1980
D. C. Tully et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1975–1980
L. W.; Tommasi, R. A.; Farley, D. L.; Quadros, E.;
Coppa, D. E.; Du, Z.; Fang, Z.; Zhou, H.; Doughty, J.;
Toscano, K. T.; Wigg, A. M.; Zhou, S. Bioorg. Med.
Chem. Lett. 2003, 13, 4121.
replacing the P3 amide of compound 2 with a heterocy-
cle, the in vivo PK of this series was dramatically im-
proved. Furthermore, optimization of the P1 aniline
moiety to a more drug-like indoline group10 has led to
potent, orally bioavailable cathepsin S inhibitors, such
as 12f, with much improved pharmacokinetics in rats
over the early lead compounds 2 and 3.
9. Haviv, F.; Ratajczyk, J. D.; DeNet, R. W.; Kerdesky, F.
A.; Walters, R. L.; Schmidt, S. P.; Holms, J. H.; Young, P.
R.; Carter, G. W. J. Med. Chem. 1988, 31, 1719.
10. The potential safety liabilities of the methoxyaniline
moiety as in compounds 1–3 have been well documented:
Park, B. K.; Kitteringham, N. R.; Maggs, J. L.; Pirmoha-
med, M.; Williams, D. P. Annu. Rev. Pharmacol. Toxicol.
2005, 45, 177.
Acknowledgments
11. Alper, P. B.; Liu, H.; Chatterjee, A. K.; Nguyen, K. T.;
Tully, D. C.; Tumanut, C.; Li, J.; Harris, J. L.; Tuntland,
T.; Chang, J.; Gordon, P.; Hollenbeck, T.; Karanewsky,
D. S. Bioorg. Med. Chem. Lett., 2006, in press.
12. Carboxylic acids 13f and g were obtained by deprotection
of the corresponding tert-butyl esters with TFA (50%) in
CH2Cl2 as previously described in Ref. 11. Ethyl ester 13h
was then prepared by heating 13g in ethanol:triethylor-
thoformate (2:1) with catalytic p-toluenesulfonic acid.
13. Pauly, T. A.; Sulea, T.; Ammirati, M.; Sivaraman, J.;
Danley, D. E.; Griffor, M. C.; Kamath, A. V.; Wang, I.
K.; Laird, E. R.; Seddon, A. P.; Menard, R.; Cygler, M.;
Rath, V. L. Biochemistry 2003, 42, 3203.
14. A similar SAR trend has been observed with a series of
dipeptide nitrile inhibitors of cathepsin S: Ward, Y. D.;
Thomson, D. S.; Frye, L. L.; Cywin, C. L.; Morwick, T.;
Emmanuel, M. J.; Zindell, R.; McNeil, D.; Bekkali, Y.;
Giradot, M.; Hrapchak, M.; DeTuri, M.; Crane, K.;
White, D.; Pav, S.; Wang, Y.; Hao, M.-H.; Grygon, C. A.;
Labadia, M. E.; Freeman, D. M.; Davidson, W.; Hopkins,
J. L.; Brown, M. L.; Spero, D. M. J. Med. Chem. 2002, 45,
5471.
The authors acknowledge Mike Hornsby for protein
production, and Perry Gordon and Tom Hollenbeck
for bioanalytical support. The authors also thank Terry
Hart, Allan Hallett, Kirk Clark, and Raviraj Kulathila
(Novartis Institutes for Biomedical Research) for valu-
able discussions.
Supplementary material
Supplementary data associated with this article can be
References and notes
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7. Experimental details of the enzymatic assays and data
from the dilution–dialysis experiments with compounds 2
and 12f are included in Supplementary material.
8. Similar approaches have been reported by others for
dipeptide nitrile inhibitors of cathepsins K and B: (a)
Robichaud, J.; Bayly, C.; Oballa, R.; Prasit, P.; Mellon,
C.; Falgueyret, J. P.; Percival, M. D.; Wesolowski, G.;
Rodan, S. B. Bioorg. Med. Chem. Lett. 2004, 14, 4291; (b)
Greenspan, P. D.; Clark, K. L.; Cowen, S. D.; McQuire,
15. Indolone derivative 12g was synthesized according to the
following scheme:
O
O
a,b
Boc
N
e
Boc
OH
N
N
F
H
H
O
c,d
N
12g
H2N
F
Reagents and conditions: (a) CBr4 (1.0 equiv), PPh3
(1.0 equiv), DCM (52%); (b) 5-fluoroisatin, NaH
(1.2 equiv), DMF, (36%); (c) H2NNH2 (50%) in EtOH,
reflux (89%); (d) TFA:DCM:H2O (50:45:5) (99%); (e) 6,
HATU, DIEA, DCM (77%).
16. During the course of this work, a series of nonpeptidic and
noncovalent inhibitors of cathepsin S have been reported
(a) Thurmond, R. L.; Sun, S.; Sehon, C. A.; Baker, S. M.;
Cai, H.; Gu, Y.; Jiang, W.; Riley, J. P.; Williams, K. N.;
Edwards, J. P.; Karlsson, L. J. Pharmacol. Exp. Ther.
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H.; Meduna, S. P.; Gustin, D. L.; Sun, S.; Almond, H. J.;
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