Potent, selective MCH-1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2008.01.010

This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.

Full text of DOI:10.1016/j.bmcl.2008.01.010

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 1402–1406
Potent, selective MCH-1 receptor antagonists
Shawn D. Erickson,a,* Bruce Banner,a Steven Berthel,a Karin Conde-Knape,b
Fiorenza Falcioni,b Irina Hakimi,b Bernard Hennessy,a Robert F. Kester,a
Kyungjin Kim,a Chun Ma,a Warren McComas,a Francis Mennona,a Steven Mischke,a
Lucy Orzechowski,a Yimin Qian,a Hamid Salari,a John Tengi,a Kshitij Thakkar,a
Rebecca Taub,b Jefferson W. Tilleya and Hong Wanga
aDiscovery Chemistry, Hoffmann—La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, USA
bDepartment of Metabolic Diseases, Hoffmann—La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, USA
Received 26 November 2007; revised 21 December 2007; accepted 2 January 2008
Available online 8 January 2008
Abstract—This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-
1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and
safety.
ꢀ 2008 Elsevier Ltd. All rights reserved.
Obesity is a major risk factor for many serious diseases
including diabetes mellitus, hypertension, cardiovascu-
lar disease, and stroke.1 At the present time, more than
1 billion adults are overweight (BMI P 25) and 300 mil-
lion are obese (BMI P 30). Perhaps more troubling, the
number of obese adolescents has tripled since 1980. A
clear factor in this trend has been an increase in calorie
consumption. The past 50 years has seen an increased
accessibility of pre-packaged, calorie-dense foods that
are high in fat and simple sugars.2 During the same per-
iod of time, it has been established that the hypothala-
mus is a critical ‘feeding center’3 and that numerous
receptors in the hypothalamus and other brain regions
mediate satiety4 and that these receptors are likely to be-
come dysregulated upon chronic overfeeding and caloric
imbalance.5 Returning these receptors to a state resem-
bling normal function via small-molecule drugs is poten-
tially a viable therapeutic strategy for obesity.
region known to play a central role in appetite and en-
ergy homeostasis. MCH is the native ligand of two G-
protein-coupled receptors, MCHR1 and MCHR2. The
two receptors show 37% sequence homology. Rodents
express only MCHR1; humans, monkeys, dogs, and
other higher mammals express both MCHR1 and
MCHR2. The role of MCHR2 in humans is not clear
and the published studies quite clearly show that
MCHR1 mediates the effects of MCH peptide on satiety
and energy balance.6b MCHR1 knockout mice are lean
and hypophagic.7 Central (icv) administration of MCH
elicits increased food intake and body weight gain in ro-
dents8 and in sheep.9 Although there are no reports of
the effects of MCH antagonists in humans, increased
MCH receptor levels were observed in the infundibular
nucleus levels in human post-mortem brain tissue from
cachectic patients.10 Taken together, these studies sug-
gest that a selective, small-molecule MCHR1 antagonist
would be an effective drug for the treatment of human
obesity.
Melanin concentrating hormone (MCH) is a peptide
hormone that was first isolated from teleost fish pitui-
tary gland in which it plays a role in skin pigmentation.6
In rats, MCH is a 19-amino acid peptide that is ex-
pressed primarily in the lateral hypothalamus, a brain
There are a relatively large number of published re-
search papers and patent applications describing
MCHR1 antagonists.11 Based upon our analysis of the
published data as well as our experimental evaluation
of reported compounds we conclude that potent and
selective MCH receptor antagonists are quite rare and
were obtained through considerable chemical lead
optimization. The critical importance of compound
Keywords: MCHR1; Antagonist; Indanylmethyl; Selectivity.
*
Corresponding author. Tel.: +1 973 235 2439; e-mail: shawn_d.
erickson@roche.com
0960-894X/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.01.010

S. D. Erickson et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1402–1406
1403
Table 1. Selectivity profile for compounds 3, 4 and 513
selectivity is twofold: (1) high selectivity over a broad
spectrum of receptors and enzymes is essential for an
acceptable human safety profile and (2) compound selec-
tivity is critical in pre-clinical animal studies in order to
establish that the effects of the compound on food intake
and body weight loss can be attributed to the target
receptor rather than to any of the myriad causes for
reduction in food intake and body weight in rodents such
as stress, sedation, nausea, and other toxicities. This pa-
per will describe our effort to develop potent and selective
MCH receptor antagonists for the treatment of obesity.
N
N
O
N
N
H
3
N
OCH3
N
Our high-throughput screen for MCHR1 antagonists
produced numerous hits, among them haloperidol (1)
and 2-hydroxypropanolamine (2). Haloperidol has been
reported by other groups to be an MCHR1 antago-
nist.12 A series of diamines of which 2 is a prototype
was the focus of our initial efforts but compounds of this
type showed brain accumulation in vivo when dosed
sub-chronically.
O
N
N
H
4
N
OCH3
N
H
N
H
Cl
OH
O
N
O
5
N
Receptor/compound
3
4
5
F
1
MCHR1; Kia (nM)
b
MCHR1; EC50 (nM)/max. eff.
25
175/96%
5.2
20/82%
31
40/74%
Human receptorsc,d
Adrenergic a2A
Dopamine D3
N
OH
37
46
18
46
97
4
15
52
11
38
74
À23
16
32
61
67
7
N
O
NHiPr
13
3
Muscarinic M2
Opiate j
Opiate l
Serotonin 5HT2C
Somatostatin-5 (SST5)
Dopamine transporter
Norepinephrine transporter
Serotonin transporter
13
45
3
N
2
13
23
57
83
À12
10
1
A focused effort to remove the hydroxypropanolamine
side chain from 2 gave rise to aryl amide 3. Selectivity
data for 3 are shown in Table 1. The receptors for the
selectivity panel were chosen based on the following
considerations: (1) the receptor is known or likely to
influence food intake and/or energy expenditure; (2)
the receptor is known to have an affinity for arylpiperi-
dines; (3) receptors critical for an acceptable safety pro-
file. Finally, cost of attaining selectivity data was an
issue in maintaining the number of receptors in the panel
to 10–15.
32
a MCHR1 binding assay (see Supplemental Data).
b Functional cAMP assay (see Supplemental Data).
c Experiments were conducted at MDS-Panlabs.
d Values are % inhibition of receptor ligand binding at 10 lM.
amides were preferred. The addition of a methoxy group
at the 3-position to give piperidine, 4, gave a marginally
better selectivity profile. Both enantiomers of the 3,4-
disubstituted piperidines gave similar potency and
selectivity.
The relatively high potency at opioid mu and the seroto-
nin and norepinephrine transporters was unacceptable;
moreover, a functional assay showed 3 to be a full ago-
nist at the opioid mu receptor. The salient SAR of com-
pound 3 and related analogs are the following: (1)
numerous 4-arylpiperidines gave potent compounds
but 3-[2-methylbenzimidazolyl]piperidine analogs were
superior in terms of selectivity; (2) lengthening or short-
ening the 3-carbon chain gave inactive compounds; (3)
the presence of a 5-methyl group on benzimidazole im-
proves potency and selectivity; (4) para-substitution of
the aryl amide gave inactive compounds; (5) small alkyl
Our surmise was that rigidifying the flexible three car-
bon ‘linker’ between the piperidine and the aryl ring
was critical to improving receptor selectivity. We identi-
fied numerous linkers that gave potent analogs including
cyclopentyl, cyclobutyl, cyclopropylmethyl, and
dihydrobenzofuran but indanylmethyl, 5, was clearly
superior in terms of receptor selectivity. The analog
shown is the R-indane but we found that both enantio-
mers of indane gave similar potency and selectivity.

1404
S. D. Erickson et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1402–1406
Isobutyryl amide, 5, is selective and potent but showed
high in vivo clearance and poor brain exposure when
dosed orally. Data from related analogs suggested that
the aryl amide negatively influenced both of these
parameters. Table 2 shows the SAR of additional indane
analogs. 5-Methyl carbamate, 6, is potent and metabol-
ically more stable than amide 5 but much less selective.
Surprisingly, 7, the 5-bromo analog, was found to be a
potent, functional MCHR1 antagonist. The unsubstitut-
ed indane, 8, is also a potent antagonist. Replacing the
2-methyl of benzimidazole with carbinol improved met-
abolic stability. Antagonist 9 is potent and selective with
acceptable oral exposure, metabolic stability, and brain
penetration. Despite potent binding at the opioid mu
receptor, analog 9 is only a weak partial agonist
(EC50 = 24.9 lM; 57% max. response). 5-Cyanoindane
analog, 10, improves upon the potency and selectivity
of 9 (Table 3).
and selective analogs were evaluated. Table 4 shows a
comparison between two potent and selective MCHR1
analogs, aryl amide 5 and aryl nitrile 10. Our efforts to
achieve brain penetration were rewarded at moderate
expense to the plasma AUC and CL.
In a rat efficacy experiment,15 MCHR1 antagonist 10
caused a 28% reduction (p = 0.001) of food intake in
an acute DIO rat model (30 mg/kg). In two weeks of
dosing at 30 mg/kg bid 10 caused a À0.7% loss of body
weight (p = 0.00001) compared to an increase of 5.1% in
the vehicle group. Clinical chemistry and histopathology
of the animals following the study showed no adverse
findings (Scheme 1).
trans-4-Benzimidazolyl-3-methoxy-Boc-piperidine: Piper-
ine (1,2,3,6-tetrahydropyridine) was Boc protected and
epoxidized using standard conditions.16 Epoxide open-
ing with azide produced the racemic trans-4-azido-3-hy-
We found subsequently that 6-fluoro substitution on
benzimidazole, 11, further improved potency and micro-
somal stability, Ki = 0.5 nM.
droxy-
and
3-azido-4-hydroxypiperidines
in
approximately 4:1 ratio. We explored a variety of reac-
tion conditions to improve the ratio without success.
Thus, the regioisomeric mixture was hydrogenated un-
der palladium and the resulting amines were arylated
under forcing conditions using 3-nitro-4-fluorotoluene.
Fortuitously, washing the crude reaction product with
hexane removed the undesired regioisomer as well as ex-
cess 3-nitro-4-fluorotoluene. Hydrogenation afforded
the phenylenediamine as a racemate. Chiral purification
by super-critical fluid chromatography (SFC)17 afforded
pure enantiomer.
OH
N
OCH3
N
CN
H
N
F
11
Benzimidazoles were synthesized from each of the enan-
tiomerically pure 4-phenylenediaminopiperidines by
well-established methods: (A) direct condensation with
a carboxylic acid, (B) condensation with an orthoester
or (C) condensation with aldehyde and subsequent oxi-
dation using oxone.18 In no instance was racemization
observed by chiral HPLC analysis. Absolute configura-
tion of the 3,4-disubstituted piperidines was established
by X-ray structure of 4-[2,5-dimethylbenzimidazolyl]-
Boc-piperidine shown in Figure 1.19
Ki = 0.5 nM
Salient SAR features of the des-amido indanes include:
(1) no strong enantioselective binding at either the 3,4-
disubstituted piperidine or the indane. (2) 2-Carbinol
benzimidazole analogs show improved metabolic stabil-
ity compared to 2-methyl with no significant reduction
on potency, oral exposure or brain penetration. (3)
–CN improves selectivity and has no significant effect
on potency or brain penetration when compared to –Br.
Indane synthesis: (S)-(+)-5-Bromo-2-indanoic acid and
its enantiomer were synthesized according to a pub-
lished synthesis.20 The carboxylic acid was reduced to
hydroxymethyl with borane. A copper-catalyzed aryl
amination effected the –Br to –NHBoc transforma-
tion.21 Bromoindan-2-ol was converted to 5-cyanoin-
dan-2-ol by known methods.22
In order to best select compounds for in vivo studies, the
ADME properties in lean Sprague–Dawley rat of potent
Table 2. Indane analogs
R
N
OCH3
Indane—piperidine coupling: Hydroxymethyl indanes
were oxidized to aldehyde with the Dess–Martin reagent
and coupled to 4-benzimidazolylpiperidines by reductive
amination. Chiral HPLC analysis of reaction products
allowed us to optimize oxidation and reductive amina-
tion conditions such that less than 2% epimerization
was observed.
N
X
H
N
Compound
R
X
6
7
–CH3
–CH3
NHCO2CH3
–Br
–H
In summary, our lead optimization of MCHR1 antago-
nists rapidly resulted in a series of potent analogs. Selec-
tivity was achieved by two critical modifications: the
addition of a 3-methoxy group to 4-benzimidazoloyl
8
–CH3
–C(CH3)2OH
–C(CH3)2OH
9
10
–Br
–CN

S. D. Erickson et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1402–1406
1405
Table 3. Selectivity of compounds 6–10
Receptor/compound
6
7
8
9
10
MCHR1; Kia (nM)
b
MCHR1; EC50 (nM)/max. eff.
20
20/81%
5
20/92%
47
69/90%
10
30/98%
3
17/85%
Human receptorsc,d
Adrenergic a2A
Dopamine D3
14
28
22
n.d.
55
85
8
81
84
48
47
91
91
À11
31
54
80
69
59
33
40
6
34
79
À8
42
61
94
14
17
n.d.
68
77
28
12
22
3
Muscarinic M2
Opiate d
Opiate j
15
76
76
À8
63
À2
8
30
32
67
À21
14
23
À6
12
6
Opiate l
Serotonin 5HT2C
Serotonin 5HT1A
Somatostatin-5 (SST5)
Dopamine transporter
Norepinephrine transporter
Serotonin transporter
29
10
65
64
95
24
14
a MCHR1 binding assay (see Supplemental Data).
b Functional cAMP assay (see Supplemental Data).
c Experiments were conducted at MDS-Panlabs.
d Values are % inhibition of receptor ligand binding at 10 lM.
Table 4. PK properties of compounds 5 and 10
5
10
Plasma AUC (h ng/mL)
Cmax (ng/mL)
CL (mL/min kg)
T1/2 (h)
8525
1280
36.5
2.5
4730
1300
49.5
1.9
Vdss (L/kg)
%F
Brain/plasma14 (5 min)
14.0
61
3.60
47
0.06
0.9
5 mg/kg IV bolus; 30 mg/kg po. Formulation: IV: DMA, PEG400,
HPBCD, phos buffer; po: 1% Klucel LF in H2O with 0.1% Tween 80.
O
a, b
c
N
N
H
Boc
Figure 1. X-ray crystal structure of 3-hydroxy-4-[2,5-dimethylbenzim-
idazolyl]-Boc piperidine.
N3
OH
NH2
N
d, e, f
NH
Boc
MCHR1 antagonists that cause reduction of food intake
and body weight in DIO rats. Moreover, we can confi-
dently attribute the in vivo efficacy, albeit modest, exclu-
sively to antagonism of the MCH-1 receptor.
Unfortunately, the compounds described have exhibited
IC50 values for the hERG channel23 ranging from
100 nM to 4.0 lM thus rendering them unsuitable for
clinical development.
OH
OH
N3
N
Boc
trans, racemic
N
Boc
Scheme 1. Reagents: (a) Boc2O, CH2Cl2; (b)NBS, H2O, CH3CN,
KOH, CH3OH; (c) NaN3, EtOH, H2O; (d) Pd/C, H2, EtOH; (d) 3-
nitro-4-fluorotoluene, Na2CO3, n-BuOH; (f) H2, Pd/C, EtOH.
Acknowledgments
We thank the following co-workers: Zhen Wang and
Ted Lambros for chiral chromatography, Navita Malla-
lieu and Petra Goelzer for their pharmacology expertise
and input into study designs, and Dr. Amy Sargeant of
Johns-Hopkins University for determining X-ray crystal
structures.
piperidine and rigidification of a carbon linker between
aryl piperidine and aryl amide with indanylmethyl. Met-
abolic stability and brain penetration were improved by
replacing aryl amide with aryl nitrile. The resulting com-
pounds are potent, selective, and CNS drug-like

1406
S. D. Erickson et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1402–1406
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Supplementary data
(c) McBriar, M. D. Curr. Opin. Drug Discov. Devel. 2006,
9, 496.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2008.01.010.
12. (a) Marzabadi, M. R.; Daniewska, I.; DeLeon, J.; Jiang,
Y.; Lu, K.; Chen, C.-A.; Li, B.; Forray, C.; Borowsky, B.;
Ogozalek, K.; Lichtblau, H.; Wetzel, J. M. Presented at
the 224th Meeting of the American Chemical Society;
Boston, MA, August 2002; MEDI-341; (b) Frimurer, T.
M.; Ulven, T.; Hoegberg, T.; Norregaard, P. K.; Little, P.
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