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.
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Baskin, D. G. Central nervous system control of food intake.
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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
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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.;
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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
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(7) Chen, Y.; Hu, C.; Hsu, C.-K.; Zhang, Q.; Bi, C.; Asnicar, M.;
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L.; Sh, Y. Targeted disruption of the melanin-concentrating
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(
8) Marsh, D. J.; Weingarth, D. T.; Novi, D. E.; Chen, H. Y.;
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S. Melanin-concentrating hormone 1 receptor-deficient mice are
lean, hyperactive, and hyperphagic and have altered metabolism.
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(
9) (a) Borowsky, B.; Durkin, M. M.; Ogozalek, K.; Marzabadi, M.
R.; DeLeon, J.; Lagu, B.; Heurich, R.; Lichtblau, H.; Shaposhnik,
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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
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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