4578
S. Malancona et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4575–4579
Table 2.
10000
F
F
O
O
O
1000
100
10
H
N
N
H
O
N
N
H
R2
O
R1
i.m.
i.v.
No.
R1
R2
Ki (lM)
F
F
F
21
Cy
Nab
F
F
F
CO2Me
H
1
0.00
1.00
2.00
3.00
Time (h)
4.00
5.00
6.00
22
23
Cy
Cy
0.45
0.10
N
CH3
S
Figure 2. Profile of compound 22 after iv (2 mg/kg) and im dosage
(10 mg/kg, solution in 80% DMSO and 20% water) to rat.
O
O
O
N
Acknowledgements
NH
N
N
The authors thank Mirko Brunetti, Gabriella Biasiol,
Mauro Cerretani, Sergio Serafini, Sergio Altamura and
CO2H
24
25
26
Ph
Ph
Ph
1.30
0.35
0.40
€
Christian Steinkuhler for providing the assay data, the
CO2H
analytical chemistry group for quantitative analysis of
the plasma samples, Silvia Pesci for NMR spectra and
Michael Rowley for valuable discussions. This work was
supported in part by a grant from the MIUR.
F
F
CO2H
CO2H
References and notes
27a
27b
Ph
Ph
1.0a
0.65a
X
X = O
X = NH
Ph
1. (a) Cohen, J. Science 1999, 285, 26; (b) Lauer, G. M.;
Walker, B. D. Natl. Engl. J. Med. 2001, 345, 41.
2. Cornberg, M.; Wedemeyer, H.; Manns, M. P. Curr.
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Investig. Drugs 2003, 12, 1269; (c) Tan, S.; Pause, A.; Shi,
Y.; Sonenberg, N. Nat. Rev. 2002, 1, 867.
H
N
CO2H
CH3
28
Ph
0.50a
F
29a
29b
Cy
Cy
0.19a
0.12a
O
CO2H Y = H
Y = Me
Y
F
4. Major, M. E.; Mihalik, K.; Fernandez, J.; Seidman, J.;
Kleiner, D.; Kolykhalov, A. A.; Rice, C. M. J. Virol. 1999,
73, 3317.
a Mixture of diastereomers.
b Na: not active at 50 lM.
€
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6. Recent references: (a) Zhang, X.; Schmitt, A. C.; Jiang,
W.; Wasserman, Z.; Decicco, C. P. Bioorg. Med. Chem.
Lett. 2003, 13, 1157; (b) Han, W.; Hu, Z.; Jiang, X.;
Wassermann, Z. R.; Decicco, C. P. Bioorg. Med. Chem.
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Table 3. PK parameters of selected phenethylamidesa
No.
t1=2 (min)
Clp (mL/
min/kg)
Vdss (L/kg)
AUC
(lM · h)
16a
17
48
72
15
19
74
222
36
44
46
9
4.5
2.4
0.4
1.3
18
0.45
0.8
2.7
0.9
22b
23
0.15
12.4
ꢀ
D. R.; Goudreau, N.; Kukolj, G.; LaPlante, S. R.; Llinas-
a Compound dosed (iv) to male Sprague–Dawley rats as a suspension
in DMSO/EtOH/water (20:20:60) at 5 mg/kg.
b Dosed at 2 mg/kg.
Brunet, M.; Nar, H.; Lamarre, D. Angew. Chem., Int. Ed.
2003, 42, 1356.
8. Lamarre, D.; Anderson, P. C.; Bailey, M.; Beaulieu, P.;
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reau, N.; Kawai, S. H.; Kukolj, G.; Lagace, L.; Laplante,
S. R.; Narjes, H.; Poupart, M.-A.; Rancourt, J.; Sentjens,
R. E.; St. George, R.; Simoneau, B.; Steinmann, G.;
Thibeault, D.; Tsantrizos, Y. S.; Weldon, S. M.; Yong,
C.-L. Nature 2003, 426, 314.
about 100 nM, less active than 20, but with lower
molecular weight. Despite its relatively peptidic nature
tetrazole 23 showed an improved behavior compared to
acid 18 upon iv dosage to rat. The acylsulfonamide
22 exhibited good exposure upon intramuscular
dosing.
€
9. Colarusso, S.; Koch, U.; Gerlach, B.; Steinkuhler, C.; De
Francesco, R.; Altamura, S.; Matassa, V. G.; Narjes, F.
J. Med. Chem. 2003, 46, 345.