Discovery and characterization of aminopiperidinecoumarin melanin concentrating hormone receptor 1 antagonists

Article abstract of DOI:10.1021/jm050598r

4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylmethyl)-6-chlorochromen-2- one (7) is a potent, orally bioavailable melanin concentrating hormone receptor 1 (MCHr1) antagonist that causes dose-dependent weight loss in diet-induced obese mice. Further evalu

Full text of DOI:10.1021/jm050598r

5
888
J. Med. Chem. 2005, 48, 5888-5891
Discovery and Characterization of
Aminopiperidinecoumarin Melanin
Concentrating Hormone Receptor 1
Antagonists
,
†
†
†
Philip R. Kym,* Rajesh Iyengar, Andrew J. Souers,
†
†
†
John K. Lynch, Andrew S. Judd, Ju Gao,
†
†
†
Jennifer Freeman, Mathew Mulhern, Gang Zhao,
†
†
Anil Vasudevan, Dariusz Wodka,
‡
‡
Christopher Blackburn, Jim Brown,
‡
‡
‡
Jennifer Lee Che, Courtney Cullis, Su Jen Lai,
‡
‡
‡
Matthew J. LaMarche, Tom Marsilje, Jon Roses,
Figure 1. Aminopiperidinecoumarin MCHr1 antagonists:
footnote a) values represent an average of at least three
‡
‡
‡
Todd Sells, Brad Geddes, Elizabeth Govek,
(
‡
†
†
Michael Patane, Dennis Fry, Brian D. Dayton,
determinations (in duplicate); (footnote b) 10 mg/kg, po in lean
mice, where interanimal variability was less than 25% for all
values; (footnote c) NT, where 1 was not evaluated in animals.
†
†
†
Sevan Brodjian, Doug Falls, Michael Brune,
†
†
Eugene Bush, Robin Shapiro,
†
†
Victoria Knourek-Segel, Thomas Fey,
†
†
Cathleen McDowell, Glenn A. Reinhart,
rapidly identified C6 substitution as being critical for
improvement in MCHr1 affinity and functional antago-
nism. Specifically, C6-chloro and C6-methoxy substitu-
tion delivered potent MCHr1 antagonists that were
evaluated further in pharmacokinetic assays in lean
mice. The C6-chloro analogue 2 demonstrated efficient
penetration into the brain upon oral dosing at 10 mg/
kg. On the basis of favorable brain exposure of the
†
†
†
Lee C. Preusser, Kennan Marsh, Lisa Hernandez,
†
†
Hing L. Sham, and Christine A. Collins
Metabolic Disease Research, Abbott Laboratories,
00 Abbott Park Road, Abbott Park, Illinois 60064, and
Millennium Pharmaceuticals, 40 Landsdowne Street,
Cambridge, Massachusetts 02139
1
Received June 23, 2005
6
-chloro analogue (1.35 and 0.44 AUCbrain:AUCplasma for
and 3, respectively), we focused our investigation of
Abstract: 4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylm-
ethyl)-6-chlorochromen-2-one (7) is a potent, orally bioavailable
melanin concentrating hormone receptor 1 (MCHr1) antago-
nist that causes dose-dependent weight loss in diet-induced
obese mice. Further evaluation of 7 in an anesthetized dog
model of cardiovascular safety revealed adverse hemodynamic
effects at a plasma concentration comparable to the minimally
effective therapeutic concentration. These results highlight the
need for scrutiny of the cardiovascular safety profile of MCHr1
antagonists.
2
the SAR of cinnamyl replacements on the 6-chlorocou-
marin series.
The synthesis of the aminopiperidinecoumarin ana-
logues is shown in Scheme 1. Treatment of hydroxy-
coumarin 4 with trifluoromethanesulfonic anhydride in
the presence of base provided the triflate, which was
subsequently displaced by 4-amino-1-N-Boc-piperidine
and deprotected under acidic conditions to provide
aminopiperidinecoumarin 5. Derivatization of the pip-
eridine nitrogen was accomplished by reductive amina-
tion of arylaldedydes or nucleophilic displacement of
cinnamyl chloride or benzyl halides to provide the
MCHr1 antagonists.
Table 1 summarizes the structure-activity relation-
ships for the MCHr1 binding affinity and functional
inhibition observed with the aminopiperidinecoumarin
analogues. The naphthyl analogue 6 maintained potency
comparable to that of the cinnamyl lead 2, indicating
steric tolerance of the receptor for bicyclic substituents.
Efforts to incorporate heteroatoms into the proximal
ring of the bicyclic system resulted in loss of MCHr1
potency (data not shown), but the receptor did tolerate
heteroatom substitution into the distal ring. In particu-
lar, [6,5]-bicyclic heterocycles were well tolerated by the
receptor, and we rapidly identified the piperonyl ana-
logue 7 as a potent inhibitor of MCH-mediated Ca2
release. Several other [6,5]-bicyclic heterocycles were
also active; in particular, potent functional MCHr1
antagonism was observed with dihydrobenzo[b]furan 8
and the indole analogues 12 and 14.
1
Melanin-concentrating hormone (MCH) is a cyclic,
9 amino acid peptide expressed by neurons in the
1
lateral hypothalamus and zona incerta and shown to
play a major role in body weight regulation in rodents.1
A single injection of MCH into the central nervous
,2
3
system stimulates food intake in rodents, and chronic
4
administration leads to increased body weight. Simi-
larly, transgenic mice overexpressing the MCH gene are
susceptible to insulin resistance and obesity.5 Mice
lacking the gene encoding MCH are hypophagic, lean,
6
and maintain elevated metabolic rates. Consistent with
this phenotype, animals that lack the gene encoding the
MCH receptor maintain elevated metabolic rates and
thus remain lean despite hyperphagia on a normal
7,8
diet. Finally, the observation that chronic administra-
tion of small-molecule MCHr1 antagonists leads to the
reduction of body weight provides further validation of
MCHr1 blockade as a novel target for antiobesity
+
9
pharmacotherapy.
Aminopiperidinecoumarin 1 was identified by high-
throughput screening as a moderate affinity (IC50 ) 191
(
40 nM) MCHr1 antagonist. Exploration of substitu-
tion effects on the coumarin ring system (Figure 1)
Representative potent MCH antagonists were subse-
quently evaluated in diet-induced obese (DIO) mice to
determine the impact of the bicyclic heterocyle on brain
and plasma exposure after oral dosing (Table 2). The
piperonyl analogue 7 provided the best combination of
*
To whom correspondence should be addressed. Phone: 847-935-
4
699. Fax: 847-938-1674. E-mail: phil.r.kym@abbott.com.
†
Abbott Laboratories.
Millennium Pharmaceuticals.
‡
1
0.1021/jm050598r CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/19/2005

Letters
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19 5889
Scheme 1. Synthesis of Aminopiperidinecoumarin
MCHr1 Antagonistsa
a
Reagents and conditions: (a) Tf2O, Et3N, CH2Cl2, 0 °C; (b)
4
-amino-1-N-Boc-piperidine, iPr2NEt, CH3CN; (c) 4 N HCl, dioxane
(
yield for steps a-c ) 92%); (d) aldehyde, NaCNBH3, MeOH (yield
)
65-90%); (e) alkyl halide, K2CO3, DMF (yield ) 28-40%).
Table 1. SAR of Heterocylic Analogues
Figure 2. Effect of 7 (dosed at 10 (O) and 30 (3) mg/kg, po,
b.i.d. in 1% Tween-80 in water) and sibutramine (10 mg/kg,
po, b.i.d., [) on the body weight of DIO mice, and the effect of
7
(30 mg/kg, po, b.i.d., b) on the body weight of lean mice.
Control DIO (9) mice were treated b.i.d. with 4 mL/kg vehicle.
All values are the mean ( SEM for n ) 12: (//) p < 0.01 and
(
/) p < 0.05 for comparisons against vehicle group by Dunnett’s
test.
sufficient drug concentration in the brain to deliver in
vivo efficacy.
Evaluation of coumarin 7 against 61 enzymes and
receptors at Novascreen11 revealed moderate cross-
reactivity against three G-protein coupled receptors that
also bind biogenic amine ligands (nonselective adren-
ergic-R1, 75% at 10 µM; nonselective opiate, 69% at 10
µM; nonselective dopamine, 60% inhibition at 10 µM)
(
see Supporting Information). Compound 7 did not show
12
appreciable affinity to MCHr2 or other receptors that
have been implicated in weight loss (galanin, CCK1, or
serotonin transporter). Compound 7 did bind to the
hERG potassium channel with moderate affinity (IC50
)
2.25 ( 0.61 µM).
Compound 7 was evaluated for its effects on body
weight in DIO mice that were fed a high-fat diet (60%
lard) ad libitum in a 28-day study. Animals were dosed
orally with 7 (10 or 30 mg/kg, b.i.d.), sibutramine (10
mg/kg, b.i.d.), or vehicle, and body weight was measured
daily (22 animals per group). Vehicle-treated DIO mice
continued to gain weight throughout the study (8% body
weight increase, Figure 2). The sibutramine-treated
animals rapidly lost weight through day 7. The weight
loss plateaued during days 7-14, and the animals
started to regain weight after 14 days of treatment.
a
Displacement of [125I]MCH from IMR-32 (I3.4.2) cell mem-
branes (MCH binding Kd ) 0.66 ( 0.25 nM, Bmax ) 0.40 ( 0.08
b
2+
pmol/mg). Inhibition of MCH-mediated Ca release in whole
c
IMR-32 cells (MCH EC50 ) 62.0 ( 3.6 nM). All values are the
mean ( SEM and are derived from at least three independent
experiments (all duplicates).
Table 2. Selected Pharmacokinetic Parameters of
Aminopiperidinecoumarin Analogues Dosed at 10 mg/kg in DIO
9
Micea
Similar to previously described MCHr1 antagonists, 7
caused a dose-dependent decrease in the body weight
of treated DIO mice throughout the study. After 28 days,
DIO mice treated with sibutramine (10 mg/kg, qd)
weighed 12% less than vehicle-treated mice (Table 3),
while mice dosed with coumarin 7 weighed 16% and
plasma AUC0-24h brain AUC0-24h brain Cmax brain C12h
compd
(µg‚h/mL)
(µg‚h/g)
(ng/g)
(ng/g)
7
8
0
2
6.35
4.17
454 ( 36
294 ( 6 00 b
175 ( 15
0.621
0.449
0
0
b
b
b
1
1
0
0
2.87
1.18
182 ( 40
18 ( 6.3
3
2% less in the 10 and 30 mg/kg b.i.d. groups, respec-
a
All values are the mean ( SEM (n ) 3). b No drug levels
tively. DIO mice treated with 7 at 30 mg/kg reached a
body weight comparable to those of lean mice within
detected in any animal (n ) 3) because of instability of compound
in plasma.
1
3 days of dosing, after which further body weight
reduction was minimal. No evidence of overt toxicity or
behavioral abnormalities was noted in drug-treated
animals (Irwin analysis) on day 28 during a 5 h
observation period immediately following administra-
tion of the final dose. A group of lean mice was also
dosed with coumarin 7 (30 mg/kg, b.i.d.) in the 28 day
study, and body weight in these mice remained stable
throughout the duration of treatment. In separate
studies, rats treated with a single 30 mg/kg dose of 7
potent functional antagonism, metabolic stability,10 and
exposure in the brain (AUC ) 4.17 µg‚h/g) and plasma
(
(
AUC ) 6.35 µg‚h/mL) with oral dosing in DIO mice
10 mg/kg) and therefore was selected for further
evaluation. Of particular importance, a 10 mg/kg dose
of 7 delivered significant drug levels in the brain
throughout a 12 h period (brain C12h ) 175 ng/g),
suggesting that twice a day (b.i.d.) dosing may provide

5
890 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19
Letters
Table 3. Body Weight (BW) of All Animal Groups at Days 0
and 28 and % Change of the Drug-Treatment Groups Relative
to Vehiclea
%
change
groupb
BWday0 (g) BWday28 (g) from vehicle
lean, 30 mg/kg 7
33.1 ( 2.5
41.9 ( 3.9
32.9 ( 2.4
45.4 ( 3.8
39.9 ( 4.0
38.1 ( 3.5
31.0 ( 2.2
DIO, vehicle
1
1
3
0 mg/kg sibutramine 41.9 ( 3.8
0 mg/kg 7
0 mg/kg 7
-12
-16
-31
41.9 ( 3.8
42.0 ( 3.8
a
All values are the mean ( SEM (n ) 12). b All doses were given
in 4 mL/kg body weight volume of vehicle (1% Tween-80 in water).
Compound 7 was administered po by gavage at doses of 10 and
0 mg/kg, b.i.d., and sibutramine was administered at a dose of
0 mg/kg, po, qd. Body weights were determined daily for 28 days.
3
1
Figure 3. Functional effects of intravenous administration
of 7 were assessed in male beagle dogs anesthetized with
sodium pentobarbital (35 mg/kg, 6 (mg/kg)/h maintenance
infusion). Animals were intubated, mechanically ventilated,
and instrumented for acute measurement of mean arterial
pressure, cardiac contractile function, and pulmonary arterial
pressure. After a 30-min baseline period, 7 was infused as a
series of three 30-min infusions followed by a 60-min post-
treatment period
Table 4. Change in Body Weight (% Change from Vehicle) and
Drug Exposure Data after Final Dose on Day 13
dose
% change
plasma
brain
a
a
(
mg/kg, po, b.i.d.) BW from vehicle
(µg/mL)
(µg/g)
1
0
0
-6.9 ( 1.4
-18.2 ( 1.9
2.00 ( 0.39 2.21 ( 0.15
6.01 ( 1.16 6.46 ( 0.42
3
a
Drug concentrations in plasma and in brain determined 1 h
half-life was 3.9 ( 0.5 h, the mean maximum plasma
concentration (Cmax) was 1.60 ( 0.12 µg/mL, the plasma
clearance (CLp) was 0.95 ( 0.15 L/(h‚kg), and the
average total exposure (AUC0f∞) achieved was 2.66 (
after the final dose. All values are the mean ( SEM (n ) 3).
demonstrated normal behavioral satiety sequence and
normal behavior in a conditioned taste-aversion test.13
0.38 µg‚h/mL. After oral administration of 7 in dogs, the
Encouraged by the dose-dependent weight loss in DIO
mice and weight-neutral effects of dosing coumarin 7
in lean mice, we performed a follow-up study to inves-
tigate the drug exposure required to achieve weight loss
in DIO mice and the food intake profile associated with
administration of 7. Dosing DIO mice for 13 days with
coumarin 7 (10 or 30 mg/kg b.i.d.) again resulted in dose-
dependent reduction in body weight in compound-
treated animals (Table 4). Interestingly, the 10 mg/kg
b.i.d. dose of 7 led to significant reduction in body weight
after 13 days of dosing but did not reduce cumulative
food intake (FI) compared to vehicle-treated controls
Cmax was 0.20 ( 0.06 µg/mL, the half-life was 4.4 ( 0.5
h, and the oral bioavailability was 48 ( 12%.
Compound 7 was evaluated further in a pentobarbital
anesthetized dog model of cardiovascular function using
14
an escalating dosing paradigm. Compound 7 was
administered intravenously as a series of three 30-min
infusions at doses of 8, 26, and 80 (mg/kg)/30 min. At
the end of the first two infusion periods, respective
plasma concentrations achieved were 3.33 ( 0.16 and
1
1.80 ( 0.49 µg/mL. The third infusion was terminated
after approximately 12 min because of pronounced
functional effects leading to risk of cardiovascular
collapse (Figure 3). Subsequently, the maximum drug
concentration measured was 19.89 ( 6.34 µg/mL. Prin-
cipal hemodynamic effects of the compound included an
initial significant increase in indices of cardiac contrac-
tility (dP/dtmax) early in the dosing cycle followed by a
steep, dose-dependent decrease as plasma drug concen-
trations approached maximum values. In addition,
pulmonary arterial pressure trended upward during the
first dose, in parallel with dP/dt. However, as dP/dt
decreased and plasma concentrations continued to
increase, pulmonary arterial pressure increased steeply
to values nearly 2-fold above baseline, and escalating
doses of 7 resulted in a dose-dependent decrease in
mean arterial pressure. Given that the minimally
effective therapeutic drug concentration derived from
the efficacy study in DIO mice was 2.0 ( 0.4 µg/mL,
further development of this compound was halted
because of an insufficient therapeutic index.
(38.7 ( 4.1 and 40.2 ( 3.6 g, respectively). The weight
loss observed upon treatment with 7 at 10 mg/kg could
be the result of an alteration in energy expenditure.
Similar findings have been reported in MCHr1 -/-
mice, which consumed the same amount of food on a
normal diet as the wild-type mice, yet were resistant to
weight gain as a result of increased energy expendi-
7,8
ture. The additional weight loss observed in DIO mice
treated with the higher dose of 7 (30 mg/kg, b.i.d., Table
4
) is accounted for by the reduction in food intake in
the animals in this dose group (cumulative FI ) 24.2 (
.7 g). Given the high end-of-study drug levels achieved
1
in the brain (6.46 µg/g), it is possible that some of the
weight loss observed in the animals dosed at 30 mg/kg
could be due to off-target activities of the compound.
The end-of-study drug levels (1 h after last dose)
indicated high levels of drug present in plasma (2 µg/
mL at 10 mg/kg; 6 µg/mL at 30 mg/kg) and brain (2.2
µg/g at 10 mg/kg; 6.5 µg/g at 30 mg/kg). The minimally
effective therapeutic plasma concentration was taken
from the plasma drug concentration 1 h (Cmax) after the
administration of the final 10 mg/kg dose (2 µg/mL).
Supported by the compelling efficacy profile in DIO
mice, coumarin 7 was selected for analysis of pharma-
cokinetic parameters in male beagle dogs and for safety
assessment in an anesthetized dog cardiovascular model.
Following a single iv bolus of 2.5 mg/kg, the apparent
Coumarin 7 is a structurally novel MCHr1 antagonist
characterized by potent functional antagonism, pro-
longed exposure in the brain with oral dosing, and dose-
dependent weight loss leading to normalization of body
weight within 13 days of dosing (30 mg/kg, b.i.d.) in DIO
mice. However, the compound fails to deliver an accept-
able therapeutic index with respect to multiple adverse
hemodynamic cardiovascular parameters after intrave-
nous dosing in male beagle dogs. The factors that

Letters
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19 5891
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
References
(
1) Saito, Y.; Nothacker, H.-P.; Civelli, O. Melanin-concentrating
hormone receptor: An orphan receptor fits the key. Trends
Endocrinol. Metab. 2000, 11, 299-303.
Figure 4. Structures and functional activities of additional
aminopiperidinecoumarins evaluated in dog cardiovascular
assay.
(2) Schwartz, M. W.; Woods, S. C.; Porte, D., Jr.; Selley, R. J.;
Baskin, D. G. Central nervous system control of food intake.
Nature 2000, 404, 661-671.
contribute to the insufficient therapeutic index for this
compound are twofold: (1) high plasma concentration
is required to deliver sufficient drug levels to the brain
to achieve chronic weight loss; (2) deleterious effects on
the cardiovascular system occur at low micromolar
plasma drug concentration. The conundrum of high
plasma concentration required to achieve efficacy (2.0
(3) Della-Zuana, O.; Presse, F.; Ortola, C.; Duhault, J.; Nahon, J.
L.; Levens, N. Acute and chronic administration of melanin-
concentrating hormone enhances food intake and body weight
in Wistar and Sprague-Dawley rats. Int. J. Obes. 2002, 26,
1289-1295.
4) Gomori, A.; Ishihara, A.; Ito, M.; Mashiko, S.; Matsushita, H.;
Yumoto, M.; Ito, M.; Tanaka, T.; Tokita, S.; Moriya, M.; Iwaasa,
H.; Kanatani, A. Chronic intracerebroventricular infusion of
MCH causes obesity in mice. Am. J. Physiol.: Endocrinol. Metab.
(
2
003, 284, E583-E588.
(
(
0.4 µg/mL) despite potent functional antagonism
(
5) Ludwig, D. S.; Tritos, N. A.; Mastaitis, J. W.; Kulkarni, R.;
Kokkotou, E.; Elmquist, J.; Lowell, B.; Flier, J. S.; Maratos-Flier,
E. Melanin-concentrating hormone overexpression in transgenic
mice leads to obesity and insulin resistance. J. Clin. Invest. 2001,
Ca2 release IC50 ) 28 ( 5 nM) is the result of multiple
+
factors, including high nonspecific plasma protein bind-
ing (96.01 ( 0.03% bound in DIO mouse plasma)
limiting the availability of free drug to interact with the
receptor. In addition, the observed cardiovascular toxic-
ity at low micromolar concentration of 7 in the anes-
thetized dog assay raises significant concern. To deter-
mine whether the deleterious cardiovascular activity
was attributable to off-target effects associated with the
aminopiperidinecoumarin chemotype or linked to MCHr1
antagonism, we evaluated two additional analogues in
the dog cardiovascular safety assay. The 6-methoxycou-
marin 16 was selected as a closely related active MCHr1
antagonist, and the 4-tert-butylphenyl substituted 17
was selected as a representative aminopiperidinecou-
marin with no MCHr1 functional antagonism observ-
able at 10 µM (Figure 4). Evaluation of 16 and 17
revealed significant compound-induced changes in mul-
tiple cardiovascular parameters, including heart con-
tractility (see Supporting Information), within the first
1
07, 379-386.
(6) Shimada, M.; Tritos, N. A.; Lowell, B. B.; Flier, J. S.; Maratos-
Flier, E. Mice lacking melanin-concentrating hormone are
hypophagic and lean. Nature 1998, 396, 670-674.
(7) Chen, Y.; Hu, C.; Hsu, C.-K.; Zhang, Q.; Bi, C.; Asnicar, M.;
Hsiung, H. M.; Fox, N.; Slieker, L. J.; Yang, D. D.; Heiman, M.
L.; Sh, Y. Targeted disruption of the melanin-concentrating
hormone receptor-1 results in hyperphagia and resistance to
diet-induced obesity. Endocrinology 2002, 143, 2469-2477.
(
8) Marsh, D. J.; Weingarth, D. T.; Novi, D. E.; Chen, H. Y.;
Trumbauer, M. E.; Chen, A. S.; Guan, X.-M.; Jiang, M. M.; Feng,
Y.; Camacho, R. E.; Shen, Z.; Frazier, E. G.; Yu, H.; Metzger, J.
M.; Kuca, S. J.; Shearman, L. P.; Gopal-Truter, S.; MacNeil, D.
J.; Strack, A. M.; MacIntyre, D. E.; Van der Ploeg, L. H. T.; Qian,
S. Melanin-concentrating hormone 1 receptor-deficient mice are
lean, hyperactive, and hyperphagic and have altered metabolism.
Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 3240-3245.
(
9) (a) Borowsky, B.; Durkin, M. M.; Ogozalek, K.; Marzabadi, M.
R.; DeLeon, J.; Lagu, B.; Heurich, R.; Lichtblau, H.; Shaposhnik,
Z.; Daniewska, I.; Blackburn, T. P.; Branchek, T. A.; Gerald, C.;
Vaysse, P. J.; Forray, C. Antidepressant, anxiolytic and anorectic
effects of a melanin-concentrating hormone-1 receptor antago-
nist. Nat. Med. 2002, 8, 779-781. (b) An orally active small
molecule MCHr1 antagonist in an acute feeding model was
reported in the following: Takekawa, S.; Asami, A.; Ishihara,
Y.; Terauchi, J.; Kato, K.; Shimomura, Y.; Mori, M.; Murakoshi,
H.; Kato, K.; Suzuki, N.; Nishimura, O.; Fujino, M. T-226296:
A novel, orally active and selective melanin-concentrating
hormone receptor antagonist. Eur. J. Pharmacol. 2002, 438 (3),
3
0 min of infusion in the dog assay. The plasma
concentrations achieved at the end of the first infusion
were 2.84 (2.75-2.93) µg/mL for the active analogue 16
and 1.39 (1.36-1.43) µg/mL for the inactive analogue
1
29-135. (c) Souers, A. J.; Gao, J.; Brune, M.; Bush, E.; Wodka,
17. These results and other data (unpublished) led to
D.; Vasudevan, A.; Judd, A. S.; Mulhern, M.; Brodjian, S.;
Dayton, B.; Shapiro, R.; Hernandez, L.; Collins, C. A.; Kym, P.
R. Identification of 2-(4-benzyloxyphenyl)-N-[1-(2-pyrrolidin-1-
yl-ethyl)-1H-indazol-6-yl]acetamide, an orally efficacious melanin-
concentrating hormone receptor 1 antagonist for the treatment
of obesity. J. Med. Chem. 2005, 48, 1318-1321.
the conclusion that the adverse cardiovascular profile
observed for this class of MCHr1 antagonist was likely
due to an unknown off-target effect of these compounds
and not to MCHr1 antagonism. Since coumarin 7 was
(
10) Microsomal stability of 7 (1 mg/mL protein, % parent @ 30
>
500-fold selective against a broad panel of receptors
min): mouse, 82% parent; human, 75% parent.
1
1
(11) Cross-reactivity assays were performed by Novascreen (ww-
w.novascreen.com).
and enzymes, the link to a specific off-target cross-
reactivity responsible for the adverse cardiovascular
effects remains undiscovered.
(
12) Functional MCHr2 is not expressed in rodents. For the identi-
fication and species characterization of MCHr2, see the follow-
ing: An, S.; Cutler, G.; Zhao, J. J.; Huang, S.; Tian, H.; Li, W.;
Liang, L.; Rich, M.; Bakleh, A.; Du, J.; Chen, J.; Dai, K.
Identification and characterization of a melanin-concentrating
hormone receptor. Proc. Natl. Acad. Sci. U.S.A. 2001, 98 (13),
The comprehensive profiling of 7 was instructive in
highlighting the exciting potential of MCHr1 antago-
nists to deliver sustained weight loss with chronic
dosing in DIO mice and the significant cardiovascular
safety hurdles that must be overcome to ultimately lead
to identification of a safe and effective pharmaceutical
agent. This led us to adopt a novel screening paradigm
focused on rapid assessment of hemodynamic liabilities
associated with multiple MCHr1 antagonist chemotypes
in our lead optimization strategy. The full details of this
strategy will be reported in due course.
7
576-7581.
(
13) Bush, E.; Fey, T.; Dickinson, R.; Shapiro, R.; Knourek-Segal, V.;
Droz, B.; Mcdowell, C.; Jacobson, P.; Muss, M.; Souers, A.;
Iyengar, R.; Kym, P.; Collins, C.; Brune, M. Obes. Res. 2004, 12
(
S), A14.
(
14) Fryer, R. M.; Preusser, L. C.; Calzadilla, S. V.; Hu, Y.; Xu, H.;
Marsh, K. C.; Cox, B. E.; Lin, C. T.; Gopalakrishnan, M.;
Reinhart, G. A. (-)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-
hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637),
a novel ATP-sensitive potassium channel opener: Hemodynamic
comparison to ZD-6169, WAY-133537 and nifedipine in the
anesthetized canine. J. Cardiovasc. Pharmacol. 2004, 44,
1
37-147.
Acknowledgment. The authors thank Paul Rich-
ardson and J. J. Jiang for MCH peptide synthesis.
JM050598R