A. J. Carpenter et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4994–5000
4999
Table 4. SAR and bioavailability of regioisomeric 2-amino-1H-benzimidazoles (compounds 48–58)
R1
N
N
N
O
N
O
N
R
R
S
S
N
N
N
R1
Cl
Cl
I
II
R1
pIC50
% Fb
a
Compound
Series
R
26
48
49
50
51
52
53
54
55
56
57
58
I
Me
4-Methoxyphenyl
4-Methoxyphenyl
Me
8.3
8.0
8.2
8.8
8.3
8.3
7.9
5.6
8.0
7.9
7.6
8.2
3
I
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NC4H8
NC4H8
16
nd
P10014b
30
21
I
II
I
Me
n-Pr
II
I
n-Pr
4-Methoxybenzyl
4-Methoxybenzyl
2-Hydroxyethyl
2-Hydroxyethyl
Me
nd
nd
II
I
59
55
II
I
nd
P10014b
II
Me
a Values are means of greater than three experiments; pIC50 = Àlog(IC50).
b Bioavailability (nd, not determined).
battery of G-protein coupled receptors, ion channels,
and enzymes. Its efficacy in inducing weight loss was
evaluated in high fat (58% kcal of fat, Research Diets
#D12331) diet-induced obese AKR/J mice.
In conclusion, a series of benzimidazole-containing thie-
nopyrimidinones was synthesized based upon a screen-
ing hit and assessed for their potency as antagonists of
MCH. SAR analysis showed that most compounds were
potent antagonists, with activities below 100 nM. There
also was a wide tolerance for a variety of sterically
demanding functional groups at ring-nitrogen substitu-
tion (positions 1 and 3) or at position 2 of the benzimid-
azole. Improvements in the bioavailability of these
antagonists were also made and one such analog, com-
pound 50, was progressed into an animal model of obes-
ity and produced weight loss over the 15-day treatment
period.
As shown in Figure 2, during a 15-day treatment, oral
administration of compound 50 at 0.3, 1, 3, and
10 mg/kg once daily caused a sustained dose-dependent
change in body weight of À1.6%, À2.1%, À5.1%, and
À10%, respectively, relative to vehicle controls.16
0
Vehicle (n=9)
References and notes
Compound 50 (0.3mg/kg, n=8)
-2
1. Burton, B. T.; Foster, W. R.; Hirsch, J.; Vanitallie, T. Int.
J. Obes. Relat. Metab. Disord. 1985, 9, 155.
Compound 50 (1mg/kg, n=8)
Compound 50 (3mg/kg, n=8)
2. For a recent review, see: Harrold, J.; Pinkney, J.; Williams,
G. Drug Discovery Today: Ther. Strateg. 2004, 1, 219.
3. (a) Presse, F.; Nahon, J.-L.; Fischer, W. H.; Vale, W. Mol.
Endocrinol. 1990, 4, 632; (b) Qu, D.; Ludwig, D. S.;
Gammeltoft, S.; Piper, M.; Pelleymounter, M. A.; Cullen,
M. J.; Mathes, W. F.; Przypek, J.; Kanarek, R.; Maratos-
Flier, E. Nature 1996, 380, 243; (c) Skofitsch, G.; Jacobo-
witz, D. M.; Zamir, N. Brain Res. Bull. 1985, 15, 635; (d)
Rossi, M.; Choi, S. J.; O’Shea, D.; Miyoshi, T.; Ghatei, M.
A.; Bloom, S. R. Endocrinology 1997, 138, 351.
Compound 50 (10mg/kg, n=8)
-4
-6
-8
4. Shimada, M.; Tritos, N. A.; Lowell, B. B.; Flier, J. S.;
Maratos-Flier, E. Nature 1998, 396, 670.
-10
-12
5. (a) 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.; MacIn-
tyre, D. E.; Van der Ploeg, L. H. T.; Qian, S. Proc. Natl.
Acad. Sci. U.S.A. 2002, 99, 3240; (b) 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.;
Shi, Y. Endocrinology 2002, 143, 2469.
Figure 2. Effect of compound 50 at 0.3, 1, 3, and 10 mg/kg (orally, qd)
on body weight loss in high fat diet-induced obese AKR/J mice.
Weight loss is expressed as percentage weight change from pre-
treatment value for each treatment group (average pre-treatment body
weight value was 49.6 0.6 g, n = 41). Values are means SEM; n,
number of mice per group.