E. L. Setti et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4296–4299
4299
only a 3.4-fold shift between enzyme and cellular assay
values.
In order to explore how far away the basic nitrogen9
could be placed without affecting potency, we synthe-
sized compound 15. We have found that this one carbon
homologation rendered the molecule slightly less potent
against Cat K (4.8 nM), possibly due to a combination
of the size and a certain loss of rigidity of the terminal
portion at which the basic nitrogen is attached.
In summary, we have shown that the insertion of a thi-
azole moiety between the piperazine and the distal phen-
yl ring of the biaryl structure 1 enabled us to synthesize a
series of more potent and selective Cat K inhibitors in
enzyme and, many instances, more potent in bone
resorption assay as well. Preliminary pharmacokinetic
evaluation of the enantiomeric mixture 12 in rat demon-
strated that members of this series could be suitable can-
didates to develop new orally active therapeutic agents
for the treatment of osteoporosis.
Figure 2. Modeled structure of compound (R)-12 bound to Cat K.7
O
N
N
N
Acknowledgments
N
H
O
N
N
The authors thank Dr. Paul Grothaus, Dr. Cameron
Black and Mr. Leland Burrill for their critical reviews
of this manuscript.
S
17
Figure 3.
References and notes
Table 2. Rat PK parameters after iv administration at 0.5 mg/kg
1. Garnero, P.; Borel, O.; Borel, O.; Byrjalsen, I.; Ferreras,
M.; Drake, F. H.; McQueney, M. S.; Foged, N. T.; Delmas,
P. D.; Delaisse, J.-M. J. Biol. Chem. 1998, 273, 2347.
2. Robichaud, J.; Oballa, R.; Prasit, P.; Falgueyret, J.-P.;
Percival, M. D.; Wesolowski, G.; Rodan, S. B.; Kimmel,
D.; Johnson, C.; Bryant, C.; Venkatraman, S.; Setti, E.;
Mendonca, R.; Palmer, J. T. J. Med. Chem. 2003, 46,
3709.
Compound
Vss (l/kg)
MRT (min)
CL (ml/kg/min)
1
11
12
13
14
15
14.8
1.7
155
54
98
32
4.3
176
106
109
140
25
12.0
6.6
114
60
9.1
65
3. The reported Cat K IC50 of compound 1 in Ref. 2 is 3 nM.
4. Falgueyret, J. P.; Oballa, R. M.; Okamoto, O.; Wesolowski,
G.; Aubin, Y.; Rydzewski, R. M.; Prasit, P.; Riendeau, D.;
Rodan, S. B.; Percival, M. D. J. Med. Chem. 2001, 44, 94.
5. Palmer, J. T.; Bryant, C.; Wang, D. –X.; Davis, D. E.; Setti,
E. L.; Rydzewski, R. M.; Venkatraman, S.; Tian, Z.-Q.;
Burrill, L. C.; Mendonca, R. V.; Springman, E.; McCarter,
J.; Chung, T.; Cheung, H.; Janc, J. W.; McGrath, M.;
Somoza, J.; Enriquez, P.; Yu, Z. W.; Strickley, R. M.; Liu,
L.; Venuti, M. C.; Percival, M. C.; Falgueyret, J.-P.; Prasit,
P.; Oballa, R.; Riendeau, D.; Young, R. N.; Wesolowski,
G.; Rodan, S. V.; Johnson, C.; Kimmel, D. B.; Rodan, G.
J. Med. Chem. 2005, 48, 7520.
Table 3. Rat PK data for compound 14
Compound Dose Cmax Tmax
(mg/kg) (mM) (min) (uM min) (h) (%)
10 1.1 200 560 3.9 85
AUC
t1/2
F
12
the nitrogen with a methyl (11, Ki: 1.3 nM) yielded an
enantiomeric mixture with similar potency against Cat
K and higher potency in cell (bone res. IC50: 59 nM),
a finding that is in agreement with results found in other
series.5
6. Setti, E. L.; Davis, D.; Janc, J.; Jeffery, D. A.; Cheung, H.;
Yu, W. Bioorg. Med. Chem. Lett. 2005, 15, 1529.
7. Docking experiment was done by using GOLD 3.0 software
from Cambridge Crystallography Data Center. Water
molecules were removed from the protein and hydrogen
Interestingly, when the thiazole–piperazine pair was at-
tached to the para-position of the distal phenyl, the
resulting mixture of compounds (13, Ki: 3.5 nM against
Cat K) turned out to be about 4-fold less potent than the
meta-substituted analogue with a poorer overall PK
profile, illustrated by its higher clearance (114 ml/kg/
min, Table 2). To our surprise, the mixture 13 showed
bond constrain was added between ligand and Asn158
8. Same enzyme assay conditions as described in Ref. 5.
.
9. The presence of a basic nitrogen at the distal position of the
molecule was shown to be essential for potency and
selectivity in other series. See Refs. 4–6.