Structure-activity relationship studies on a series of piperazinebenzylalcohols and their ketone and amine analogs as melanocortin-4 receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2008.07.076

A series of piperazinebenzylalcohols were prepared and studied to compare with their ketone and amine analogs as MC4R antagonists. Several benzylalcohols such as 14a and 14g displayed low nanomolar binding affinities (K_i < 10 nM), and high sele

Full text of DOI:10.1016/j.bmcl.2008.07.076

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4817–4822
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure–activity relationship studies on a series of piperazinebenzylalcohols
and their ketone and amine analogs as melanocortin-4 receptor ligands
Dragan Marinkovic a, Fabio C. Tucci a, Joe A. Tran a, Beth A. Fleck b, Jenny Wen c, Chen Chen a,
*
a Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92121, USA
b Department of Pharmacology, Neurocrine Biosciences, Inc., San Diego, CA 92121, USA
c Department of Preclinical Development, Neurocrine Biosciences, Inc., San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of piperazinebenzylalcohols were prepared and studied to compare with their ketone and amine
analogs as MC4R antagonists. Several benzylalcohols such as 14a and 14g displayed low nanomolar bind-
ing affinities (Ki < 10 nM), and high selectivities over other melanocortin receptor subtypes.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 1 July 2008
Revised 18 July 2008
Accepted 22 July 2008
Available online 25 July 2008
Keywords:
Melanocortin
Receptor
Ligand
Structure–activity relationship
Benzylalcohol
Ketone
Amine
Synthesis
The melanocortin receptors, which consist of five subtypes
MC1-5R and belong to the class A GPCR superfamily,1 have been
identified and cloned.2 Among them, MC4R controls feeding behav-
ior.3 Therefore, MC4R agonists have been sought for the possible
treatment of obesity.4 Moreover, recent studies have also demon-
strated that MC4R-selective antagonists might be useful in
cachexia.5
bears a polar functionality at the ortho-position is a potent MC4R
agonist with high binding affinity.11–13 Thus, Dyck et al. reported
a Ki value of 270 nM for the weakly basic triazole 1a (Fig. 1). In
comparison to 1a, the basic benzylamine 1b possessed a similar
Ki value of 380 nM, while its 2-thienylethyl derivative 1c
(Ki = 11 nM) displayed a substantially increased binding affinity,
indicating that a basic nitrogen in combination with a small lipo-
philic group significantly contributes to receptor binding.14 Com-
pounds 1a–c are full agonists, suggesting an important role of
the Tic (1,2,3,4-tetrahydro-isoquinolinecarbonyl) group in the
The melanocyte-stimulating hormones (
a-MSH, b-MSH and
c-MSH) and adrenocorticotropin (ACTH) are the endogenous ago-
nists for the melanocortin receptors. All these peptides possess a
His-Phe-Arg-Trp motif which is crucial for receptor binding and
activation.6 In addition, two endogenous antagonists, agouti-pro-
tein and agouti-related protein (AgRP) contain an Arg-Phe-Phe
moiety located in a loop known to interact with the melanocor-
tin receptors,7 and are believed to be important for functional
antagonism.8 Mutagenesis and modeling studies have provided
some information for understanding how a peptide ligand inter-
acts with the receptor.9 The requirement of a basic and an aro-
matic group for a MC4R ligand is also evidenced by many
known non-peptide MC4R agonists and antagonists from several
chemical classes.10 For example, studies have shown that the
receptor binding and activation. In contrast, the b-Ala-
D
-(2,4-
Cl)Phe analog of
2 (Ki = 1.8 nM) is a highly potent MC4R
antagonist.14
Based on receptor modeling studies, the basic amine of the Tic
group of 1 possibly interacts with an aspartic residue (Asp-126)
at the top of the transmembrane domain-3 (TM-3) of the human
MC4 receptor (hMC4R), while another acidic Asp-122 may contact
with the polar triazole of 1a via a hydrogen-bond, or the amine of
1b and 1c via a charge–charge interaction.15–17
We have shown that the binding affinity of benzylamine 3
(Ki = 490 nM) is improved when a small isobutyl group is incorpo-
dipeptide
D
-Tic-
D
-(4-Cl)Phe attaching to a piperazinebenzene that
rated (4, Ki = 74 nM).18 In addition, b-Ala-
D-(2,4-Cl)Phe-piperazines
bearing a cyclohexyl-carboxylate such as 5 are potent MC4R antag-
onists,19 indicating a basic amine in 4 might not be crucial for
receptor binding. To further explore the structure–activity rela-
* Corresponding author. Tel.: +1 858 617 7600; fax: +1 858 617 7967.
E-mail address: cchen@neurocrine.com (C. Chen).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.07.076

4818
D. Marinkovic et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4817–4822
Cl
S
Cl
X
Cl
HN
NH
O O HN
N
N
NH
O O
N
N
1a: X = 1,2,4-triazol-1-yl,
1b: X = NH2,
Ki = 270 nM
Ki = 380 nM
NH2
1c: X = NHCH2CH2-2-thienyl, Ki = 11 nM
2: Ki = 1.8 nM
Cl
Cl
Cl
R
Cl
NH2
O
O
N
F3C
N
N
NH
O O
5: Ki = 6.3 nM
O
N
NH2
3: R = Me, Ki = 490 nM
4: R = S-iBu, Ki = 74 nM
Figure 1. Chemical structures of some non-peptide MC4R ligands.
tionship and understand the ligand–receptor interactions, we syn-
thesize a series of alcohols, as well as their amines and ketone ana-
logs, to study their binding affinities at MC4R and the role of these
functional groups in receptor binding.
The ketones 10 and 11 were synthesized from 2-fluorobenzoni-
trile 6a as described in Scheme 1. Reaction of 6a with isobutylmag-
nesium bromide gave the corresponding ketone 6b in 74% yield,
which was condensed with Boc-protected piperazine to give 7 in
N
a
b
O
O
F
F
N
NBoc
6a
6b
7
c,d
Cl
Cl
Cl
Cl
Cl
Cl
O
O
O
c,e
c,f
N
O
N
N
N
R1
N
N
Boc
N
H
R
N
R2
NHBoc
O
O
O
10a-h
8
9a-f
c
g
g,c
Cl
Cl
Cl
O
Cl
Cl
Cl
X
N
X
O
N
O
N
N
R1
N
N
R3
N
R2
N
H
R3
N
H
O
O
O
12a-h: X = OH
13a-h: X = NH2
14a-f: X = OH
15a-f: X = NH2
11a-f
i
Scheme 1. Reagents and conditions: (a) BuMgBr/THF/rt, 2 h, 74%; (b) N-Boc-piperazine/K2CO3/DMF/130 °C, 10 h, 62%; (c) TFA/DCM/rt, 0.5 h; (d)
D
-N-Boc-(2,4-Cl)Phe-OH/-
HBTU/DMF/40 °C, 10 h, 59%; (e) i—(iPr)2NEt/DCM; ii—aldehyde/NaBH(OAc)3/THF/rt, 8 h; (f) N-Boc-amino acid/HBTU/(iPr)2NEt/DMF/40 °C, 10 h; (g) NH4OAc/NaB(CN)H3/-
iPrOH/70 °C, 6 h.

D. Marinkovic et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4817–4822
4819
62% yield. Deprotection of 7 with TFA, followed by a coupling reac-
tion with -N-Boc-(2,4-Cl)Phe-OH under standard amide coupling
The R- or S-benzylalcohols (R-14b and S-14b) was synthesized
from the ketone 8 by a stereo-selective reduction using S- or R-
diphenylprolinol chiral auxiliary as show in Scheme 3. Thus, treat-
ment of 8 using a Corey protocol gave the corresponding R- or S-
benzylalcohol 31 (the stereochemistry was assigned based on
mechanism),20 which was converted to the targeted R-14b or S-
14b. Their ee values were determined to be >93% based on chiral
HPLC analyses.
D
conditions gave the amide 8 (59%). After deprotection with TFA,
8 was subjected to reductive alkylations with several aldehydes
to afford the ketones 10a–h. Alternatively, coupling reactions of
the deprotected 8 with Boc-protected amino acids gave the inter-
mediates 9, which were deprotected with TFA to provide the
dipeptides 11a–f.
Reactions of 10 with sodium cyanoborohydride in the presence
of ammonium acetate gave a mixture of the corresponding alco-
hols 12a–h and the amines 13a–h, which were separated using a
HPLC system. The alcohols 14a–f and the amines 15a–f were ob-
tained from 9 using the same procedure as 12 and 13, followed
by a TFA-deprotection.
The Boc-protected piperazine-benzaldehyde 17a and pipera-
zine-acetophenone 17b were prepared from the fluorobenzenes
16 and Boc-piperazine (Scheme 2). Reduction of 17a with sodium
borohydride gave the benzyl alcohol 19 after Boc-deprotection.
Reactions of 17a with various alkyl Grignard reagents afforded
the secondary alcohols 20a–j. The tertiary alcohol 21 was obtained
from 17b and propylmagnesium bromide. Alternatively, the ester
18 was converted to 22 with ethylmagnesium bromide. Coupling
Compounds 10–15, 23–26, 27, and 29 were measured for their
abilities to inhibit [125I]-NDP-MSH binding to hMC4R stably trans-
fected in HEK293 cells in a binding assay,21 and the results are
summarized in Tables 1–3.
In comparison to the amines 13, the alcohols 12 were significant
less potent (6- to 15-fold). The binding affinity of the pyridine
derivative 12h (Ki = 83 nM) was over 40-fold lower than that of
the corresponding amine 13h (Ki = 2.0 nM). The ketones 10 exhib-
ited similar binding affinities to the alcohols 12 (Table 1). These re-
sults indicate an important role of the basic benzylamine in 13. For
the dipeptides 11, 14 and 15, the amines 15 were still more potent
than the alcohols 14 and the ketones 11. For example, the binding
affinity of the alcohol 14a (Ki = 8.1 nM) was about 3-fold lower
than that of the amine 15a (Ki = 3.2 nM). However, the difference
between 15 and 14 was small (66-fold). In contrast, the binding
affinities between the ketones 11 and the alcohols were relatively
large (up to 8-fold).
reactions of 19–22 with N-Boc-b-Ala-
the dipeptide derivatives 23–26 after deprotection. Alternatively,
coupling reactions of 20e (R4 = H, R5 = iBu) and 22 with N-Boc-
D-(2,4-Cl)Phe-OH provided
D
-
(2,4-Cl)Phe-OH afforded the amides 28a–b, respectively, after
deprotection. Coupling reactions of 27 and 28 with various N-Boc
amino acids gave the dipeptides 14g–i and 26a–h after deprotec-
tion. Finally, a coupling reaction of 22 with (2R)-(2-oxopyrroli-
din-1-yl)-3-(2, 4-dichlorophenyl)-propionic acid gave the amide
29.
Next, we surveyed a series of alcohols 23–26a (Table 2). The pri-
mary alcohol 23 (Ki = 870 nM) was only weakly active in the bind-
ing assay. Addition of a propyl group to 23 significantly increased
its binding affinity by almost 35-fold (24a, Ki= 26 nM). This result
is parallel to that of the benzylamines 3 and 4.14 While the isopro-
pyl, 1-vinylethyl and sec-butyl (24b–d) were minimally effective,
Cl
R4
F
R4
N
R4
R5
a
Cl
OH
O
O
N
O
N
16a: R4 = H
16b: R4 = Me
NBoc
N
H
NH2
17a,b
O
23-26
b,c
f,c
or d,c
Cl
R4
R5
R4
R5
O
O
N
Cl
g
OH
e,c
OH
N
N
N
NHBoc
NH
NBoc
O
19: R4 = R5 = H
27a: R4 = H, R5 = iBu
27b: R4 = R5 = Et
18
i
20a-j: R4 = H, R5 = alkyl
21: R4 = Me, R5 = Pr
22: R4 = R5 = Et
c
Cl
Cl
R4
R5
R4 R5
Cl
O
Cl
OH
Cl
h,c
OH
Cl
OH
N
O
N
N
N
N
N
H
R3
N
NH2
N
O
O
O
14g-i: R4 = H, R5 = iBu
28a: R4 = H, R5 = iBu
28b: R4 = R5 = Et
29
26a-h: R4 = R5 = Et
Scheme 2. Reagents and conditions: (a) N-Boc-piperazine/DMF/160 °C, 10 h; (b) NaBH4/MeOH/rt, 0.5 h; (c) TFA/DCM/rt, 0.5 h; (d) R5MgBr/THF/À78 °C, 0.5 h, then rt, 1–4 h;
(e) 2EtMgBr/THF/Et2O/rt, 4 h, 69%; (f) N-Boc-Ala-D-(2,4-Cl)Phe-OH/HBTU/(iPr)2NEt/DMF/30 °C, 16 h; (g) D-N-Boc-(2,4-Cl)Phe-OH/HBTU/(iPr)2NEt/DMF/rt, 1 h; (h) N-Boc-
amino acid/HBTU/DMF/rt, 16 h; (i) (2R)-(2-oxopyrrolidin-1-yl)-3-(2,4-dichlorophenyl)propionic acid/HBTU/DMF/rt, 8 h.

4820
D. Marinkovic et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4817–4822
Cl
Ph
N
B O
Ph
Cl
OH
OH
O
c,b
N
O
N
N
a,b
N
NH2
NH
NBoc
N
H
O
R
-14b
R-31
8
Scheme 3. Reagents and conditions: (a) BH3/THF/rt, 1 h, 17%, 88% e.e.; (b) TFA/DCM/rt, 0.5 h; (c) D-N-Boc-Gly-(2,4-Cl)Phe-OH/HBTU/(iPr)2NEt/DMF/rt, 16 h, 30%.
Table 2
the isobutyl 14a (Ki = 8.1 nM) was 3-fold better than 24a. The other
secondary alcohols 24e–i were not better than 14a. The two ter-
tiary alcohols 25 and 26a were also potent (Ki = 11 nM).
SAR of alcohols 23–26 at hMC4R
Cl
R4
R5
Studies on several amides 26a–h showed that a small variation
at this site had no significant effect (Table 3), similar to some ben-
zylamine analogs.14 The amino group at this side-chain played a
small role since the R-configured alanine derivative 26f was over
3-fold less potent than its S-analog 26e. The intermediate 27b
(Ki = 390 nM) was significantly less active than 26a–h. The non-ba-
sic lactam 29 (Ki = 110 nM) was 10-fold less active than the b-ala-
nine 26a.
Cl
OH
N
O
N
N
H
NH2
O
23-26
Compound
R4
R5
H
Ki (nM)
The binding affinities of the two stereoisomers of 14b were only
marginally different and the R-isomer (R-14b, Ki = 9 nM) was
slightly more potent than its S-isomer (S-14b, Ki = 28 nM). This is
somewhat surprised since we have shown that an S-benzylamine
was more potent than its R-isomer.22 It is worth noting that the
stereochemistry of these two isomeric alcohols was assigned based
on the reported mechanism only.16 The amide 14b was 20-fold
more active than its precursor amine 28a (Ki = 280 nM). In compar-
ison, the cyclic amine 14h was 6-fold less active than the b-analine
14a. These results further prove that the amino group at the amide
side-chain plays a role in receptor interactions.
23
H
H
H
H
H
H
H
H
H
H
H
Me
870
26
110
29
47
8.1
54
66
66
32
23
11
11
24a
24b
24c
24d
14a
24e
24f
24g
24h
24i
25
CH2CH2CH3
CHMe2
CH(CH@CH2)CH3
CH(CH2CH3)CH3
CH2CH(CH3)2
CH2C6H5
CH2C6H4(OCH3)-2
CH2C6H4(OCH3)-3
CH2CH2C6H5
CH2CH2C6H4(OCH3)-4
CH2CH2CH3
26a
CH2CH3
CH2CH3
Results from this study showed that the SAR of benzylalcohols
was quite similar to that of some benzylamines reported earlier,14
Table 1
Comparison of ketones (10, 11), alcohols (12, 14), and amines (13, 15) at hMC4R (Ki, nM)
Cl
Cl
Y
Y
N
Cl
Cl
N
O
R1
10: Y = CO
12: Y = CHOH
13: Y = CHNH2
11: Y = CO
14: Y = CHOH
15: Y = CHNH2
N
N
N
R2
N
H
R3
O
O
Compound
R1 NR2
NHCHMe2
10
12
13
a
b
c
d
e
f
560
230
150
1700
5800
>10,000
>10,000
110
380
330
89
1400
3200
>10,000
>10,000
83
53
21
15
120
350
1200
350
2.0
NH(CH2)3SMe
NHCH2-3-THF
N[(CH2)3Me]2
N[(CH2)4Me]2
NH(CH2CHMe2)2
N(CH2-c-Pr)2
N(CH2-2-Py)2
g
h
NHCOR3
11
14
15
a
b
c
d
e
f
NHCOCH2CH2NH2
NHCOCH2NH2
NHCOCH2NHMe
S-NHCOCH(NH2)Me
NHCOC(NH2)Me2
NHCOC(NHMe)Me2
24
33
31
26
110
91
8.1
13
8.3
16
46
21
3.2
2.0
1.7
4.2
7.7
4.7

D. Marinkovic et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4817–4822
4821
Table 3
The alcohols 14a, 14c, 14g, and 26d were further tested for their
binding affinities to the other subtypes of the human melanocortin
receptors to compare with the ketone 11a and amine 15a, and the
results are summarized in Table 4. None of these compounds
showed a significant interaction with MC1R (642% inhibition at
SAR of acyl substituents at hMC4R
Cl
Cl
*
Cl
OH
Cl
OH
10 lM concentration), and they possessed micromolar affinities
at the MC3 and MC5 receptors, demonstrating high selectivities.
None of these alcohols had a significant stimulation of cAMP
production in cells expressing the human MC4 receptor at a
N
O
N
O
N
N
R3
N
H
R3
N
H
10
lM concentration. In contrast, they dose-dependently inhibited
O
O
14
26a-h
a-MSH-stimulated cAMP accumulation, demonstrating functional
antagonist activities. For example, compound 14a exhibited an
Cl
IC50 value of 260 nM in this assay (Table 5).
Cl
The measured log D values were 2.4, 2.2, and 0.15, respectively,
for 11a, 14a, and 15a. In an in vitro human liver microsomal assay,
the lipophilic ketone 11a exhibited much lower metabolic stability
(systemic clearance CLsys = 18.4 mL.min kg) than the hydrophilic
amine 15a (CLsys3.6 mL/min kg), while the alcohol 14a was moder-
ately stable (CLsys = 14.7 mL/min kg).
OH
N
O
N
N
O
29
The pharmacokinetic parameters of 14a and 15a were com-
pared in rats after an intravenous injection at a 5 mg/kg dose
(Table 6). The alcohol 14a displayed a high plasma clearance
Compound
R3
Ki (nM)
28a
14b
R-14b
S-14b
14g
14h
26a
26b
26c
26d
26e
26f
280
13
9
(CLp = 64.5 mL/min kg) and
a large volume of distribution
CH2NH2
CH2NH2
CH2NH2
CH2N(CH3)2
3-Piperidine
CH2CH2NH2
CH2NH2
CH2NHCH3
CH2N(CH3)2
S-CH(NH2)CH3
R-CH(NH2)CH3
C(CH3)2NH2
(Vd = 42.3 L/kg), resulting in a very long elimination half-life (t1/
2 = 7.6 h). The brain concentration measured at 1 h after i.v.
administration was moderate (Cbrain = 117 ng/g), resulting in a
brain/plasma ratio of 0.53. The plasma exposure of 14a
(AUC = 30 ng/mL.h) was very poor after an oral gavage at
10 mg/kg, resulting in an oral bioavailability of 1.2%. In compar-
ison, the amine 15a exhibited a very similar profile (CLp = 68 mL/
min kg, Vd = 41.5 L/kg, t1/2 = 7.1 and F = 2.1%), although its brain
penetration (Cbrain = 245 ng/g, brain/plasma ratio = 1.8) was
slightly better than that of 14a.
In conclusion, a series of piperazinebenzylalcohols were synthe-
sized and studied as MC4R antagonists, to compare with their ke-
tone and amine analogs. While the alcohols 14a–f were less active
than the corresponding amines 15a–f in general, potent com-
pounds such as 14a, 14c, 14g, and 26d (Ki < 10 nM) were identified.
Like their amine counterparts, these alcohols showed good selec-
tivity over other melanocortin receptor subtypes. In addition, these
28
9.6
49
11
26
13
9.4
18
65
38
42
390
110
26g
26h
27b
29
1-Amino-cyclopropyl
OC(CH3)3
indicating that the hydroxyl group of 14 might directly mimic the
amino moiety of 15 in the receptor with lower intensity, possibly
via hydrogen bonding with the receptor.
Since the Asp-122 at the top of TM-3 of hMC4R has been deter-
mined to play an important role in ligand interactions,9,15 we
tested if the hydroxyl group of 14 might have a contact with this
residue. The binding affinities of 11c, 14c, and 15c were deter-
mined at the Asp122Ala mutant receptor as well as the wild-type
MC4R (Table 4).
Table 5
Selectivity and antagonist activity of alcohols at melanocortin receptor subtypes (Ki,
nM)
MC1Ra
MC3R
MC4R
MC5R
IC50 (nM)
b,c
Compound
The results showed that the alcohol 14c at the mutant receptor
was 60-fold lower than that at the wild-type. Its fold of reduction
was similar to that of the amine 15c (58-fold), indicating that the
Asp-122 residue may have a specific interaction with the hydroxyl
or amino group of compound 14c or 15c. However, it is worth not-
15a
11a
14a
14c
14g
26d
38%
42%
24%
34%
36%
34%
870
2300
1700
2500
3100
3100
3.2
24
8.1
8.3
9.6
9.4
540
330
970
1800
1300
950
250
650
260
420
250
400
ing that the endogenous a-MSH reduced its binding affinity by 28-
a
fold from the wild-typ (Ki = 45 nM) to the Asp122Ala MC4R mutant
(Ki = 1250 nM). It is also interesting that reduction in binding affin-
ity for the ketone 11c was less significant compared to 14c and
15c.
Percentage of inhibition at 10
Dose-dependent inhibition of
lM concentration.
b
a-MSH-stimulated cAMP production in cells
expressing hMC4R.
c
At MC4R.
Table 4
Table 6
Binding affinities of compound 11c, 14c and 15c at the Asp122Ala mutant in
comparison with those at the wild-type MC4R (Ki, nM)
Pharmacokinetic parameters of 14a and 15a in rats (N = 3)a
Compound
CLp
Vd
t1/2
Cbrain
b/p
F
(%)
Compound
Wild-type
Asp122Alaa
Fold
(mL/min kg)
(L/kg)
(h)
(ng/g)b
Ratiob
11c
14c
15c
31
8.3
1.7
290
500
99
9
60
58
14a
15a
64.5
68
42.3
41.5
7.6
7.1
117
245
0.53
1.8
1.2
2.1
a
Intravenous dose at 5 mg/kg and oral gavage at 10 mg/kg.
Determined 1-h postdosing.
a
b
At Asp122Ala MC4R mutant.

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15. Fleck, B. A.; Chen, C.; Yang, W.; Huntley, R.; Markison, S.; Nickolls, S. A.; Foster,
A. C.; Hoare, S. R. Biochemistry 2005, 44, 14494.
alcohols were functional antagonists in a cAMP assay. These results
might provide useful information for understanding the ligand–
receptor interactions.
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