Design and synthesis of potent and selective 1,3,4-trisubstituted-2-oxopiperazine based melanocortin-4 receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2006.05.087

The design and synthesis of a series of potent 1,3,4-trisubstituted-2-oxopiperazine based MC4 agonists are described. The tripeptidomimetic analogs (12a,b and 23) and the dipeptidomimetic 27 displayed single-nanomolar binding affinity and agonist potency

Full text of DOI:10.1016/j.bmcl.2006.05.087

Bioorganic & Medicinal Chemistry Letters 16 (2006) 4668–4673
Design and synthesis of potent and selective 1,3,4-trisubstituted-2-
oxopiperazine based melanocortin-4 receptor agonists
Xinrong Tian,* Rajesh K. Mishra, Adrian G. Switzer, X. Eric Hu, Nick Kim,
Adam W. Mazur, Frank H. Ebetino, John A. Wos, Doreen Crossdoersen,
Beth B. Pinney, Julie A. Farmer and Russell J. Sheldon
Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason Montgomery Rd., Mason, OH 45040, USA
Received 8 May 2006; revised 23 May 2006; accepted 30 May 2006
Available online 12 June 2006
Abstract—The design and synthesis of a series of potent 1,3,4-trisubstituted-2-oxopiperazine based MC4 agonists are described.
The tripeptidomimetic analogs (12a,b and 23) and the dipeptidomimetic 27 displayed single-nanomolar binding affinity and agonist
potency for MC4R and excellent selectivity for MC4R relative to MC1R.
Ó 2006 Elsevier Ltd. All rights reserved.
The melanocortin receptors (MCRs) belong to a fam-
ily of 7-transmembrane G-protein coupled receptors.
Five different subtypes (MC1R–MC5R) have been
identified and are activated by the peptide ligands:
a,b,c-melanocyte stimulating hormones (MSH) and
adrenocorticotrpin (ACTH). These endogenous ligands
are derived from a common precursor protein, proopi-
omelanocortin (POMC) by post-translational cleav-
age.1 Over the last decade, significant progress has
been made toward the design of peptidic and non-pep-
tidic ligands as potential therapeutic agents for mela-
nocortin-mediated diseases.2–4 In particular, MC4R
has attracted an enormous level of attention as a ther-
apeutic target for obesity, sexual dysfunction, and
involuntary weight loss associated diseases.5,6 The
intensive efforts targeted at MC4R have led to the
discovery of a number of selective, non-peptide small
molecule MC4 agonists.7–19
five-membered ring constrained Arg-Nal dipeptide
mimic and led to the discovery of a number of pyrrol-
idine analogs that exhibited single-nanomolar binding
affinity and agonist potency at MC4R. These results
further demonstrated that the approach of using a
conformationally constrained dipeptide mimic to re-
place the Arg-Trp dipeptide of the tetrapeptide leads
is a viable design strategy to develop peptidomimetic
MCR agonists. Our quest for more potent and selec-
tive small molecule MC4R agonists prompted us to
extend this strategy to other scaffolds as conforma-
tional control elements for the Arg and Trp side
chain, that is, guanidine moiety and naphthyl ring.
One type of Arg-2-Nal dipeptide mimitic we have
investigated contained a more flexible six-membered
ring 2-oxopiperazine (Fig. 1), which was derived by
inserting a CH2–CH2 unit between the amide nitrogen
atoms of the two amino acids. The 2-oxopiperazine
template has been explored in the design of thyrotro-
pin releasing hormone (TRH)21 and in non-peptide
fibrinogen receptor antagonists.22 During the course
of our program to develop constrained peptidomimet-
ic MCR agonists, we have investigated this scaffold as
a conformational constraining element to design Arg-
2-Nal dipeptide mimics, based on our success achieved
with the pyrrolidine scaffold. In comparison with the
pyrrolidine scaffold (3), the targeted 1,3,4-trisubstitut-
ed 2-oxopiperazine analogs 2 (Fig. 1) contain a C-ter-
minus (carboxamide moiety), in addition to the
expanded ring size and the amide moiety in the ring,
thus providing opportunity to probe the role of the
We recently reported the design of a series of proline
and pyrrolidine based melanocortin agonists using a
conformationally constrained dipeptide mimic ap-
proach.20 The design was based on the coupling of
Xaa-D-Phe dipeptide, corresponding to two amino
acids at the left side of early tetrapeptide leads, to a
Keywords: 2-Oxopiperazine; Peptidomimetics; Melanocortin-4;
Agonists.
*
Corresponding author. Tel.: +1 513 622 1444; fax: +1 513 622
1195; e-mail: tian.x@hotmail.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.05.087

X. Tian et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4668–4673
4669
NHR
X
X
NHR
NHR
O
O
NH
NH2
O
NH
NH2
NH
NH2
N
N
N
N
HN
HN
N
N
H
H
H
O
O
H
O
H
N
N
O
O
1
2
3
Figure 1. Design of 1,3,4-trisubstituted 2-oxopiperazine analogs.
C-terminus in potency and selectivity. Herein, we re-
port on the synthesis and evaluation of 1,3,4-trisubsti-
tuted 2-oxopiperazine based melanocortin-4 receptor
agonists.
pseudo-tetrapeptide and pyrrolidine based analogs as
well.26 Therefore, both D-Phe and 4-F-D-Phe residues
were employed in our research efforts of designing
2-oxopiperazine based MCR agonists. Along this line,
we initially synthesized and screened tripeptidomimetic,
12a (Table 2), and remarkably found that this tripeptide
analog showed single-nanomolar binding and agonist
potency at MC4R, representing a 480-fold improvement
in potency as compared to linear tetrapeptide 30. More
importantly, 12a was selective for MC4R relative to
MC1R and MC3R (116- and 42-fold, respectively, based
on binding affinity). In contrast with the previous SAR
observations with the linear peptides, 4-F-D-Phe analog
12b was found to exhibit similar binding affinity and
functional potency at MC1R and MC4R to those of
12a.
The
2-oxopiperazine
guanidine
analogs
were
synthesized using a route similar to one reported by
Just and co-workers.21,23,24 In the case of analogs
containing Arg-2-Nal residues, the synthesis began with
H-Orn(Cbz)-OH, which was converted to 2-nitroben-
zenesulfonamide 5, Scheme 1. The coupling of 5 with
6 under EDCI activation afforded dipeptide 7. The
oxopiperazine ring was assembled by treatment of 7
with 1,2-dibromoethane in the presence of potassium
carbonate in DMF at 75 °C. Cleavage of the NOS
group of 8 afforded 9, which was then coupled with
Boc-D-Phe-OH or Boc-D-(4-F)-Phe-OH to produce
10. Reductive cleavage of the Cbz group of 10 followed
by guanidination and removal of Boc groups yielded
tripeptidomimetics 12a,b. For the synthesis of
N-capped tripeptidomimetics or tetrapeptidomimetics,
10 was treated with trifluoroacetic acid and the
primary amine was then coupled with acetic acid or
amino acids to give 14a,b and 18a–f, which were then
converted to the guanidine analogs 17a,b and 21a–f
by means of a three-step sequence as described above.
The discovery of tripeptide mimetics 12a,b as potent and
selective MC4R agonists provided additional compel-
ling evidence for our strategy of conformationally con-
straining the Arg-2-Nal dipeptide region. To further
explore this oxopiperazine based Arg-Nal dipeptide
mimetic in the design of MCR agonists, we then moved
on to investigate tetrapeptide mimetics to gain SAR of
the top side chain. The corresponding constrained ana-
logs of linear tetrapeptides 28 and 29 (17a,b), were first
synthesized. It was interesting to find that capping the D-
Phe residue of 12a with the His residue resulted in 1650-,
240-, and 7-fold increased binding affinity, respectively,
at MC1R, MC3R, and MC4R along with similar mag-
nitude of increase in functional activity across the three
MCRs tested (Table 2). The analog 17a showed sub-
nanomolar binding affinity and agonist potency at
MC1R and MC4R, and was significantly less selective
for MC4R relative to MC1R as compared to 12a. The
Tyr analog 17b had also sub-nanomolar binding and
potency at MC4R and single-nanomolar binding and
potency at MC1 and MC3R. Both analogs were signifi-
cantly more potent than the corresponding linear ana-
logs 28 and 29 across the three MCRs.
Analog 23 containing a shorter C-3 guanidino side chain
was prepared from H-DAB(Cbz)-OH (22) using the
reaction sequences described for 12b (Scheme 1).
N-Terminus truncated analog 27 was synthesized from
intermediate 9 (Scheme 2). The coupling of 9 with 3-
(4-fluorophenyl)propanoic acid afforded 24, which was
converted to the guanidine analog 27 using reaction
sequences as described above.
Our early efforts directed toward the development of
melanocortin agonists on the basis of the His-D-Phe-
Arg-His tetrapeptide led to the discovery of a series of
MC4R agonists which possess a D-Phe-Arg-2-Nal-
NHCH3 tripeptide fragment, as exemplified by Ac-His-
D-Phe-Arg-2-Nal-NHCH3 (28) and Ac-Tyr-D-Phe-Arg-
2-Nal-NHCH3 29 (Table 1). We also found that
tripeptide D-Phe-Arg-2-Nal-NHCH3 (30) itself had
weak affinity and agonist potency at MC4R. However,
substitution of the D-Phe residue of the tripeptide for
D-Phe (D-(4-F)-Phe-Arg-2-Nal-NHCH3, 31) resulted in
ꢀ6-fold increase in binding and agonist potency at
MC4R. Similarly, the enhancement in potency by
incorporating D-(4-F)Phe was observed with the
Tetrapeptide analogs containing the D-(4-F) Phe residue
revealed slightly different SAR insights. The capping of
the D-Phe of 12b with the His residue (21a) did not affect
binding affinity and agonist potency at MC4R but led to
only 190- and 2-fold increase in binding affinity at MC1
and MC3R, versus 1650- and 240-fold in the case of 17a,
respectively. On the other hand, Tyr analog 21b showed
similar affinity and agonist potency at MC3R and
MC4R to those of D-Phe analog 17b but was ꢀ14-fold
less potent at MC1R (Ki, 14 nM vs 1 nM).

4670
X. Tian et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4668–4673
R
N
NHCbz
NHCbz
NHCbz
O
NHCbz
b
c
O
O
H2N OH
4
a
N
O
H
+
N
HN
Nos
HN
NOS NH OH
H2N CONHCH3
CONHCH3
O
5
6
7
8 R=Nos
9 R=H
d
NO2
e
Nos=
S
O
X
O
X
X
NHBoc
O
NH2
NHBoc
O
O
NH
NH2
g, h
f
N
N
N
N
NHCbz
N
NH2
H
N
O
H
N
O
O
N
O
H
N
H
N
O
O
10 (X=F, H)
12a X=H
12b X=F
11a X=H
11b X=F
h
R2
X
R2
F
g
F
NH2
O
HN
HN
O
O
N
NR1
NHR1
j
N
N
N
NHCbz
NHR1
N
H
N
O
O
H
N
O
H
N
O
H
N
N
O
13
O
18a-f R1=Cbz
19a-f R1=H
20a-f R1=Boc
f
h
21a-f R1=H
i
R2
R2
HN
HN
F
O
NH2
O
O
NR1
NHR1
g
N
N
CbzHN
N
H
NHR1
N
NH2
NH
N
N
a-h
H
O
O
N
O
H
N
O
H
N
O
N
O
H
H2N OH
N
22
14a-b R1=Cbz
15a-b R1=H
O
16a-b R1=Boc
f
23
h
17a-b R1=H
Scheme 1. Reagents and conditions: (a) 2-nitrobenzenesulfonyl chloride, Et3N, THF/H2O; (b) EDCI, HOBt, NMM, DMF; (c) 1,2-dibromoethane,
K2CO3, 75 °C, DMF; (d) 4-mercaptophenol, K2CO3, CH3CN; (e) Boc-D-Phe(4-F)-OH, EDCI, NMM, HOBt; (f) H2, Pd/C, CH3OH; (g) 1,3-bis(tert-
butoxycarbonyl)2-methyl-2-thiopseudourea, HgCl2, Et3N, DMF; (h) TFA, CH2Cl2; (i) R2OH(Ac-His(Trt)-OH, Ac-Tyr-OH), EDCI, HOBt, NMM,
DMF; (j) R2OH (Ac-His(Trt)-OH, Ac-Tyr-OH, Boc-Tic-OH, Boc-Pip-OH, Ac-Gln-OH, AcOH), EDCI, HOBt, NMM, DMF.
F
F
H
N
O
O
NR
NHR
NHCbz
N
N
N
N
a
c
NHR
N
N
O
H
H
O
O
N
H
H
N
N
O
O
O
9
24 R=Cbz
25 R=H
26 R=Boc
27 R=H
b
d
Scheme 2. Reagents and conditions: (a) 3-(4-fluorophenyl)propanoic acid, EDCI, NMM, HOBt, DMF; (b) H2, Pd/C, CH3OH; (c) 1,3-bis(tert-
butoxycarbonyl)2-methyl-2-thiopseudourea, HgCl2, Et3N, DMF; (d) TFA, CH2Cl2.
Additional tetrapeptide analogs were synthesized using
12b as a template to expand SAR of the top side chain.
Incorporation of the Tic residue to 12b did not affect
potency at MC1R and MC4R but led to a ꢀ4-fold loss
in potency at MC4R. This result was not expected as sig-
nificant enhancement in potency has been observed

X. Tian et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4668–4673
Table 1. Binding affinity and agonist potency for peptides 28–31a,b
4671
Compound
MC1R
MC3R
EC50 (Emax, %) (nM)
541 88 (106)
20,000 (51)
MC4R
Ki (nM)
EC50 (Emax, %) (nM)
Ki (nM)
Ki (nM)
EC50 (Emax, %), (nM)
28
29
30
31
13
2
14 1 (98)
20,000 (83)
1195 326
1727 67
29
5
5.7 0.7 (101)
44 5 (84)
4520 1257
4384 820
4058 942
104 10
1248 185
225 15
20,000 0 (26)
21,667 1667(46)
22,562 108,74
1143 207
20,000 0 (20)
20,000 0(32)
809 122 (77)
140 20(93)
a The analogs were screened against the human MC1R, MC3R, and MC4R as previously reported.25
b The data represent means of at least three experiments SEM.
Table 2. Binding affinity and agonist activity of 2-oxopiperazine guanidine analogsa,b
R2
X
HN
O
NH
NH2
N
N
N
n
H
O
H
N
O
Compound
n
X
R2
MC1R
EC50 (Emax, %) (nM) Ki (nM)
MC3R
EC50 (Emax, %) (nM) Ki (nM)
MC4R
Ki (nM)
EC50 (Emax, %) (nM)
12a
12b
17a
17b
21a
21b
21c
21d
21e
21f
23
1
1
1
1
1
1
1
1
1
1
0
H
F
H
H
F
F
F
F
F
F
F
H
659 187
366 18
0.4 0.1
526 78 (108)
317 67 (106)
0.07 0.02 (92)
1.7 0.7 (99)
1.7 0.6 (106)
30 12 (122)
239 46
41 3.6 (102)
37 10 (113)
0.4 0.1 (152)
5.7 1.7
7.0 0.6
0.8 0.3
0.6 0.2
1.7 0.7 (105)
1.6 0.3 (98)
0.3 0.1 (149)
0.2 0.1 (149)
H
75
1
7
0
0
8
Ac-His
Ac-Tyr
Ac-His
Ac-Tyr
Tic
1
2.0 0.6
0
1
1
0 (133)
6.0 1.5 (105)
0 (77)
352 114 163 39 (108)
35
5
0.4 0.1
2
2
0 (110)
14
313
6
4
1.1 0.5
2
8.7 2.3 (98)
1.6 0.3 (110)
1.6 0.3 (103)
104 29 (120)
3.7 0.9 (102)
0.37 0.03 (96)
2.3 0.9 (103)
353 6 (105)
1391 136 (96)
6
1.3 0.4
1
Pip
Ac-Gln
Ac
4.3 0.3
17
3.3 0.9
2
5.6 0.3 (103)
0.5 0.1 (100)
10 0 (64)
2
18
0
5
1.1 0.4 0.34 0.03 (110)
7
1
1.3 0.3
11
5.3 1.2
0.5 0.2 (98)
2.2 0.2 (106)
H
1120 151
958
470 50
206 76
84 15 (86)
142 57 (69)
1
27
7
9
3 (91)
a The analogs were screened against the human MC1R, MC3R, and MC4R as previously reported.25
b The data represent means of at least three experiments SEM.
when the Tic moiety was introduced into linear tripep-
tide D-Phe-Arg-2-Nal (30).26 However, substitution of
Tic moiety for a less sterically bulky Pip residue (21d)
resulted in increase in binding affinity (85-, 4-, and
5-fold, respectively) and agonist potency across three
MCRs as compared to 12b. Similarly, appending of a
linear amino acid, Ac-Gln, to the D-Phe of 12b afforded
an analog (21e) showing sub-nanomolar functional
activity across three MCR receptors.
To further optimize this novel 2-oxopiperazine dipeptide
mimetic, we have briefly investigated the effect of the
space between the guanidine moiety and the six-mem-
bered piperazine ring. The shortening of the linkage
length by one methylene unit led to only a marginal
change for MC4 activity but the resulting analog 23
had 4- and 5-fold reduced binding for MC1 and
MC3R, thus improving the selectivity for MC4R.
We have previously demonstrated within the class of
pyrrolidine based MCR agonists that presence of the
N-terminus on the D-Phe side chain was critical for the
binding affinity and functional potency.20 To further ex-
plore the 2-oxopiperazine based tripeptide mimetics and
to better understand the minimal structural fragment re-
quired for significant binding affinity and functional
activity, we then investigated the effect of removal of
the N-terminus from D-Phe on the biological activity.
Surprisingly, the resulting dipeptide mimetic 27 showed
single-nanomolar binding affinity (Ki, 5 nM), compara-
ble to those of D-Phe analog 12b, with an EC50 of
9 nM at MC4R. Furthermore, it was more selective
for MC4R relative to MC1R and MC3R than 12b. This
result is remarkable, given that a majority of small
Amino acids were not the only capping groups that pro-
duced analogs with significantly increased affinity and
functional activity. A simple acetylation of 12b resulted
in 5- to 20-fold increase in affinity at the three MCRs
tested and the resulting analog 21f exhibited an EC50
value of 0.52 nM and a Ki value of 1.3 nM at MC4R.
Furthermore, 21f had better affinity and agonist potency
at MC3R and MC4R than His and Tic analogs and
comparable potency for MC3R and MC4R to those of
Pip and Ac-Gln analogs. These results might suggest
that H-bond capacity and steric bulk of amino acids in
comparison with the acetyl group were not key factors
contributing to the enhancement of potency across the
three receptors observed when 12a or 12b was capped.

4672
X. Tian et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4668–4673
Table 3. Binding affinity and agonist activity of non-guanidino 2-oxopiperazine analogsa,b
F
NH2
O
N
N
R
O
H
N
O
Compound
R
MC1R Ki (nM)
5000
MC3R Ki (nM)
MC4R Ki (nM)
MC4R EC50 (Emax, %) (nM)
31
0
3237 679
85 19
62 18 (98)
NH2
NH2
32
33
5820 514
2132 142
4122 240
461 183
189 59
261 61
45 9 (105)
12 2 (85)
H
N
NH2
O
H
N
NH2
34
21,703 1696
6107 189
365 72
18 2 (94)
O
a The analogs were screened against the human MC1R, MC3R, and MC4R as previously reported.25
b The data represent means of at least three experiments SEM.
2. Wikberg, J. E. S. Expert Opin. Ther. Patents 2001, 11, 61.
3. Holder, J. R.; Haskell-Luevano, C. Med. Res. Rev. 2004,
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M.; Joseph, C. G.; Wilson, K. R.; Haskell-Luevano, C.
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molecule MC4 agonists reported to date possesses a D-
Phe residue. Compound 27 might serve as a new tem-
plate for the design of potent MC4R agonists with re-
duced peptide character and molecular weight.
The basic guanidine moiety contained in tripeptidomi-
metics discussed above seems to be important for bind-
ing affinity and agonist potency. The amino analogs 31
and 32, precursors for guanidine analogs 12b and 23,
were found to have Ki values of 89 nM and 189 nM (Ta-
ble 3) as well as EC50s <100 nM, significantly less potent
than the corresponding guanidine analogs. Use of a neu-
tral urea moiety to replace the guanidine of 12b and 23
led to ꢀ35-fold reduced binding affinity at MC4R (33
and 34).
5. Goodfellow, V. S.; Saunders, J. Curr. Top. Med. Chem.
2003, 3, 855.
6. Marks, D. L.; Ling, N.; Cone, R. D. Cancer Res. 2001, 61,
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Walsh, T. F.; Wyvratt, M. J.; Kalyani, R. N.; Macneil, T.;
Tang, R.; Weinberg, D. H.; Van der Ploeg, L. H. T.;
Goulet, M. T. Bioorg. Med. Chem. Lett. 2005, 15, 4023.
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L.; Sebhat, I. K.; Bakshi, R. K.; Tang, R.; Kalyani, R. N.;
Vongs, A.; Chen, A. S.; Chen, H. Y.; Rosenblum, C. I.;
MacNeil, T.; Weinberg, D. H.; Peng, Q.; Tamvakopoulos,
C.; Miller, R. R.; Stearns, R. A.; Cashen, D. E.; Martin,
W. J.; Metzger, J. M.; Strack, A. M.; MacIntyre, D. E.;
Van der Ploeg, L. H. T.; Patchett, A. A.; Wyvratt, M. J.;
Nargund, R. P. Bioorg. Med. Chem. Lett. 2005, 3501.
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In summary, we have demonstrated that 1,3,4,-trisubsti-
tuted 2-oxopiperazine based Arg-2-Nal dipeptide mimic
is an effective replacement for Arg-2-Nal for designing
potent MC4R agonists. The coupling of the appropriate
D-Phe residue to this novel dipeptide mimic led to potent
and selective MC4R agonists 12a,b. Furthermore, cap-
ping the D-Phe of 12a,b with an acetyl group or amino
acids (with the exception of Tic) resulted in significant
increase in binding affinity and agonist potency at
MC1R and MC3R, thus reducing selectivity for
MC4R over MC1R and MC3R. Another notable SAR
finding was that truncation of the N-terminus from
12b led to 27, which displayed single-nanomolar affinity
and agonist potency at MC4R. We have subsequently
incorporated these findings into the design of the orally
active ketopiperazine based MC4R agonists and details
will be reported in due course.
11. Fotsch, C.; Han, N.; Arasasingham, P.; Bo, Y.; Carmou-
che, M.; Chen, N.; Davis, J.; Goldberg, M. H.; Hale, C.;
Hsieh, F.-Y.; Kelly, M. G.; Liu, Q.; Norman, M. H.;
Smith, D. M.; Stec, M.; Tamayo, N.; Xi, N.; Xu, S.;
Bannon, A. W.; Baumgartner, J. W. Bioorg. Med. Chem.
Lett. 2005, 15, 1623.
12. Palucki, B. L.; Park, M. K.; Nargund, R. P.; Ye, Z.;
Sebhat, I. K.; Pollard, P. G.; Kalyani, R. N.; Tang, R.;
Macneil, T.; Weinberg, D. H.; Vongs, A.; Rosenblum, C.
I.; Doss, G. A.; Miller, R. R.; Stearns, R. A.; Peng, Q.;
Tamvakopoulos, C.; McGowan, E.; Martin, W. J.; Metz-
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