A. G. Arvanitis et al. / Bioorg. Med. Chem. Lett. 13 (2003) 125–128
127
such as OMe can be accomodated in high receptor affi-
nity ligands (e.g., 7–10).
Data in Table 3 indicate that binding affinity is pri-
marily dependent on the size than polarity of the phenyl
substituents. The 2-aryl position has very stringent
steric requirements and replacement of the 20- Cl with
an acetyl led to drastic reduction in affinity (21). The 40-
aryl position can tolerate a larger number of sub-
stituents with various functionalities such as OMe,
COMe, SO2Me, SMe and CH(OH)Me.
Substituents were introduced on the 2-position using
procedures described in Scheme 1. Data are listed in
Table 2 and indicate that the only good replacement for
an ethyl chain is a methoxy group (11). Small increases
in size to a cyclopropyl or difluoromethyl (12 and 13)
led to drastic reduction in affinity. Further increases in
size to a methoxymethyl group gave a compound with
modest affinity (14).
The best compounds with respect to binding affinity
and physical properties (ClogP) were tested in the dog
N-in-1 pharmacokinetics at 1 mg/kg po and in the rat
situational anxiety model at 3 mg/kg po to assess
anxiolytic efficacy. Data for three compounds are listed
in Table 4.
After exploring the 2-position, we turned our efforts on
the optimization of the substitution on the 7-aryl ring.
We wanted to introduce substitution that would main-
tain receptor affinity, while improving physical proper-
ties such as reducing lipohilicity.
Table 4 shows that two of the compounds showed good
plasma levels in the dog N-in-1 study. Plasma con-
centration was dependent on substitution and the
4-methoxyphenyl group seemed to give the lowest
exposure. All of the compounds showed efficacy in the
rat situational anxiety model at 3 mpk po.
Table 3. The SAR of various aryl groups
In conclusion the 4-arylimidazo[4,5-b]pyridine series
represent a new series of potent CRF receptor ligands.
Additionally, certain analogues possessed good oral
bioavailability in dog at 1 mg/kg po and showed efficacy
in the rat situational anxiety model.
Compd
R1
R2
R3
Ki (nM)a
SD
Acknowledgements
15
16
17
18
19
20
21
22
23
24
25
26
27
Cl
CF3
Me
CF3
Me
Cl
CF3
OMe
OMe
SMe
OMe
H
H
H
H
Me
F
H
H
H
H
H
H
H
1.1
0.7
0.8
1.4
0.6
2.4
95.6
1.0
5.1
24.0
3.5
6.8
2.3
0.7
0.0
0.3
0.1
0.2
0.6
—
0.2
1.1
0.4
0.2
1.3
0.1
The authors wish to acknowledge Walt Meredith, Jan
Hyterk, Jim Piecara, Christine Tabaka-Blom of the
Chemical Synthesis group for large scale synthesis of
2-benzyloxy-4-chloro-3-nitropyridine and several aryl-
boronic acid intermediates and Anne Marshall, Sue
Keim, Deborah Conklin, and Carol Krause for provid-
ing primary screen data.
F
Cl
COMe12
Cl
Cl
COMe13
CH(OH)Me
C(OH)Me2
CH(OMe)Me
SO2Me
C(Me)NOMe
Cl
Cl
CF3
Cl
References and Notes
aValues are means of two or more experiments, except 21. Receptor
binding affinity for all compounds was determined using rat cortical
homogenates. SD, standard deviation.
1. Vale, W.; Spiess, J.; Rivier, C.; Rivier, J. Science 1981, 213,
1394.
2. (a) Nemeroff, C. B. Neuropsycophamcacology 1992, 6, 69.
(b) Owens, M. J., Nemeroff, C. B., Eds. Corticotropin-Rea-
leasing Factor: Basic and Clinical Studies of a Neuropeptide.
CRC: Boca Raton, 1990.
Table 4. Dog N-in-1 pharmacokinetic parameters14 at 1 mg/kg and
rat situational anxiety model efficacy for selected compounds
3. (a) Heinrichs, S. C. Curr. Opin. Drug Disc. Dev. 1999, 2,
491. (b) Gilligan, P. J.; Robertson, D. W.; Zaczek, R. J. Med.
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Curry, M. A.; Robertson, D.W.; Sun, J. H.; Arneric, S. P.;
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5. Koeglet, F.; Van Der Want, G. M.; Salemink, C. A. Recl.
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see: Stanforth, S. P. Tetrahedron 1998, 54, 263.
7. Hoffman, J. M.; Smith, A. M.; Rooney, C. S.; Fisher, T. E.;
R
R1
R2
Ki
AUC Cmax T1/2
Situational
(nM) (nM) (nM) (h) anxiety ED50
CH(nPr)Me CF3 OMe 0.7
CH(nPr)Me Cl CF3 1.1
CH(cBu)Me Cl OCF2 0.7
182
604
795
62
159
185 10
5.9
4.9
3 mpk (po)
3 mpk (po)
<3 mpk (po)