e were studied in rats for their
pharmacokinetic properties, and the results are summarized in
Table 4. Whole brain concentrations were sampled at 1 and 4
h after oral administration. The diamine 9 had a very large
volume of distribution (Vd), which might be associated with its
dibasic structure,30 resulting in a very long half-life (t1/2) of 17
h. Oral bioavailability (F%) was moderate in this species.
Despite its large Vd value, the compound was undetectable in
the brain, presumably due to its P-glycoprotein activity, which
prevented penetration through the blood-brain barrier.31 The
N,N-dimethyl-â-alanine 10b penetrated into the brain with a
brain/plasma (b/p) ratio of 0.2 and 0.3 at 1 and 4 h time points,
respectively, after oral administration.
Among the three N,N-dimethyl-â-alanines 10b-d, the 4-chlo-
rophenyl analog 10d had the best oral bioavailability (43%) in
rats. It also had a high Vd value and a moderate t1/2, resulting
from a high plasma clearance (CL). In vitro incubation with
liver microsomes suggested a major metabolite of 10d from
N-demethylation. This metabolite 10e was also profiled in rats.
Thus, 10e had a lower plasma clearance and a higher Vd value
than its parent 10d, which resulted in a longer half-life of 8.1
h. However, this compound was unable to penetrate into the
brain, which excluded it from further studies.
In a separate study in rats, the brain concentration-time
relation of 10d was studied after an oral administration at 10
mg/kg. The maximal whole brain concentration of 10d was 41
ng/g, appearing at the 6 h time point, and the AUC was 254
ng/g‚h. The brain to plasma ratio was 0.17 based on AUC
values, suggesting low CNS penetration (Table 5). In mice, the
brain/plasma ratio of 10d based on AUC values was 0.15, which
was very similar to that in rats.
Because of its favored pharmacological and pharmacokinetic
properties, the effect of 10d was then studied in a model of
tumor-induced cachexia. Compound 10d displayed good binding
affinity at the mouse MC4R (Ki ) 3.2 nM), similar to what
was seen at the human receptor. In this study, male C57BL/6J
mice, individually housed for at least one week, were subcu-
taneously injected into the upper flank with a subcloned line of
Lewis lung carcinoma (LLC) cells as previously described.17
Figure 2. Effect of 10d (5, 20 mg/kg, p.o.) on food intake in LLC
tumor bearing mice. Daily food intake was significantly increased on
days 10, 11, and 12 by treatment with 5 or 20 mg/kg of 10d compared
to tumor-bearing vehicle-treated controls. Values are mean ( SEM.
Four days after inoculation, food intake was measured daily.
On day 9 after tumor inoculation, treatment with compound 10d
was begun. Mice were divided into three groups (balanced for
body weight and tumor size) and given vehicle (sterile water),
5, or 20 mg/kg of 10d twice a day over 4 days. Both the 5 and
20 mg/kg doses of 10d significantly increased food intake on
days 10, 11, and 12 (Figure 2, p < 0.05).
In addition to its low CYP3A4 inhibitory activity, compound
10d also exhibited low affinity toward other major liver enzymes
for drug metabolism: CYP1A2, 2D6, 2C9, and 2C19 (IC50
>
10 µM). Its pKa was measured to be 7.8. As a hydrochloride
salt, 10d had very good aqueous solubility (33 mg/mL at pH 7,
and >71 mg/mL at pH 3). This compound was also profiled in
liver microsomes from several animal species. The scaled
intrinsic clearances of 10d were determined to be 46, 24, 15,
and 39 mL/min‚kg, respectively, for CD-1 mice, S-D rats, beagle
dogs, and rhesus monkeys, predicting oral bioavailabilities of
49, 66, 40, and 13%, respectively, assuming complete absorp-
tion.

5252 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22
Letters
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Identification of 2-[2-[2-(5-bromo-2- methoxyphenyl)-ethyl]-3-fluo-
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(17) Markison, S.; Foster, A. C.; Chen, C.; Brookhart, G. B.; Hesse, A.;
et al. The regulation of feeding and metabolic rate and the prevention
of murine cancer cachexia with a small-molecule melanocortin-4
receptor antagonist. Endocrinology 2005, 146, 2766-2773.
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Structure-activity relationships of novel piperazines as antagonists
for the melanocortin-4 receptor. Bioorg. Med. Chem. 2007, 15, 1989-
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(19) Nozawa, D.; Okubo, T.; Ishii, T.; Takamori, K.; Chaki, S.; et al.
Novel piperazines: Potent melanocortin-4 receptor antagonists with
anxiolytic-like activity. Bioorg. Med. Chem. 2007, 15, 2375-2385.
(20) Shimazaki, T.; Chaki, S. Anxiolytic-like effect of a selective and
non-peptidergic melanocortin 4 receptor antagonist, MCL0129, in a
social interaction test. Pharmacol. Biochem. BehaV. 2005, 80, 395-
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(21) Foster, A. C.; Chen, C.; Markison, S.; Marks, D. L. MC4 receptor
antagonists: A potential treatment for cachexia. IDrugs 2005, 8, 314-
319.
(22) Jiang, W.; Tucci, F. C.; Chen, C. W.; Arellano, M.; Tran, J. A.; et
al. Arylpropionylpiperazines as antagonists of the human melano-
cortin-4 receptor. Bioorg. Med. Chem. Lett. 2006, 16, 4674-4678.
(23) Chen, C. W.; Tran, J. A.; Jiang, W.; Tucci, F. C.; Arellano, M.; et
al. Propionylpiperazines as human melanocortin-4 receptor ligands.
Bioorg. Med. Chem. Lett. 2006, 16, 4800-4803.
(24) Jiang, W.; Chen, C.; Marinkovic, D.; Tran, J. A.; Chen, C. W.; et al.
Practical asymmetric synthesis of alpha-branched 2-piperazinylben-
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Compound 10d was also studied in mice, dogs, and monkeys
for its PK properties in these species (Table 5). In mice, 10d
exhibited a moderate plasma clearance of 29.6 mL/min‚kg and
its bioavailability was 32%. Its half-life of 1.6 h was short and
its brain penetration was relatively low. The low brain penetra-
tion or short t1/2 of 10d might explain the requirement of a high
dose for its in vivo efficacy in this species. In dogs and monkeys,
10d displayed a moderate oral bioavailability of 19%. The half-
life of this compound was 6.7 h in dogs, much longer than that
in monkeys (t1/2 ) 2.9 h), which might be associated with its
lower volume of distribution in this species.
In conclusion, we conducted a detailed study on a set of
piperazinebenzylamines bearing an amine side chain as potent
and selective antagonists of the human melanocortin-4 receptor.
One analog, 1-{2-[(1S)-(3-dimethylaminopropionyl)amino-2-
methylpropyl]-4-methylphenyl}-4-[(2R)-methyl-3-(4-chlorophe-
nyl)propionyl]piperazine (10d) was identified to have good
potency and selectivity. Despite its relatively high logD value
(3.4), 10d had good aqueous solubility. It was profiled for its
metabolic and pharmacokinetic properties in several animal
species. Finally, this compound demonstrated oral efficacy in
a mouse tumor-induced cachexia model.
Acknowledgment. The authors would like to thank Dr.
Daniel Marks of Oregon Health & Science University for his
help in performing the mouse cachexia study.
Supporting Information Available: The synthesis and char-
acterization of compounds 7c, 8a-c, 9, and 10a-f, the protocols
for pharmacokinetics, and in vivo efficacy studies. This material
is available free of charge via the Internet at http://pubs.acs.org.
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