2212
C. A. Grice et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2209–2212
Table 4. Effect of varying the headgroup on cathepsin S activity
3. Shi, G.-P.; Villadangos, J. A.; Dranoff, G.; Small, C.; Gu,
L.; Haley, K. J.; Riese, R.; Ploegh, H. L.; Chapman, H. A.
Immunity 1999, 10, 197; Nakagawa, T. Y.; Brissette, W.
H.; Lira, P. D.; Griffiths, R. J.; Petrushova, N.; Stock, J.;
McNeish, J. D.; Eastman, S. E.; Howard, E. D.; Clarke, S.
R. M.; Rosloniec, E. F.; Elliott, E. A.; Rudensky, A. Y.
Immunity 1999, 10, 207.
R3
N
Amine
N
OH
N
SO2Me
Entry Amines (Fig. 1) R3
CatS IC50 (nM) Ii IC50 (lM)
a
4. Thurmond, R. L.; Beavers, M. P.; Cai, H.; Meduna, S. P.;
Gustin, D. L.; Sun, S.; Almond, H. J.; Karlsson, L.;
Edwards, J. P. J. Med. Chem. 2004, 47, 4799; Kuntz, I. D.;
Blaney, J. M.; Oatley, S. J.; Langridge, R.; Ferrin, T. E. J.
Mol. Biol. 1982, 161, 269, The DOCK software suite of
programs is available from the University of California,
San Francisco, CA. DOCK 4.0 was used for this study.
5. Gustin, D. J.; Sehon, C. A.; Wei, J.; Cai, H.; Meduna, S.
P.; Khatuya, H.; Sun, S.; Gu, Y.; Jiang, W.; Thurmond,
R. L.; Karlsson, L.; Edwards, J. P. Bioorg. Med. Chem.
Lett. 2005, 15, 1687.
48
49
50
51
52
53
9
10
8
Br
Br
322
1775
30
—
—
CF3
Br
1.3
2.7b
0.93b
—
8
75
163
11
12
CF3
CF3 1700
a Average of four determinations.
b Single determination.
6. For the pharmacological characterization of a CatS
inhibitor from this series, see: 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. Pharmcol. Exp. Ther. 2004, 308, 268.
position are equipotent to analogs 42 and 43, further
supporting this hypothesis. Ring expansion of the oxa-
zine ring, as illustrated by compound 52, resulted in a
10-fold loss in enzymatic activity over compound 23.
Interestingly, these compounds show similar potency
in the cellular assay. Maintaining the benzylic substitu-
tion but increasing the aromaticity of the pendant group
with concomitant incorporation of a piperazine ring
resulted in a significant drop in enzymatic activity as
illustrated by compound 53.
7. Bunce, R. A.; Schilling, C. L., III Tetrahedron 1997, 53,
9477.
8. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Marya-
noff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
9. An alternative preparation of 1 was reported previously.
Ogawa, H.; Yamamura, Y.; Miyamoto, H.; Kondo, K.;
Yamashita, H.; Nakaya, K.; Chihara, T.; Mori, T.;
Tominaga, M.; Yabuuchi, Y. J. Med. Chem. 1993, 36,
2011.
10. Compounds 3, 6, and 7 were prepared using slight reagent
modifications of the procedures described in the patent
application. Bock, M. G.; Evans, B. E.; Willams, P. D.;
Anderson, P. S.; Freidinger, R. M.; Pettibone, D. J. PCT
Int. Appl. WO 9502405.
In conclusion, replacement of the N-arylpiperazine in
our original series of inhibitors with 4-(6,6-bicyclic) pip-
eridines resulted in the identification of several potent,
noncovalent CatS inhibitors. The incorporation of sub-
stituents on the remote aryl ring of the bicyclic head-
groups provided improved selectivity over the a1a
adrenergic receptor while maintaining CatS activity.
Several of these analogs have been selected for further
evaluation.
11. Preparation of compounds 4 and 5. Takai, H.; Obase, H.;
Nakamizo, N.; Teranishi, M.; Kubo, K.; Shuto, K.;
Kasuya, Y.; Shigenobl, K.; Hashikami, M.; Karashima,
N. Chem. Pharm. Bull. 1985, 33, 1116.
12. Preparation of compound 8. Takai, H.; Obase, H.;
Nakamizo, N.; Teranishi, M.; Kubo, K.; Shuto, K.;
Hashimoto, T. Chem. Pharm. Bull. 1985, 33, 1104.
13. Bell, I. M.; Erb, J. M.; Freidinger, R. M.; Gallicchio, S.
N.; Guare, J. P.; Guidotti, M. T.; Halpin, R. A.; Hobbs,
D. W.; Homnick, C. F.; Kuo, M. S.; Lis, E. V.; Mathre, D.
J.; Michelson, S. R.; Pawluczyk, J. M.; Pettibone, D. J.;
Reiss, D. R.; Vickers, S.; Williams, P. D.; Woyden, C. J.
J. Med. Chem. 1998, 41, 2146.
References and notes
1. Villandangos, J. A.; Bryant, R. A. R.; Deussing, J.;
Driessen, C.; Lennon-Dumenil, A.-M.; Riese, R. J.; Roth,
W.; Saftig, P.; Shi, G.-P.; Chapman, H. A.; Peters, C.;
Ploegh, H. L. Immunol. Rev. 1999, 172, 109.
2. Nakagawa, T. Y.; Rudensky, A. Y. Immunol. Rev. 1999,
172, 121.