Aminomethyl tetrahydronaphthalene biphenyl carboxamide MCH-R1 antagonists-Increasing selectivity over hERG

Article abstract of DOI:10.1016/j.bmcl.2006.10.053

Aminomethyl tetrahydronaphthalene biphenyl carboxamide MCH-R1 antagonists with greater selectivity over hERG were identified. SAR studies addressing two distinct alternatives for structural modifications leading to improve hERG selectivity are described.

Full text of DOI:10.1016/j.bmcl.2006.10.053

Bioorganic & Medicinal Chemistry Letters 17 (2007) 814–818
Aminomethyl tetrahydronaphthalene biphenyl carboxamide
MCH-R1 antagonists—Increasing selectivity over hERG
à
*
´
´
Kenneth M. Meyers, Nicholas Kim, Jose L. Mendez-Andino, X. Eric Hu,
Rashid N. Mumin, Sean R. Klopfenstein, John A. Wos, Maria C. Mitchell,
Jennifer L. Paris, David C. Ackley, Jerry K. Holbert,
Scott W. Mittelstadt and Ofer Reizes§
Procter & Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, OH 45039, USA
Received 15 September 2006; revised 16 October 2006; accepted 23 October 2006
Available online 25 October 2006
Abstract—Aminomethyl tetrahydronaphthalene biphenyl carboxamide MCH-R1 antagonists with greater selectivity over hERG
were identified. SAR studies addressing two distinct alternatives for structural modifications leading to improve hERG selectivity
are described.
Ó 2006 Elsevier Ltd. All rights reserved.
Estimates indicate that more than 30% of the U.S. adult
population is obese, and that obesity-related health care
costs are in the range of $100 billion per year.1,2 The
G-protein-coupled receptor MCH-R1 has received sig-
nificant attention in recent years as a potential target
for effective anti-obesity therapy.3 It has been suggested
that CNS-located MCH-R1 is involved in biological
processes related to mammalian feeding behaviors and
energy expenditure.4 Identification of a small molecule
MCH-R1 antagonist is being heavily pursued by many
laboratories trying to find drug-molecule that may be
effective for the treatment of obesity.5
in a 4 day mouse diet induced obesity (mDIO) weight
loss model.4b,c In addition, compound 1 exhibited excel-
lent weight loss in our long-term mouse model. In a 28
day mDIO study, 1 dosed at 20 mg/kg PO QD promoted
7.8% decrease in body weight compared to vehicle. Mag-
netic Resonance Relaxometry (MRR)7 body weight
composition analysis of the mice in both studies revealed
a reduction in fat mass with negligible change in lean
mass.
Despite the attractive in vivo results, further develop-
ment of 1 as a MCH-R1 antagonist for the treatment
of obesity was compromised by its potent hERG ion
channel activity (IC50 = 1.8 lM).8 hERG blockers may
induce QTc interval prolongation, which is associated
with potentially lethal arrhythmias known as torsades
We recently disclosed aminomethyl tetrahydronaphtha-
lene biphenyl carboxamide 1 as a potent MCH-R1
antagonist.6 Compound 1 dosed at 20 mg/kg PO BID
promoted 5.7% vehicle corrected body weight reduction
Tyr-652
Cation-π
Keywords: Melanin-concentrating hormone; MCH-R1 antagonists;
Obesity; hERG; Aminomethyl tetrahydronaphthalene biphenyl
carboxamide.
*
Corresponding author. Tel.: +1 513 622 0304; fax: +1 513 622
1433; e-mail: mendezandino.jl@pg.com
O
N
Present address: Boehringer Ingelheim Pharmaceuticals, 900 Ridge-
bury Road, Ridgefield, CT 06877, USA.
N
Hydrophobic
Hydrophobic
à
Present address: Genome Research Institute, University of Cincin-
nati, 2180 E. Galbraith Road, Cincinnati, OH 45237, USA.
Present address: Lerner Research Institute, Cleveland Clinic Foun-
dation, 9500 Euclid Avenue-NC10, Cleveland, OH 44195, USA.
1
F
§
Figure 1. Postulated interactions between 1 and hERG.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.10.053

K. M. Meyers et al. / Bioorg. Med. Chem. Lett. 17 (2007) 814–818
815
de points (TdP). hERG associated TdP has led to the
removal of several drugs from the market.9 We desired
aminomethyl tetrahydronaphthalene biphenyl carbox-
amide compounds analogous to 1 but having lower
hERG inhibition activity.
The benzylic tertiary amine may participate in a cat-
ion-p interaction with the Tyr-652 residue of the hERG
channel. In addition, the lipophilic tetrahydronaphtha-
lene and biphenyl moieties may interact with hydropho-
bic residues of the hERG channel such as Phe-656. We
chose to keep the aminomethyl tetrahydronaphthalene
biphenyl carboxamide core intact and focused efforts
to discover compounds with greater selectivity over
Review of recent literature led us to postulate that 1 may
interact with hERG in the following fashion (Fig. 1).10
O
O
N
a
b
c
O
N
OH
N
O
N
45-60%
77-91%
75-84%
H
H2N
O
H
3
2
4
N
O
Cl
O
R
d
e
X
N
X
N
X
N
89-96%
78-90%
6
5
7
X = biphenyl group
R = alkyl amine
Scheme 1. Reagents and conditions: (a) i—Boc-anhydride, NaOH, THF, H2O, rt; ii—dimethylamine, EDCI, HOBt, NMM, DMF, rt; (b) LAH,
THF, 0 °C; (c) biphenyl carboxylic acid, EDCI, HOBt, NMM, DMF, rt; (d) ethylchloroformate, N,N-diisopropylethylamine, CH3CN, rt;
(e) secondary alkyl amine, CH3CN, MW 100 W, 120 °C, 5 min.
Table 1. Biphenyl substitutions
O
N
X
N
Compound
X
hERG (lM)
MCH-R1 Ki (nM)
5HT2C IC50 (lM)
1
IC50 = 1.8
7.4
55
F
N
5a
5b
5c
5d
5e
5f
IC50 = 2.6
11
12
56
9.5
Cl
Cl
F
IC50 = 5.1
N
N
IC50 = 5.2
20
17
IC50 = 10
184
18
16
N
F
IC50 = 14
27
N
Cl
IC50 = 20
118
140
2480
890
22
N
5g
5h
5i
IC50 = 30
>100
>100
>100
N
% inh. at 10 lM < 50
% inh. at 10 lM < 50
N
N

816
K. M. Meyers et al. / Bioorg. Med. Chem. Lett. 17 (2007) 814–818
hERG through substitution at the benzylic tertiary
amine and biphenyl sites.
aromatic ring decreased hERG activity considerably
(5g–i). These results suggest that interactions between
the terminal aromatic ring and hydrophobic residues
of the hERG ion channel are critical for high affinity
binding. A general trend for 5g–i was structural changes
that resulted in decreased hERG binding had a negative
effect on MCH-R1 activity13 but resulted in selectivity
over 5HT2c.14
The synthesis of 1 and its tertiary amine and biphenyl
analogs is outlined in Scheme 1. Commercially available
amino acid 2 was protected as a Boc carbamate and cou-
pled with dimethylamine to yield 3. Reduction of both
the carbamate and amide with LAH yielded diamine
4. Reaction with various biphenyl carboxylic acids
(either commercial or prepared via Suzuki reaction)
and EDCI/HOBt yielded 5. The dimethylamino group
was reacted with ethyl chloroformate11 to yield benzylic
chloride 6. Displacement of the chloride with secondary
amines yielded compounds 7.
We also incorporated polar functionality proximal to
the tertiary amine, a technique utilized previously in
the literature to reduce hERG binding.15 Results are
summarized in Table 2. Unfortunately, substitution
at the tertiary amine did not have as dramatic an
effect as biphenyl substitutions. Introduction of an
amide moiety beta to the benzylic tertiary amine had
no effect on hERG for glycine derivative 7a; however,
this substitution resulted in decreased hERG binding
for both proline 7b and ketopiperazine 7e derivatives.
The restricted rotation of 7b and 7e may present the
amide moiety in such a fashion that prevents high
affinity binding with hERG. Urea and acetyl pipera-
zines 7d and 7f also had decreased hERG activity
compared to 1. Except for sulfone 7c, moderate
MCH-R1 activity was retained within this series of
compounds, suggesting a tolerance by the MCH-R1
receptor for polar functionality proximal to the ben-
zylic tertiary amine, a key interaction site. Compounds
7a–f did not bind to 5HT2C, suggesting that incorpo-
ration of polar functionality proximal to the benzylic
tertiary amine helps to decrease 5HT2C activity. N-Ac-
etyl piperazine was identified as the best tertiary amine
group having decreased hERG activity with retained
MCH-R1 activity.
In vitro results for substitutions at the biphenyl position
(5a–b) are summarized in Table 1. We desired selectivity
over 5HT2C due to its suggested role in the modulation
of feeding behavior that could interfere with effects
related to inhibition of MCH-R1.12 We sought to de-
crease the lipophilicity of 1 and potentially its hERG
binding affinity by substituting either of the aromatic
rings of the biphenyl moiety with a pyridine ring. Intro-
duction of nitrogen into the inner aromatic ring de-
creased hERG binding compared to 1. The position of
the nitrogen in the inner aromatic ring affected hERG
activity; 5b and 5d were less active than their corre-
sponding isomers 5a and 5c.
The greatest effects on decreasing hERG binding were
achieved through terminal aromatic ring substitutions.
Halogen substitution of the outer aromatic ring effected
hERG activity (4-chloro (5a) > 4-flouro (5c) > unsubsti-
tuted (5f)). Introduction of nitrogen in the terminal
Table 2. Benzylic tertiary amine substitutions
O
R
N
7a-f
F
Compound
R
hERG (lM)
MCH-R1 Ki (nM)
5HT2C IC50 (lM)
O
7a
IC50 = 1.8
24
>100
N
N
O
N
7b
7c
7d
7e
7f
IC50 = 5.0
146
755
129
145
103
>100
>100
>100
>100
>100
N
O
O
a
IC25 = 2.5
N
N
S
N
O
IC50 = 6.7
IC25a = 7.6
NH2
O
N
N
NH
O
% inh. at 10 lM < 50
N
a Activity measured as IC25. Compound insolubility prevented IC50 determination.

K. M. Meyers et al. / Bioorg. Med. Chem. Lett. 17 (2007) 814–818
Table 3. Combined benzylic tertiary amine and biphenyl substitutions
817
O
R
X
N
7g-j
a
Compound
X
R
hERG IC25 (lM)
MCH-R1 Ki (nM)
5HT2C IC50 (lM)
O
O
N
7g
7h
7i
14
20
30
34
302
727
>100
>100
>100
>100
N
N
N
F
N
N
N
O
NA
N
S
O
O
7j
3465
N
N
NH
F
a Activity measured as IC25. Compound insolubility prevented IC50 determination.
Bioorg. Med. Chem. Lett. 2004, 14, 5075; (c) Shearman, L.
P.; Camacho, R. E.; Sloan, S. D.; Zhou, D.; Bednarek, M.
A.; Hreniuk, D. L.; Feighner, S. D.; Tan, C. P.; Howard,
A. D.; Van der Ploeg, L. H.; MacIntyre, D. E.; Hickey, G.
J.; Strack, A. M. Eur. J. Pharmacol. 2003, 475, 37.
Our next series of compounds combined SAR learnings
from the biphenyl and benzylic tertiary amine substitu-
tions (Table 3). We desired compounds with much lower
hERG activity while retaining MCH-R1 activity.
Compounds 7g–j exhibited decreased hERG activity
5. (a) Kanuma, K.; Omodera, K.; Nishiguchi, M.; Funako-
shi, T.; Chki, S.; Semple, G.; Tran, T.-A.; Kramer, B.;
Hsu, D.; Casper, M.; Thomsen, B.; Sekiguchi, Y. Bioorg.
Med. Chem. Lett. 2005, 15, 3853; (b) Souers, A. J.; Gao, J.;
Brune, M.; Bush, E.; Wodka, D.; Vasudevan, A.; Judd, A.
S.; Mulhern, M.; Brodjian, S.; Dayton, B.; Shapiro, R.;
Hernandez, L. E.; Marsh, K. C.; Sham, H. L.; Collins, C.
A.; Kym, P. R. J. Med. Chem. 2005, 48, 1318; (c) Ulven,
T.; Little, P. B.; Receveur, J.-M.; Frimurer, T. M.; Rist,
Ø.; Nørregaard, P. K.; Ho¨gberg, T. Bioorg. Med. Chem.
Lett. 2006, 16, 1070; (d) Palani, A.; Shapiro, S.; McBriar,
M. D.; Clader, J. W.; Greenlee, W. J.; Spar, B.; Kowalski,
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compared to 1. Unfortunately, the combined changes
of introducing a nitrogen into the biphenyl and polar
functionality proximal to the benzylic tertiary amine
resulted in greatly reduced MCH-R1 activity. As
predicted from the above SAR studies, 7g–j did not
exhibit 5HT2C activity.
In summary, aminomethyl tetrahydronaphthalene
biphenyl carboxamide MCH-R1 antagonists with great-
er selectivity over hERG were identified. A nitrogen-
containing biphenyl moiety was necessary for decreasing
hERG activity for this series of compounds. Also, N-
acetyl piperazine was identified as an optimal tertiary
amine group for hERG selectivity with retained MCH-
R1 activity. By incorporating changes at both the biphe-
nyl and tertiary amine moieties, decreases in hERG
binding came at the expense of reduced MCH-R1 bind-
ing activity.
6. Hu, X. E. Patent WO 2005/033063.
7. (a) Nicholson, Janet R.; Kohler, Gotz; Schaerer, Florian;
Senn, Claudia; Weyermann, Philipp; Hofbauer, Karl G.
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Taicher, G. Z.; Heiman, M. L. Obes. Res. 2004, 12, 150.
8. Patch-clamp hERG IC50 determinations were carried out
as described in Zhou, Z.; Gong, Q.; Ye, B.; Fan, Z.;
Makielski, J. C.; Robertson, G. A.; January, C. T.
Biophys. J. 1998, 74, 230.
References and notes
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Rockville, MD, 2001; www.surgeongeneral.gov/topics/
obesity.
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13. MCH binding using a Flashplate radioligand binding
assay was performed by Perkin-Elmer Biosignal (Toronto,

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K. M. Meyers et al. / Bioorg. Med. Chem. Lett. 17 (2007) 814–818
Ontario). Full competition curves were generated with
the membranes with [3H] mesulergine and excess 10 lM
mianserin (ICN). After incubating the mixture at room
temperature for 60 min, bound mesulergine was sepa-
rated from unbound mesulergine by filtration through
glass fiber B filter (GF/B) plates (Millipore). Bound
radioactive mesulergine was detected using a scintilla-
tion counter.
compound concentration varied from 100 lM to 11 fM.
Potency (Ki) and maximal efficacy were determined and
used to define structure–activity relationship.
14. 5HT2C assay was performed using a membrane prepa-
ration from cells that over-express the receptor. Mem-
branes were purchased from Euroscreen (ES-318-M)
and used according to established protocols. Briefly,
membranes were incubated in a reaction mixture con-
taining varying concentrations of the compound and
[3H] mesulergine (final concentration 0.33 nM; Amer-
sham), a compound known to bind to the 5HT2C
receptor. The binding buffer contained 50 mM Tris–
HCl, 0.1% ascorbic acid, 5 mM CaCl2, and 10 lg/ml
saponin. Nonspecific binding was assessed by incubating
15. Bilodeau, M. T.; Balitza, A. E.; Koester, T. J.; Manley, P.
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