Bicyclo[3.1.0]hexyl urea melanin concentrating hormone (MCH) receptor-1 antagonists: Impacting hERG liability via aryl modifications

Article abstract of DOI:10.1016/j.bmcl.2006.05.069

Herein, we report the discovery of an effective strategy to modulate liabilities related to affinity of previously disclosed bicyclohexane MCHR-1 antagonists for the hERG channel. This paper describes one of several strategies incorporated to limit hERG b

Full text of DOI:10.1016/j.bmcl.2006.05.069

Bioorganic & Medicinal Chemistry Letters 16 (2006) 4262–4265
Bicyclo[3.1.0]hexyl urea melanin concentrating hormone (MCH)
receptor-1 antagonists: Impacting hERG liability
via aryl modifications
Mark D. McBriar,* Henry Guzik, Sherry Shapiro, Ruo Xu, Jaroslava Paruchova,
John W. Clader, Kim O’Neill, Brian Hawes, Steve Sorota, Michael Margulis,
Kristal Tucker, Daniel J. Weston and Kathleen Cox
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Received 20 April 2006; revised 19 May 2006; accepted 19 May 2006
Available online 5 June 2006
Abstract—Herein, we report the discovery of an effective strategy to modulate liabilities related to affinity of previously disclosed
bicyclohexane MCHR-1 antagonists for the hERG channel. This paper describes one of several strategies incorporated to limit
hERG binding via modifications of a terminal aryl group in an otherwise promising bicyclohexyl urea series.
Ó 2006 Elsevier Ltd. All rights reserved.
Melanin concentrating hormone (MCH) is a 19-amino
acid cyclic peptide found in the brains of all vertebrate
species which has been clearly established as an impor-
tant regulator of food intake and energy homeostasis.1,2
Central administration of MCH in rats stimulates food
intake,3 and chronic infusion induces hyperphagia lead-
ing to obesity.4 Similarly, mice overexpressing the MCH
gene are hyperphagic, obese, hyperglycemic, and insulin
resistant.5 In contrast, mice null for the gene encoding
MCH (prepro-MCH) are lean and hypophagic.6 Two
MCH receptor subtypes have been identified, of which
MCHR-1 is only found in rodents. Several groups,
including our own, have disclosed small molecule
MCH receptor antagonists which have demonstrated
oral efficacy in rodent feeding models.7,8
to the biaryl anilines and related bicyclo[4.1.0]hep-
tanes,10 the substituent could be appended at the m- or
p-positions of the aryl ring. As a result, further explora-
tion of both structure and positional attachment of sub-
stitution on this ring was undertaken.8
During biological profiling of the bicyclo[3.1.0]hexane
series, in vitro assays aimed at estimating cardiovascular
liabilities related to hERG (human ether-a-go-go-related
gene) affinity were employed.11 The potassium channel
encoded by hERG is a voltage gated ion channel in-
volved in cardiac repolarization. Mutations in hERG
are responsible for one type of congenital long QT syn-
drome (LQT2), which is associated with an increased
risk of torsade de points, ventricular fibrillation, and sud-
den death. Pharmacological blockade of this potassium
channel is a side effect profile of many drug candidates,
and is also associated with QT prolongation, proar-
rhythmia, and death.12–14 Recent methods in drug dis-
covery have been aimed at measuring inhibition of
hERG currents of potential drug candidates. The most
reliable procedure in this regard is the whole-cell voltage
clamp technique, however, the labor intensive nature of
this procedure limits throughput. One of the higher
throughput screens for evaluation of hERG liability is
the rubidium efflux assay which, while serving as a use-
ful screen, does not exhibit ideal potency correlations
with the voltage clamp method. This limitation notwith-
standing, the correlation between Rb efflux data and
We recently reported the discovery of bicyclo[3.1.0]hexyl
urea 1 as a potent and selective MCH-R1 antagonist
which exhibited in vivo efficacy in rodents.8 As a result
of efforts aimed at removing a mutagenic biaryl aniline
substructure from an earlier series,9 the bicyclohexane
1 served as a structurally unique substitute. Unique in
an alternative sense, the SAR of the distal aryl substitu-
ent of the bicyclo[3.1.0]hexane indicated that, contrary
Keywords: Melanin concentrating hormone; hERG; MCH; Obesity.
*
Corresponding author. Tel.: +1 908 740 2618; fax: +1 908 740
7152; e-mail: mark.mcbriar@spcorp.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.05.069

M. D. McBriar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4262–4265
4263
voltage clamp enables one to employ the Rb efflux assay
as a useful tool for the preliminary evaluation of hERG
liabilities in the discovery process.
flux data relative to conventional patch clamp methods
have been detailed elsewhere.16 Efforts to limit or elim-
inate the cardiovascular liabilities associated with inhi-
bition of hERG were then undertaken in the
bicyclohexane series, of which we chronicle our focus
on aryl modifications in this letter.
As a preliminary screen, a rubidium efflux assay (Rb
efflux) was used to determine inhibition of the volt-
age-gated potassium channel encoded by hERG.15 In
this assay, bicyclohexyl urea 1 (Fig. 1) showed 86%
inhibition at 5 lg/mL, which was of significant concern
recognizing the potential for widespread patient use of
an antiobesity agent and the inherent necessity of lim-
iting the side effect profile. Follow up in a voltage
clamp assay showed that 1 had an IC50 of 52 nM for
the hERG channel, which validated our concerns.16
Experimentally determined potency shifts of the Rb ef-
To assess binding to the hERG channel in our bicyclo-
hexane series, several compounds were tested in the
rubidium (Rb) efflux assay. Table 1 shows the MCH-
R1 activities of several representative bicyclohexanes,8
along with percent inhibition of the hERG channel as
measured in the Rb efflux assay.
Preliminary results indicated that several substituents at
the aryl terminus provided little or no improvement with
respect to hERG liabilities. Electron withdrawing or
electron donating groups were equally offensive. Nota-
bly, sulfones such as 7, amines (4), and amides (8)
showed a significant reduction of hERG inhibition.
Having established the requirements for electron with-
drawing groups on the aryl urea and the presence of
an ionizable nitrogen atom on the side chain, it was
decided to further pursue reduction of hERG liability
by exploration of aryl variations, as several different aryl
functional groups were tolerated.
Figure 1. Bicyclo[3.1.0]hexyl urea MCHR-1 antagonist (1).
Table 1. Selected bicyclohexane aryl SAR
The synthesis of the bicyclohexyl ureas has been previ-
ously detailed; however, specific modifications of the
aryl region are included in Schemes 1 and 2.8 For the
aminoaryl bicyclohexanes, the synthetic sequence pro-
ceeded according to Scheme 1. Amination of the aryl
bromide 9 was followed by side chain installation and
isocyanate treatment to provide the fully elaborated ure-
as 11–13. Unmasking of the aniline nitrogen atom with
TFA was followed by reductive amination, acylation or
sulfonylation to provide the aminoaryl bicyclohexanes
4, 14–21.
Compound R1
R2
MCH-R1 Rb effluxb
Kia (nM) (% inh.)
1
2
3
4
5
6
7
8
p-CN
H
3-CF3, 4-F
3-Cl, 4-F
3-CF3, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-CF3, 4-F
2.7
8.9
5.4
9.6
2.6
2.7
8.5
86
58
63
25
87
70
46
25
Heteroaryl bicyclohexyl ureas were synthesized as
shown in Scheme 2. Methoxypyridine 2217 was treated
with TMSI to provide pyridone 23. The aminobenzisox-
p-CO2Me
m-NH2
p-F
17
azoles 26 and 27 were derived from 24
and 2517,
m-OCH3
p-SO2Me
respectively, via treatment with acetohydroxamic acid
and in situ cyclization. The pinacol derivative of
oxindole was coupled to vinyl bromide 28, followed by
standard manipulations to provide the oxindolyl bicy-
clohexyl urea 32.
p-CONHMe 3-CF3, 4-F 17
a Mean values (n = 8) SEM.
b Measured at 5 lg/mL.
Scheme 1. Reagents and conditions: (a) carbamate or amide, N,N0-dimethylethylenediamine, CuI, K2CO3, toluene, 110 °C; (b) 1-(3-aminopropyl)-4-
methylpiperazine, Ti(O-i-Pr)4, 18 h, then NaBH4, MeOH; (c) aryl isocyanate, i-Pr2NEt, CH2Cl2; (d) TFA, CH2Cl2 (for R = BOC); (e) aldehyde,
NaB(OAc)3H, CH2Cl2; (f) acid chloride, isocyanate or sulfonyl chloride, i-Pr2NEt, CH2Cl2.

4264
M. D. McBriar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4262–4265
Scheme 2. Reagents: (a) TMSI, CH2Cl2; (b) acetohydroxamic acid, K(O-t-Bu), DMF; (c) Pd(dppf)Cl2, K3PO4, DME/H2O; (d) Et2Zn, ClCH2I,
CH2Cl2; (e) TBAF, THF; (f) Dess–Martin periodinane, pyridine, CH2Cl2; (g) 1-(3-aminopropyl)-4-methylpiperazine, Ti(O-i-Pr)4, 18 h, then NaBH4,
MeOH; (h) aryl isocyanate, i-Pr2NEt, CH2Cl2.
Given the promising reduction of hERG affinity ob-
served with aniline 4, a series of derivatives were made
from the parent anilines in order to probe the bound-
aries of acceptable changes that would reduce hERG
inhibition while retaining activity for MCH-R1 (Table
2). Substitution at either the m- or p-positions with
amines and relatively small alkyl amides (branched or
n-alkyl) proceeded with good retention of MCH-R1
binding while significantly reducing hERG inhibition.
Unfortunately, pharmacokinetic properties suffered as
indicated by low rat AUC data. It was speculated that
cyclic amides would impart increased stability in vivo,
which was indeed the case with pyrrolidinone 13, though
a significant loss in MCH-R1 affinity was observed. The
cyclopropylamide 19 served to improve binding and
AUC, however, increased hERG inhibition as well.
Small alkyl ureas such as 21 also served to balance affin-
ity and hERG liability, while sulfonamides, t-butyl car-
bamates, and pivaloyl amides all were inferior.
Further efforts to reduce hERG channel affinity focused
on heterocyclic aryl groups (Table 3). Heterocycles such
as pyridines17 and thiophenes17 were tolerated; however,
these did not significantly affect hERG affinity. In con-
trast, thiazole 3517 produced a significant drop in hERG
liability along with a decrease in MCH-R1 activity.
Elaboration to methoxypyridine 22 provided a promis-
ing reduction in hERG affinity, as did the pyridone
derivative 23, however, the pyridones suffered from infe-
rior activity for MCH-R1. Oxindoles such as 32 retained
Table 2. Aminoaryl bicyclohexane SAR
R1
MCH-R1 Kia (nM)
Rb effluxb (% inh.)
c
Rat AUC0–6 h (ng h/mL)
Compound
4
11
12
13
14
15
16
17
18
19
20
21
m-NH2
p-NHBOC
9.6
139
25
25
87
29
14
16
19
18
34
37
46
27
17
m-NH-azetidinyl
m-NH-pyrrolidinyl
p-NH2
57
822
251
4.4
2.5
4.8
3.1
15.1
6.8
115
28
m-NHAc
p-NHAc
m-NH-propionyl
m-NH-isopropionyl
m-NH-cyclopropionyl
m-NH-pivaloyl
m-NHCONHEt
533
339
634
127
a Mean values (n = 8).
b Measured at 5 lg/mL.
c Mean values (n = 3). Dosed at 10 mg/kg po.

M. D. McBriar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4262–4265
Table 3. Heteroaryl bicyclohexane SAR
4265
Acknowledgments
We thank Dr. Michael Graziano and Dr. William
Greenlee for helpful discussions, support, and
encouragement.
References and notes
c
Compound Ar
MCH-R1 Rb effluxb Rat AUC0–6 h
Kia (nM) (% inh.)
(ng h/mL)
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acceptable MCH-R1 inhibition, and showed significant
reductions in hERG binding, as did aminobenzisoxazole
26. Follow up in a voltage clamp assay showed that 26
had an IC50 of 0.69 lM in a voltage clamp assay. Phar-
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exposure in rodents could be obtained. Interestingly,
the regioisomeric derivative 27 exhibited a 2-fold reduc-
tion in affinity relative to 26.
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clohexyl MCH-R1 antagonists.16 Changes in the
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binding properties, with amide substituents providing
consistent reductions in hERG affinity. Further studies
revealed that aminomethyl substituents and several het-
eroaryl derivatives also exhibited significant reductions
in hERG binding while maintaining acceptable activity
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17. Synthesized via Method B in reference 8.