4396
C. Zhu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4393–4396
OEt
Acknowledgments
The authors thank Richard Berger, Ramona Gray, and Amanda
Makarewicz for intermediates scale-up. The authors acknowledge
Stephanie Spann for the help of in vivo studies. The authors also
thank Tracy Johnson and Chris Nunes for dosing the animals used
in pharmacokinetic experiments. Alan Kopin at the Tufts University
School of Medicine is acknowledged for the use of CCK1RÀ/À mice.
N
CO2R
N
N
N
44: R = H
44a: R = Na
Me
O
Figure 4. Compound 44 (free acid) and sodium salt 44a.
Supplementary data
Table 6
Active in vivo CCK1R agonists pharmacokinetic profilea
Supplementary data associated with this article can be found, in
Compound
Species
Clp
(mL/min/kg)
Vd
(L/kg)
po AUCN
M h)
t1/2
(h)
F
(%)
Cmax
M)
(
l
(
l
44
44a
45
Mouse
Mouse
Mouse
Mouse
5.3
3.1
6.4
0.47
0.56
0.73
0.59
0.39
4.2
1.5
3.5
3.4
2.7
1.7
7
43
33
22
0.28
4.9
1.1
References and notes
1. Wank, S. A. Am. J. Physiol. 1998, 274, G607.
46
10.4
0.61
0.82
2. Gibbs, J.; Young, R. C.; Smith, G. P. J. Comp. Physiol. Psychol. 1973, 84, 488.
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aiv administration dosed at 1.0 mg/kg, po administration dosed at 10 mg/kg.
The mouse pharmacokinetic profiles of selected compounds are
shown in Table 6. Compound 45 had higher oral exposure and bio-
availability than 44, however, 45 was not more active in vivo to-
ward mouse ONFI reduction. It is notable that compounds 44
(mouse EC50 = 1.3 nM, % activity at 10
EC50 = 1.5 nM, % activity at 10 M = 101%) had similar in vitro
4. For lead CCK1R medicinal chemistry reviews see (a) Szewczyk, J. R.; Laudeman,
´
C. Curr. Top. Med. Chem. 2003, 3, 837; (b) Garcıa-López, M. T.; González-Mu ñiz,
´
´
R.; Martın-Martınez, M.; Herranz, R. Curr. Top. Med. Chem. 2007, 7, 1180.
5. (a) Jordan, J.; Greenway, F. L.; Leiter, L. A.; Li, Z.; Jacobson, P.; Murphy, K.; Hill, J.;
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lM = 103%) and 45 (mouse
l
mouse CCK1R activities (Table 5). The sodium salt form 44a in-
creased the plasma exposure after an oral dose relative to the tri-
fluoroacetic acid salt of 44. Additionally, Cmax and oral
bioavailability increased. Paradoxically, however, 44a exhibited
similar ONFI reduction as the corresponding acid form 44. These
results suggest that systemic exposure of the compound may not
play an important role for in vivo efficacy.14
In conclusion, optimization of the heterocyclic core of HTS hit
3 led to the identification of a novel series of 1,2-diaryl imidaz-
ole carboxamides. Further optimization of the B, C, and D rings
led to the discovery of a class of highly potent and selective
CCK1R agonists. Quinoline 38 showed only modest in vivo mGBE
activity in spite of potent in vitro CCK1R functional and binding
activities. Introduction of a carboxylic acid group at the 1-posi-
tion of the naphthyl ring not only further improved the in vitro
profile, but most importantly also improved the in vivo CCK1R
mediated activities in mice such as gallbladder emptying and
overnight food intake reduction. Compounds 44, 44a, 46, and
49 all exhibited excellent in vivo mouse gallbladder emptying
(mGBE) activity and lean mouse overnight food intake (ONFI)
reduction. Since 44/44a (Fig. 4) showed a superior in vitro, in
vivo, and pharmacokinetic profile, this compound was selected
for extensive in vivo testing, and those results will be reported
in due course.
6. Pan, J.; Weingarth, D. T.; Qian, S.; Morin, N.; Edmondson, S. D.; Zhu, C.; Berger,
R.; Hansen, A. R.; Lee, S. J.; Hubert, J. A.; Strack, A. M.; MacNeil, D. J., in
preparation. All CCK1R EC50 values are human IP3 (NFAT) agonist data except
in Table 6 which are mouse CCK1R IP3 data. Both CCK1 and CCK2 % activation
are expressed as the
protocols are given in Supporting Information.
A series of 1,2-diary imidazoles have recently been reported as CCK1R
% of activation relative to CCK-8. Additional assay
7.
antagonists: (a) McClure, K.; Hack, M.; Huang, L.; Sehon, C.; Morton, M.; Li, L.;
Barrett, T. D.; Shankley, N.; Breitenbucher, J. G. Bioorg. Med. Chem. Lett. 2006, 16,
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10. Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722.
11. CCK2R % activation and CCK2R % inhibition at 10,000 nM data for compounds
38–50 are given in Supporting Information.
12. No distinguishable behavioral features were noted between treatment and
vehicle control groups of the ONFI mice at both administered doses (0.3 and
3 mg/kg). Subsequent manuscripts describing the in vivo characteristics
(tolerability and efficacy) are in preparation.
13. Kopin, A. S.; Mathes, W. F.; McBride, E. W.; Nguyen, M.; Al-Haider, W.; Schmitz,
F.; Bonner-Weir, S.; Kanarek, R.; Beinborn, M. J. Clin. Invest. 1999, 103, 383.
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507.