J. J. M. Wiener et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2375–2378
2377
A variety of analogs (Table 2) exploring changes to the P3 sub-
stituent in conjunction with the 2-hydroxypropyl linker and the
piperidine P5 moiety were prepared using the methods of Scheme
1 or methods similar to those reported previously.4 Replacement
of piperidine with a simple primary amine (18) decreases enzy-
matic inhibition, as does inclusion of rings such as morpholine,
pyrrolidine, and substituted piperazine (19–21). Substitution of
the piperidine at the 4-position with a hydroxyl was not benefi-
cial (22). Though fluorine substitution on the piperidine, as in
racemate 23, does not appreciably affect potency, the stereo-
chemical orientation of the hydroxyl moiety has a marked effect.
Comparison of compounds 24 and 25 reveals that the (S) orienta-
tion is preferred to the (R) orientation. Indeed, the (S)-2-hydroxy-
propyl linker analog 25 offers the best combination of increased
potency and low molecular weight, and, as such, was selected
for further optimization through variation of the P4 binding
element.
Table 3
Aminothioethers with (S)-2-hydroxypropyl linker: variation of P4 region
Following a sequence similar to that shown in Scheme 1,
replacement of the sulfonamide moiety to modify the P4 region
of these molecules was accomplished as shown in Scheme 2. The
sequence started from the Boc substituted pyrazole intermediate
26, prepared analogously to the sulfonamide material. Following
introduction of the P3 and P5 amino fragments, removal of the
Boc group was accomplished using HCl, and this secondary amine
intermediate was treated with a variety of acid chlorides, sulfonyl
chlorides, carboxylic acids, or alkyl halides under the appropriate
conditions to afford the desired analogs.
As shown in Table 3, removal of the P4 substituent altogether
leads to a molecule without appreciable potency (29), as does
replacement of the methyl sulfonamide with a simple methyl sub-
stituent (30). Other sulfonamides such as 31 and 32 are slightly
less potent than the methyl sulfonamide parent 25, as are ureas
and aromatic amides (33–36). Simple acetamide and propiona-
mide substituents (37 and 38), as well as substituted acetamides
(39–42), are somewhat deleterious to potency. Basic amine sub-
stituents on the acetamide are not beneficial (43), though, impor-
tantly, preserving the overall length of the amino-acetamide
substituent while also reducing the basicity in the context of an
oxamide substituent as in analog 44 reproduces the enzymatic
and cellular potency of sulfonamide analog 25. Though none of
these P4 variations successfully improved potency relative to the
sulfonamide P4 element, the ability to retain potency with a
non-sulfonamide entity offers opportunities for further exploration
of other P4 substituents.
CF3
F
N
(S)
N
S
N
N
OH
N
R4
a
Compound
R4
hCatS IC50 (lM)
0.058 (0.120)c
25
SO2Me
H
Me
SO2iPr
SO2Pr
29b
30b
31
9.6
9.0
0.35
0.30
32
O
33
34
0.235
1.19
NH2
O
N
O
O
S
35
36
0.355
N
0.205 (0.32)c
N
NH
O
These studies with pyrazole-based CatS inhibitors have pro-
vided an expanded understanding of SAR within several relevant
enzyme binding regions. The fluoro-piperidine P3 substituent, an
enantiomerically-pure (S)-2-hydroxypropyl linker, and a variety
of non-sulfonamide P4 substituents have been identified as bene-
ficial, offering favorable enzymatic and cellular potency. Further
investigations with these and other, related structures will be re-
ported in due course.
37
38
39
0.385
0.690
0.235
Me
O
O
O
Me
OH
OH
40
0.245
References and notes
Me
1. (a) Gupta, S.; Kumar Singh, R.; Dastidar, S.; Ray, A. Exp. Opin. Ther. Targets 2008,
12, 291; (b) 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; (c) Nakagawa, T. Y.; Rudensky, A.
Y. Immunol. Rev. 1999, 172, 121; (d) 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.
2. (a) Liu, H.; Tully, D. C.; Epple, R.; Bursulaya, B.; Li, J.; Harris, J. L.; Williams, J. A.;
Russo, R.; Tumanut, C.; Roberts, M. J.; Alper, P. B.; He, Y.; Karanewsky, D. S.
Bioorg. Med. Chem. Lett. 2005, 15, 4979; (b) 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, 16,
1486; (c) Tully, D. C.; Liu, H.; Alper, P. B.; Chatterjee, A. K.; Epple, R.; Roberts, M.
J.; Williams, J. A.; Nguyen, K. T.; Woodmansee, D. H.; Tumanut, C.; Li, J.;
Spraggon, G.; Chang, J.; Tuntland, T.; Harris, J. L.; Karanewsky, D. S. Bioorg. Med.
Chem. Lett. 2006, 16, 1975; (d) Tully, D. C.; Liu, H.; Chatterjee, A. K.; Alper, P. B.;
Williams, J. A.; Roberts, M. J.; Mutnick, D.; Woodmansee, D. H.; Hollenbeck, T.;
Gordon, P.; Chang, J.; Tuntland, T.; Tumanut, C.; Li, J.; Harris, J. L.; Karanewsky, D.
S. Bioorg. Med. Chem. Lett. 2006, 16, 5107; (e) Tully, D. C.; Liu, H.; Chatterjee, A.
K.; Alper, P. B.; Epple, R.; Williams, J. A.; Roberts, M. J.; Woodmansee, D. H.;
Masick, B. T.; Tumanut, C.; Li, J.; Spraggon, G.; Hornsby, M.; Chang, J.; Tuntland,
T.; Hollenbeck, T.; Gordon, P.; Harris, J. L.; Karanewsky, D. S. Bioorg. Med. Chem.
Lett. 2006, 16, 5112; (f) Chatterjee, A. K.; Liu, H.; Tully, D. C.; Guo, J.; Epple, R.;
O
O
O
O
41
0.470
0.310
0.810
OMe
SMe
NH2
42
43b
44
0.07 (0.19)c
NH2
O
a
CatS IC50 values are the mean of n P 2 runs and determined as described pre-
viously.3a All IC50s were within a twofold range.
b
Data reported are for the racemate.
c
JY Ii degradation IC50 (lM) data are in parentheses. Values are the mean of
n P 2 runs and determined as described previously.3c All IC50s were within a
twofold range.