Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 17 (2007) 6096–6100
Novel scaffold for cathepsin K inhibitors
a
a,
a
a
a
*
Naoki Teno, Takahiro Miyake, Takeru Ehara, Osamu Irie, Junichi Sakaki,
a
a
a
a,ꢀ
a
Osamu Ohmori, Hiroki Gunji, Naoko Matsuura, Keiichi Masuya, Yuko Hitomi,
a
a,ꢁ
a,§
a
Kazuhiko Nonomura, Miyuki Horiuchi, Keigo Gohda, Atsuko Iwasaki,
a
a,–
a
a
Ichiro Umemura, Sachiyo Tada, Motohiko Kometani, Genji Iwasaki,
b
b
b
a,ꢀ
Sandra W. Cowan-Jacob, Martin Missbach, Ren e´ Lattmann and Claudia Betschart
a
Novartis Institutes for BioMedical Research, Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan
b
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland
Received 20 August 2007; revised 10 September 2007; accepted 12 September 2007
Available online 15 September 2007
Abstract—Pyrrolopyrimidine, a novel scaffold, allows to adjust interactions within the S3 subsite of cathepsin K. The core interme-
diate 10 facilitated the P3 optimization and identified highly potent and selective cathepsin K inhibitors 11–20.
Ó 2007 Elsevier Ltd. All rights reserved.
A healthy bone metabolism depends on an appropriate
balance between osteoclast-mediated bone resorption
and osteoblast-mediated bone formation. If the bone
resorption is exceeding the bone formation, bone mass
is reduced and leads to disease conditions like post-men-
opausal osteoporosis and tumor-induced osteolysis. A
reduction of the bone formation rate, which is observed
in senile-osteoporosis, also reduces bone mass and
finally induces bone fractures. In the 1980s bisphospho-
nates were found to act as bone resorption inhibitors
lished, and its inhibition is now perceived as a promising
new principle for a treatment of the diseases caused by
increased bone resorption.
6
The sugar derivative 1 was identified in a high through-
put screening as a potent inhibitor of cathepsin K
7
[IC50 = 14 nM]. Surprisingly, removal of the hydro-
philic sugar moiety and also simplification of the ring
system to the pyrimidine 2 resulted with retained
8
potency [IC50 = 170 nM]. A molecular modeling with
(
likely through inhibition of farnesyl diphosphate
the nitrile group covalently bound to the active site cys-
teine suggests that the cyclohexyl group occupies the S2
subsite while the S3 is unoccupied. Therefore, the small
molecule 2 was a good starting point for further optimi-
zation. We expected to make further increase in the
potency by extending into the S3. In addition, due to
differences in the corresponding S3 subsites, higher
selectivity over related proteases, such as cathepsin L
and cathepsin S, was anticipated.
synthase in osteoclasts), and today, bisphosphonates
are widely used for the treatment of osteoporosis and
tumor-induced osteolysis.
1
,2
In the 1990s three independent groups have reported on
cathepsin K, cysteine protease predominantly
expressed in osteoclasts.
a
3
–5
In the meantime, the role
of cathepsin K in degradation of bone matrix was estab-
Three attachment sites for the P3 moiety were consid-
Keywords: Cathepsin K inhibitors; Pyrrolopyrimidine; Novel scaffold.
*
7
9
ered (A, B , and C in Fig. 1). For scaffold C, the mod-
eling suggested acetylenes as rigid linkers between the
pyrimidine and S3 (scaffold D in Fig. 2). Indeed, the
compounds with high potency and good selectivity
against related proteases could be identified in this series
2
ꢀ
Present address: Novartis Institutes for BioMedical Research,
CH-4002 Basel, Switzerland.
ꢁ
§
YASUTOMI & Associates, MT-2 BLDG, 5-36, Miyahara 3-chome,
Yodogawa-ku, Osaka 532-0003 Japan.
Computer-Aided Molecular Modeling Research Center Kansai,
9
as reported elsewhere.
1
-3-12, Honjyocho, Higashinada-ku, Kobe, Hyogo 658-0012, Japan.
2
2
–
Depending on the structure of R (in the case of R with
benzyl propargyl moiety) in Figure 2, the direct product
Central Research Laboratories, Sysmex Co., 4-4-4, Takatsuka-dai,
Nishi-ku, Kobe, Hyogo 651-2271, Japan.
0
960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.09.047