Discovery of a piperazine urea based compound as a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist

Article abstract of DOI:10.1016/j.bmcl.2011.02.090

We report the discovery of piperazine urea based compound 1, a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist. Compound 1 shows anti-obesity efficacy without potentiating erectile activity in the rodent models.

Full text of DOI:10.1016/j.bmcl.2011.02.090

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2330–2334
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a piperazine urea based compound as a potent, selective,
orally bioavailable melanocortin subtype-4 receptor partial agonist
Qingmei Hong a, , Raman K. Bakshi a, Brenda L. Palucki a, Min K. Park a, Zhixiong Ye a, Shuwen He a,
⇑
Patrick G. Pollard a, Iyassu K. Sebhat a, Jian Liu a, Liangqin Guo a, Doreen E. Cashen b, William J. Martin b,
David H. Weinberg c, Tanya MacNeil c, Rui Tang c, Constantin Tamvakopoulos d, Qianping Peng d,
Randy R. Miller d, Ralph A. Stearns d, Howard Y. Chen c, Airu S. Chen c, Alison M. Strack b,
Tung M. Fong c, D. Euan MacIntyre b, Matthew J. Wyvratt a, Ravi P. Nargund a
a Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA
b Department of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065-0900, USA
c Department of Obesity Research, Merck Research Laboratories, Rahway, NJ 07065-0900, USA
d Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Rahway, NJ 07065-0900, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the discovery of piperazine urea based compound 1, a potent, selective, orally bioavailable
melanocortin subtype-4 receptor partial agonist. Compound 1 shows anti-obesity efficacy without poten-
tiating erectile activity in the rodent models.
Received 7 January 2011
Revised 17 February 2011
Accepted 22 February 2011
Available online 1 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Melanocortin subtype-4 receptor
MC4R
Partial agonist
Urea piperazine
Erectile dysfunction
Obesity
The melanocortin receptors are a family of seven-transmem-
brane G-protein coupled receptors. The five known subtypes inter-
act with the endogenous ligands, namely the melanocortins and
corticotropins, to mediate a wide range of physiologic functions
including feeding behavior and body weight homeostasis, skin pig-
mentation, steroid production, sexual behaviors, energy metabo-
lism and exocrine gland secretion.1–3
The melanocortin subtype-4 receptor (MC4R), primarily
expressed in the brain, is implicated in the regulation of feeding
behavior and sexual function.4–11 In the past decade, there have
been intensive studies on identifying small molecular MC4 recep-
tor agonists based on both peptides and non-peptides.12–18 Previ-
ous efforts at Merck have led to the identification of THIQ and
MB243 as potent and selective MC4R full agonists (Fig. 1).19,20
Compound THIQ is the first selective small-molecule agonist of
MC4R receptor with submicromolar potency (EC50 = 2.1 nM,
>100-fold functional selectivity over the other MC subtypes) to
be disclosed in the literature.19 It was shown to stimulate erectile
activity as well as significantly reduce food intake in rats. These
effects of THIQ were mediated by MC4R since none of these effects
was found in MC4R/3R knockout mice.19,35 THIQ served as an
important tool for studying MC4R pharmacology, but its limited
oral bioavailability and off-target activity prevented further devel-
opment of this compound.12,19 Compound MB243 (MC4R
EC50 = 11 nM) also displayed proerectile activity and food intake
reduction in rodent models. However, undesirable properties such
as high covalent protein-binding activity in vitro prompted further
optimization of this series.20 Recently a series of reports from
Merck Research Laboratories and others described the discovery
of potent and selective non-peptide MC4R full agonists for poten-
tial treatment obesity and dysfunction.21–28 For example, potent,
selective, oral bioavailable MC4R full agonist MK0493 showed
good food intake reduction and proerectile activity in rodents.21
In clinical trial, MK0493 was associated with modest weight reduc-
tion from baseline but had only small, statistically insignificant
effects relative to placebo after 12 weeks trial and this compound
did not provide clinically meaningful effects in proerectile effects
(PE) study.29,30 Recently, researchers from Pfizer reported MC4R
agonist 231 that showed clinical erectogenic activity. Compound
⇑
Corresponding author. Tel.: +1 732 594 5996; fax: +1 732 594 3007.
E-mail address: Qingmei_hong@merck.com (Q. Hong).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.02.090

Q. Hong et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2330–2334
2331
O
O
c, d, e
a, b
H2N
H2N
BocHN
N(CH2Ph)2
N(CH2Ph)2
OH
N
O
HN
HN
HN
HN
8
7
6
O
O
O
O
f
N
N
N
N
10 g
HO
TfO
NH
O
O
N
O
O
10
9
Ph
H•HCl
N
O
O
Cl
F
h, i
j
O
N
HN
THIQ
MB243
N(CH2Ph)2
k
N
N
H
H•HCl
F
F
13 (2R, 6R)
11
12
F
N
N
O
H•HCl
N
H•HCl
N
F
N
N
O
HO
N
N
H•HCl
H•HCl
HN
14 (2R, 6R)
15 (2S, 6S)
O
Cl
Scheme 2. Reagents and conditions: (a) NH(CH2Ph)2, EDC, HOBt, NMM; (b) TFA,
CH2Cl2; (c) BH3ÁTHF; (d) HCl; (e) KOH reflux; (f) Tf2O, 2,6-lutidine, CH2Cl2, 0 °C,
20 min; (g) Et3N, CH2Cl2, 0 °C, 2 h, rt, 3 h; (h) H2, Pd/C, HCl; (i) p-TsOH, reflux; (j)
BH3ÁTHF; (k) Pd(OH)2, H2, HCl, CH3OH.
2
MK-0493
NH
H
N
N
O O
N
H
NH2•HCl
O
F
N
NHBoc
X
H
N
H
N
O
+
OH
a, b
N
X
H
N
O
O
1
16
17
O
18
Figure 1. MC4R selective agonists.
H
N
R
2 was a potent full agonist of MC4R (EC50 = 12 nM) with good
selectivity over other melanocortin receptor subtypes. MC4R
agonist 2 at 200 mg dose showed efficacy similar to 100 mg of
sildenafil in a pilot clinical study of male erectile dysfunction,
although lower doses were not efficacious.31
O
O
X
c, d
N
H
N
O
Most MC4R agonists previously reported are full agonists with
activation larger than 90%. In this Letter, we describe a piperazine
urea based MC4R partial agonist 1 (<60% activation) and difference
between MC4R full agonists and partial agonists in animal penile
erections (PE) model.
Synthetic effort of piperazine-based urea compounds 1, 19–24
focused on the modification of the substituted piperazine.
cis-Diethyl piperazine 5 was synthesized via nickel-catalyzed
Grignard coupling of dichloro pyrazine 3 followed by hydrogena-
tion in the presence of platinum oxide (Scheme 1).
X=F, R =
H
N
H
N
H
N
N
N
N
N
N
,
,
,
,
21
20
1
19
H
N
H
N
N
N
,
,
The synthesis of trans 2,6-dialkylpiperazine was shown in
Scheme 2. A commercially available N-t-Boc-alanine 6 was coupled
with dibenzyamine, followed by the removal of Boc group to give
amide 7. Borane-THF reduction provided diamine 8. Alkylation of
23
22
H
X=Cl, R =
N
8
with methyl(S)-2-[(trifluoromethanesulfonyl)oxy]propionate
N
10, which was generated by the sequential treatment of methyl
(S)-lactate 9 with trifluoromethanesulfonic anhydride and 2,6-
lutidine, proceeded with inversion of stereo-chemistry to give the
ester 11. Hydrogenolysis in Pd (OH)2/C of 11 resulted in monodeb-
enzylation and partial cyclization. The completed cyclization
24
Scheme 3. Reagents: (a) EDC, HOBt, NMM, CH2Cl2; (b) HCl, dioxane, CH2Cl2; (c)
triphosgene, CH2Cl2, NaHCO3; (d) various piperzine, Et3N.
product 12 was obtained by heating the reaction mixture in the
presence of the catalytic p-toluene sulfonic acid. Borane reduction
of 12 followed by hydrogenolysis of the benzyl group with
palladium hydroxide catalyst in methanol and HCl gave (2R,6R)-
dimethyl piperazine dihydrochloride salt 13. (2R,6R)-diethylpiper-
azine 14 and (2S,6S)-dimethyl piperazine 15 were prepared
analogously.
H
Cl
N
Cl
N
N
N
a
b
N
N
H
5
3
4
Scheme 1. Reagents: (a) [DPPP]NiCl2, EtMgBr, THF; (b) H2, PtO2, AcOH.

2332
Q. Hong et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2330–2334
Table 1
Binding affinity and functional activity of compounds at human melanocortin receptorsa
Compounds
Receptor
Bindingb IC50 (nM)
cAMPc EC50 (nM)
Activationd at 10
lM (%)
1
hMC1R
hMC3R
hMC4R
hMC5R
5100 950e
650 67
4.9 0.3
––
––
22 4.4
>3000
30
3.6
59
22
850 75
19
20
21
22
23
24
hMC1R
hMC3R
hMC4R
hMC5R
2100 190
230 20
420 110
––
13 3.3
––
910 290f
––
60 7.8
––
24
1.2
41
14
4.7 0.3
430 120e
hMC1R
hMC3R
hMC4R
hMC5R
7800 445e
760 70
16 1.3
1400f
14
0.6
21
14
hMC1R
hMC3R
hMC4R
hMC5R
2100 172
970 60
11 0.8
260 78
––
18 2.6
1000 110
250 20e
––
58 15
1400 340
39
2.8
66
31
1400 280
hMC1R
hMC3R
hMC4R
hMC5R
3300 500
740 160
12 2.0
1400f
46
2
58
30
hMC1R
hMC3R
hMC4R
hMC5R
2800 280
390 65
400 87
––
––
31
0f
5.1 0.5
18
1300 510f
––
1f
hMC1R
hMC3R
hMC4R
hMC5R
1500 88e
33 4.5
0.78 0.1
54f
280 80f
––
––
24
1.3
15e
26
210 110
a
b
c
d
e
f
Values represent mean standard error. All data represent at least three determinations except for where indicated.
Displacement of [125I]-NDP-
-MSH from human receptors expressed in CHO cells.
Concentration of compound at 50% maximum cAMP accumulation.
a
Percentage of cAMP accumulation at 10
Values (n = 2) with standard error.
Values (n = 1).
lM compound relative to a-MSH.
The general procedure for the synthesis of urea analogs
included EDC coupling of Boc- -fluoro-Phe or Boc- -chloro-Phe
functional activity (EC50 = 13 nM), but reduced activation to 41%
and diminished the MC1 selectivity (32-folds). Compound 20 with
a methyl group on the nitrogen reduced both binding and func-
tional activity by 2- to 3-folds and had low activation (21%) and
it also reduced MC1 selectivity. trans (2R,6R)-Dimethyl piperazine
compound 21 has potency similar to the corresponding cis com-
pound 1. (2S,6S)-Dimethyl piperazine compound 22 reduced func-
tional activity and selectivity agonist MC1 and MC5. When the two
methyl group on compound 21 was replaced by two ethyl group,
trans (2R,6R)-diethyl piperazine compound 23 had good binding
activity (IC50 = 5.1 nM), but no functional activity. Replacement of
fluorine with chlorine in compound 1 gave compound 24, which
reduced the functional activity and became MC4R antagonist.
Interestingly, unlikely piperazine compound MB 243, all those urea
compounds had high binding potency, but weak agonism with
activation below 60%.
D
D
16 and amine 17, followed by removal of Boc gave compound 18.
It was then treated with triphosgene in the presence of sodium
bicarbonate to form isocyanate followed by addition with various
substituted piperazine to give urea compounds 1, 19, and 21–24.
Alkylation of compound 1 gave compound 20 (Scheme 3).
Compounds 1, 19–24 were initially evaluated in a competitive
binding assays and functional assays (Table 1). Binding assay was
performed to assess the competitive binding of test compounds
vs [129I]-NDP-
a-MSH. The functional assay was conducted by mea-
suring the accumulated cAMP in CHO cells expressing the human
receptors.32,33
As shown in Table 1, compound 1 had potent MC4R binding
activity (IC50 = 4.9 nM). In contrast to most MC4R compounds
reported previously, compound 1 showed partial activation (59%)
on MC4R with subnanomolar EC50 (22 nM). It also had excellent
selectivity against other human sub-types receptors (over 100-fold
selectivity). Diethyl piperazine analog 19 slightly improved the
Table 3
Pharmacokinetic data for 1
PK parameter
Rata
Dogb
Monkeyc
Table 2
F (%)
28
35
4.7
2.0
0.24
118
5.4
1.8
5.1
6.6
20
Pharmacokinetic data in rata
Cl (mL minÀ1 kgÀ1
)
5.2
1.0
5.3
1.3
Vdss (L kgÀ1
t1/2 (h)
AUCNpo (lM h/mpk)
)
Compound
1
19
21
23
F (%)
28
35
4.7
2.0
0.24
46
36
4.7
1.7
0.37
1.9
43
9.2
4.2
0.02
18
62
8.2
1.8
0.09
Cl (mL minÀ1 kgÀ1
)
a
Vdss (L kgÀ1
t1/2 (h)
)
Compound dosed in Sprague–Dawley rats as a solution in EtOH/PEG400/water
(10:40:50) at 1 mg/kg, iv and 4 mg/kg, po.
Compound dosed in beagles as a solution in EtOH/PEG400/water (10:40:50) at
0.5 mg/kg, iv and in 0.5% methylcellulose in water at 1.0 mg/kg, po.
Compound dosed in rhesus as a solution in EtOH/PEG400/water (10:40:50) at
0.5 mg/kg, iv and in 0.5% methylcellulose in water at 1 mg/kg po.
b
AUCn (lM h/mpk)
a
c
Compounds dosed in Sprague–Dawley rats as a solution in EtOH/PEG400/water
(10:40:50) at 1 mg/kg, iv and 4 mg/kg, po.

Q. Hong et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2330–2334
2333
1.2
1
-1%
60
50
40
30
20
10
0
0.8
0.6
0.4
0.2
0
-37%
-10
-20
-30
Vehicle-WT
586-WT
Vehicle-KO
586-KO
A
1
A
Cpd
Cpd
Cpd
10 mg/kg, i.v.
1 mg/kg, i.v.
Graph 1. Food intake of compound 1 on 4 h in wild type (WT) and MC3R/MC4R
knockout (KO) mice.
0.3 mg/kg, i.v.
Graph 3. Erectile activity study in CN-stimulated mouse of compound 1 using
MC4R full agonist compound A as comparison.
The pharmacokinetic (PK) properties of compounds 1, 19, 21
and 23 were further evaluated in the rat (Table 2). cis-Dimethyl-
piperazine compound 1 had better oral bioavailability (28%) and
(10 mpk dose) as controls. As illustrated in Graph 2, compound 1
reduced body weigh at 5, 10, 20 mpk in comparison with the vehi-
cle. It was also comparable to MC4R full agonist A in reducing the
body weight.
plasma drug exposure (0.24
l
M h/mpk) than trans-dimethyl piper-
M h/mpk). cis-
azine compound 21 (F = 1.9% and AUCN = 0.02
l
Finally, erectogenic activity of compound 1 was also evaluated
using a conscious rat model in which the occurrence of spontane-
ous erections was quantified in the absence of an external stimu-
lus.1,34,35 This study was performed using MC4R full agonist A23
as comparison (Graph 3). Consistent with previously reported
MC4R full agonists, full agonist A had significant increase the erec-
tile activity at 10 mpk, even enhanced the erectile activity in
0.3 mpk. However, when compound 1 was dosed at 10 mpk there
was no effect on erectile activity. After 15 min administration,
Diethyl piperazine compound 19 had improved oral bioavailability
(F = 46%) in comparing to compound 1. Similarly, the trans diethyl
compound 23 also reduced oral bioavailability (F = 18%) and AUCN
level (AUCN = 0.02 lM h/mpk).
Overall, compound 1 was the most promising compound in the
series. As a partial agonist, it exhibited excellent binding affinity
(IC50 of 4.9 nM) and functional activity (EC50 of 22 nM) at the
human MC4 receptor and excellent selectivity agonist other MCR
subtype (over 100-folds). It also had good oral bioavailability in
rat. Compound 1 was further characterized in pharmacokinetics
studies with other species. It showed an outstanding pharmacoki-
netic profile with excellent bioavailability, low clearance, and high
plasma drug exposure, especially in dog (Table 3).
compound 1 had excellent plasma exposure (4.7 lM dosed at
10 mpk) compared with compound A (47 nM dosed at 0.3 mpk).
Therefore, Compound 1 lacks PE activity in CN-stimulated mouse.
Earlier studies showed that dipeptide and non-peptide selective
MC4R full agonists had both food intake reduction and proerectile
activity in rodent models.9–12,19,20 The effect of MC4R agonists on
sexual functions represents a complication in the development of
the compounds for obesity. It is unclear whether these effects will
be a manageable side-effect or will outweigh any benefits of MC4R
in the treatment of obesity in human.10 Therefore, for the treat-
ment of obesity purposes, increased erectile activity could be an
undesirable adverse effect. This finding provides the potential for
developing MC4R partial agonists for obesity without modulation
of sexual behavior.
Compound 1 was tested in off-target activity screenings. It was
very clean in Panlabs against hundreds of receptors, enzymes, and
transporters. (>10
l
M). It was also selective against ion channels
(MK-499 >10
l
M, Ca+2 9.6
l
M, Na+ 6.8
lM)
Compound 1 was evaluated on food intake in rodent in vivo
obesity models (Graph 1). It showed mechanism based acute
food-intake reduction in DIO mice (Graph 1). It reduced food intake
37% (P <0.05) in wild type mouse comparing to the vehicle and had
no effects in MC3R/MC4R knockout mouse at 20 mpk dose at 4 h
post dosing.
In summary, we report the synthesis and evaluation of MC4R
partial agonists containing piperazine substructure. This study
led to the discovery of MC4R partial agonist compound 1 with high
in vitro potency and excellent pharmacokinetic profiles. Com-
pound 1 also exhibits an excellent off-target activity profile. Final-
ly, the efficacy of MC4R partial agonist compound 1 is comparable
to MC4R full agonist A in our animal models for both food intake
and body weigh study, while it has no effect on erectile activity.
Therefore, MC4R partial agonists could be utilized to treat anti-
obesity without potentiating erectile activity.
The efficacy of 1 was investigated in vivo rat obesity model.
Compound 1 was administered orally at 5, 10, 20 mpk bid for four-
teen days with vehicle and MC4R full agonist compound A23
Body weight change
Change in body weight (gm)
70
0.5% methylcellulose
60
50
40
30
20
10
0
Cpd 1 5 mg/kg
Cpd 1 10 mg/kg
Cpd 1 20 m g/kg
Cpd A 10 mg/kg
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