Acyclic, orally bioavailable ketone-based cathepsin K inhibitors

Article abstract of DOI:10.1016/j.bmcl.2006.10.102

Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P²-P³ elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better

Full text of DOI:10.1016/j.bmcl.2006.10.102

Bioorganic & Medicinal Chemistry Letters 17 (2007) 22–27
Acyclic, orally bioavailable ketone-based cathepsin K inhibitors
David G. Barrett,a, John G. Catalano,a David N. Deaton,a,* Stacey T. Long,b
Robert B. McFadyen,a Aaron B. Miller,c Larry R. Miller,d Vicente Samano,a
Francis X. Tavares,a Kevin J. Wells-Knecht,e,à
Lois L. Wrightf and Hui-Qiang Q. Zhoua
aDepartment of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA
bDepartment of World Wide Physical Properties, GlaxoSmithKline, Research Triangle Park, NC 27709, USA
cDiscovery Research Computational, Analytical, and Structural Sciences, GlaxoSmithKline, Research Triangle Park, NC 27709, USA
dDepartment of Molecular Pharmacology, GlaxoSmithKline, Research Triangle Park, NC 27709, USA
eDepartment of Research Bioanalysis and Drug Metabolism, GlaxoSmithKline, Research Triangle Park, NC 27709, USA
fDiscovery Research Biology, GlaxoSmithKline, Research Triangle Park, NC 27709, USA
Received 30 August 2006; revised 3 October 2006; accepted 4 October 2006
Available online 17 November 2006
Abstract—Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P2–P3 elements from a
ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral
bioavailability than the starting ketone.
Ó 2006 Elsevier Ltd. All rights reserved.
The function of the CA1 clan proteases, the cysteine
cathepsins, has traditionally been assumed to involve
degradation of proteins in lysosomes; however, in the
last 10 years, research has revealed unique roles for indi-
vidual family members in bone resorption, antigen pre-
sentation and processing, prohormone activation,
protease maturation, and hair follicle development.1
Furthermore, discoveries during the last decade have
implicated cathepsins in various pathologies including
osteoporosis, rheumatoid arthritis, atherosclerosis,
neurodegeneration, and cancer, resulting in accelerated
development of inhibitors as potential interventions in
these diseases. In light of the mounting evidence of the
potential utility of inhibitors of cathepsin K, the major
bone matrix degrading protease in osteoclasts, in
preventing excess bone resorption, much research has
focused on the development of such inhibitors as drugs
for the treatment of osteoporosis.2
Typically, inhibitors of cathepsins utilize an electrophilic
warhead to interact with the active site thiol moiety as
well as enzyme recognition motifs to facilitate potency
and specificity. SmithKline Beecham researchers have
developed ketone-based cathepsin K inhibitors exempli-
fied by compound 1.3,4 Although potent (cat K IC50
=
7.5 nM), ketone 1 showed moderate to high clearance
(Cl = 33 mL/min/kg) and poor oral bioavailability
(F = 3.2%) in rats. GlaxoWellcome scientists have de-
scribed ketoamide-based cathepsin K inhibitors such
as 2.5 Inhibitor 2 is an even more potent inhibitor (cat
K IC50 = 0.072 nM) than ketone 1, as one would expect
given the greater electrophilicity of its warhead. It is
cleared less rapidly (Cl = 9.6 mL/min/kg) and is more
bioavailable (F = 42%) in rats than 1. In 2000, following
the formation of GlaxoSmithKline, these researchers
decided to explore the idea of incorporating elements
from both inhibitor classes to identify a new ketone-
based inhibitor series with potentially improved potency
and pharmacokinetic properties.
Keywords: Cathepsin K; Cysteine protease inhibitor; Osteoporosis;
Electrophilic warhead.
*
The strategy involved combining the perceived best
elements of each inhibitor series in the formation of a
hybrid inhibitor. Ketone 1 and ketoamide 2 were
modeled6 into the active site of cathepsin K based on
Corresponding author. Tel.: +1 919 483 6270; fax: +1 919 315
0430; e-mail: david.n.deaton@gsk.com
Present address: Lilly Forschung GmbH, Essener Str. 93, 22419
Hamburg, Germany.
à
Present address: Schering-Plough Research Institute, 2015 Galloping
Hill, Kenilworth, NJ 07033, USA.
the ketone (1BGO)7 and ketoamide (1YT7)5 X-ray
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.10.102

D. G. Barrett et al. / Bioorg. Med. Chem. Lett. 17 (2007) 22–27
23
co-crystal structures (Brookhaven Protein Data Bank)
as shown in Figure 1. The model of ketone 1 and ketoa-
mide 2 reveals significant overlap between the two inhib-
itors. The i-butyl moiety of ketone 1 and the tert-butyl
group of ketoamide 2 both occupy the S2 pocket, with
the benzofuran element of ketone 1 and the 3-phenyl
pyrazole component of ketoamide 2 in the substrate
trough pointing toward the S3 subsite, and the methyl
and n-butyl of ketone 1 and ketoamide 2, respectively,
in the S1 trough. The major differences between these
two inhibitors arise from different modes of attack by
the active site thiol on the electrophilic warheads. The
cysteine thiol attacks the ketone 1 from the Si face
inserting the hydroxyl of the thiohemiketal into the oxy-
anion hole, while the ketoamide is approached from the
opposite face placing the amide into the oxyanion hole.
Despite this difference the two P1 groups, the pyridine of
ketone 1 and the pyrazole of ketoamide 2 occupy similar
space. Given this similarity, it was surmised that the P2–
P3 groups of the two inhibitors could be interchanged.
The ketone, although inherently less electrophilic and
therefore less potent, was chosen as the warhead for
the hybrid because it might interact with fewer nucleo-
philic moieties in vivo, and thereby potentially produce
fewer side effects during chronic therapy.8 Furthermore,
hypothesizing that the presence of two amide bonds in
inhibitor 1 contributed to its high clearance, it was sur-
mised that replacement of these fragments with the P2–
P3 carbamate element of inhibitor 2 would afford a hy-
brid ketone series 3 with enhanced metabolic stability
and improved pharmacokinetics relative to the starting
ketone.9
The ketone analogs 3a–m were prepared as depicted in
Scheme 1. The known aldehydes 4b (R2 = Me) and 4c
(R2 = n-Bu) were converted to their corresponding cya-
nohydrins under acidic catalysis, then the nitriles were
reduced to provide the amines 5b and 5c as mixtures
of hydroxyl epimers.10 The alcohol 5a (R2 = H) has pre-
viously been disclosed.11 Alcohols 7a–e were prepared
by reacting amines 5a and 5b with sulfonyl chloride 6a
or amine 5c with sulfonyl chloride 6a, carbamoyl chlo-
ride 6b, or difluoropyridine 6c, respectively. Then, acid
catalyzed cleavage of the tert-butyl carbamate protect-
ing group afforded amines which were coupled with
the known para-nitrophenyl carbonates 8a–g to provide
the carbamates 9a–m.12 Finally, Dess–Martin oxidation
of the secondary alcohols 9a–m produced the desired
ketones 3a–m.
O
O
O
O
H
H
N
N
N
H
S
N
O O
O
N
O
O
O
1
H
H
H
N
O
O
N
N
N
F3C
N
nBu
R2
O
2
As shown in Table 1, the hybrid analogs 3a–m that
contain the ketone electrophile of inhibitor 1 and the
P2 tert-butyl carbamate of ketoamide 2 are potent
cathepsin K inhibitors, many of which show similar
activity to the starting ketone 1. A quick study of the
structure–activity relationships of the S1 wall of cathep-
H
N
H
N
R1
R3
3
sin K revealed that the P1 n-Bu moiety of 3c (IC50
4.0 nM) is apparently more potent than the P1 hydrogen
=
O
OH
H
N
H
N
O
O
O
NH2
a, b
c, d, or e
O
R2
O
O
R2
5a-c
4b-c
R1
OH
O
H
N
H
N
O
+
R3
f, g
NO2
7a-e
8a-g
O
R2
R1
OH R3
NH
R1
O
R3
H
H
N
O
N
O
NH
O
R2
O
R2
h
9a-m
3a-m
O
Figure 1. An overlay of ketone 1 and ketoamide 2 docked into the
active site of the X-ray structure of cathepsin K based on X-ray co-
crystal structures of similar ketones (1BGO) and ketoamides (1YT7).
The cathepsin K carbons are colored green with inhibitor 1 carbons
colored magenta and inhibitor 2 carbons colored yellow. The semi-
transparent gray surface represents the molecular surface, while
hydrogen bonds are depicted as yellow/red dashed lines. This figure
was generated using PYMOL version 0.99 (Delano Scientific,
www.pymol.org).
Cl
Cl
N
S
N
F
N
6c
F
O O 6a
6b
O
Scheme 1. Reagents: (a) KCN, HOAc, MeOH; (b) H2/PtO2–C, HOAc,
46%; (c) 5a–5c, 6a, CH2Cl2, NaHCO3, H2O, 34–65%; (d) 5c, 6b,
i-Pr2NEt, CH2Cl2, 89%; (e) 5c, 6c, i-Pr2NEt, dioxane, 29%; (f) HCl,
dioxane, 99%; (g) 8a–g, i-Pr2NEt, DMF, 45–93%; (h) Dess–Martin
periodinane, CH2Cl2, NaHCO3, 15–68%.

24
D. G. Barrett et al. / Bioorg. Med. Chem. Lett. 17 (2007) 22–27
Table 1. Inhibition of human cathepsin K
R1
R2
R3
a
IC50 (nM)
Compound
1
7.5
0.072
65
2
3a
O
N
N
N
O
O
O
O
O
O
O
O
O
N
N
N
H
S
F3C
F3C
F3C
F3C
N
N
N
N
N
N
N
N
N
O
S
3b
3c
3d
3e
3f
Me
18
4.0
300
32
O
S
n-Bu
Me
O
S
N
N
N
N
O
S
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
F3C
F3C
O
S
N
6.4
7.6
3.8
5.5
N
O
S
N
N
3g
3h
3i
F3C
O
S
N
N
N
N
O
S
N
N
O
S
Cl
N
O
3j
Me
1.4
N
N
N
Cl
Cl
O
S
N
N
O
O
3k
3l
n-Bu
n-Bu
n-Bu
3.2
>250
2.1
Cl
N
N
N
N
F3C
N
N
O
F
3m
F3C
a Inhibition of recombinant human cathepsin K activity in a fluorescence assay using 10 lM Cbz-Phe-Arg-AMC as substrate in 100 mM NaOAc,
10 mM DTT, and 120 mM NaCl, pH 5.5. The IC50 values are the mean of two or three inhibition assays, individual data points in each experiment
were within a threefold range of each other.
analog 3a (IC50 = 65 nM) and the P1 methyl analog 3b
(IC50 = 18 nM) (compare also 3d to 3e). A similar P1
SAR trend was also seen in the ketoamide series
exemplified by inhibitor 2.13
series. For example, the pyrazole 3c (IC50 = 4.0 nM),
imidazole 3f (IC50 = 6.4 nM), and isomeric pyrazole 3g
(IC50 = 7.6 nM) were equipotent cathepsin K inhibitors.
Apparently, this structural element serves mainly to ori-
ent the P3 group toward the S3 subsite as well as to en-
hance the aqueous solubility of the inhibitor. Altering
the electronics of this conformational constraint has lit-
tle effect on inhibitor potency. Since cathepsin K con-
tains a carboxylic acid group (61Asp) in its S3 subsite,
analogs with a complementary charge in P3 were also
explored to try to form an ionic bond with the acidic
S3 element.14 Both of the isomeric pyridyl derivatives
3h (IC50 = 3.8 nM) and 3i (IC50 = 5.5 nM) were equipo-
tent to the neutral phenyl analog 3c despite the higher
entropic cost paid by these analogs to desolvate the
In addition to the exploration of the S1 groove of the en-
zyme, the S3 subsite of cathepsin K was also investigated
in the hybrid ketone series. Truncation of the P3 group
by removing the terminal phenyl ring as in analogs 3d
(IC50 = 300 nM) and 3e (IC50 = 32 nM) resulted in a 5-
to 10-fold loss in activity (compare 3d to 3b or 3e to
3c), presumably arising from reduced interactions with
the S3 subsite of the enzyme. In contrast, the nature of
the five-membered aryl spacer between P2 and P3 did
not greatly influence the inhibitory activity within this

D. G. Barrett et al. / Bioorg. Med. Chem. Lett. 17 (2007) 22–27
Table 2. Cathepsin B, L, and S inhibition and selectivity
25
a
Cat B IC50 (nM)
b
Cat L IC50 (nM)
c
Cat S IC50 (nM)
Compound
Cat K IC50 (nM)
1
7.5
0.072
18
59
20
—
8.7
20
0.21
64
35
10
26
11
15
7.9
10
19
2
3b
3c
3f
3g
3h
3i
310
170
130
72
>250
>250
1100
7100
38
4.0
6.4
7.6
3.8
5.5
1.4
3.2
2.1
13
79
100
38
3j
71
40
3k
3m
16
>250
68
a Inhibition of recombinant human cathepsin B activity in a fluorescence assay using 10 lM Cbz-Phe-Arg-AMC as substrate in 100 mM NaOAc,
10 mM DTT, and 120 mM NaCl, pH 5.5.
b Inhibition of recombinant human cathepsin L activity in a fluorescence assay using 5 lM Cbz-Phe-Arg-AMC as substrate in 100 mM NaOAc,
10 mM DTT, and 120 mM NaCl, pH 5.5.
c Inhibition of recombinant human cathepsin S activity in a fluorescence assay using 10 lM Cbz-Val-Val-Arg-AMC as substrate in 100 mM NaOAc,
10 mM DTT, and 120 mM NaCl, pH 5.5.
Table 3. Serum pharmacokinetics of hybrid ketone analogs
Sol. FS-SIFa (mg/mL)
Clc (mL/min/kg)
Fe (%)
b
t1/2 (min)
d
VSS (mL/kg)
Compound
clogP
MDCK PAPP (nm/s)
1
3.4
5.5
5.6
7.2
3.7
6.8
4.9
7.0
—
91
—
33
320
32
33
9.6
82
26
21
47
16
31
710
1600
1800
1800
460
3.2
42
2
0.11
0.097
0.041
—
3b
3c
3e
3f
3h
3k
300
160
340
190
68
27
21
120
24
20
22
0.040
0.060
0.028
67
1600
1700
1300
120
46
100
32
150
a FS-SIF is the equilibrium solubility in fasted state-simulated intestinal fluid at pH 6.8. The values are the mean of two measurements.
b t1/2 is the iv terminal half-life dosed as a solution in male Han Wistar rats. All in vivo pharmacokinetic values are the mean of two experiments.
c Cl is the total clearance.
d VSS is the steady-state volume of distribution.
e F is the oral bioavailability when dosed as a solution.
pyridine moiety relative to the phenyl group upon bind-
ing to the enzyme. This suggests that the pyridines do in-
deed form a charge complex with the carboxylic acid of
61Asp in cathepsin K, but that the enthalpic gain is offset
by the entropic cost of desolvation. Although potency
was not enhanced, aqueous solubility should be in-
creased, potentially leading to improved oral absorp-
tion. Interestingly, incorporation of the particularly
potent P3 benzimidazole group from the ketoamide ser-
ies into the hybrid ketone series afforded mixed results.
The benzimidazole group was more potent in the P1
methyl analog 3j (compare 3j IC50 = 1.4 nM to 3b),
but not the P1 n-butyl analog 3k (compare 3k
IC50 = 3.2 nM to 3c).
After investigating the S3 subsite of cathepsin K with
various P3 probes, a brief study of the carboxy-terminal
Figure 2. An overlay of ketone 1 and ketone 3c docked into the active
substrate binding region of the enzyme was pursued.
0
site of the X-ray structure of cathepsin K based on X-ray co-crystal
structure of a similar ketone (1BGO). The cathepsin K carbons are
colored green with inhibitor 1 carbons colored magenta and inhibitor
3c carbons colored cyan. The semi-transparent gray surface represents
the molecular surface, while hydrogen bonds are depicted as white/red
dashed lines. This figure was generated using PYMOL version 0.99
(Delano Scientific, www.pymol.org).
The P1 morpholinocarbamate analog 3l showed little
inhibition at concentrations up to 250 nM. In contrast,
the fluoropyridyl derivative 3m (IC50 = 2.1 nM) was
equipotent with the pyridylsulfonamide 3c. This result
0
suggested that further efforts in the P1 region might
prove fruitful; however, for strategic reasons further

26
D. G. Barrett et al. / Bioorg. Med. Chem. Lett. 17 (2007) 22–27
exploration of this hybrid ketone series was not
undertaken.
ketone 3c and the starting ketone 1 occupy very similar
space reflective of their similar potencies.
Similar to the ketoamide series, these hybrid ketones
showed moderate to good selectivity versus cathepsin
L (e.g., analogs 3f, 3g, and 3m P100-fold selective for
cathepsin K), as shown in Table 2. In contrast, these hy-
brid ketones were substantially less selective than the
corresponding ketoamides against cathepsin B (only
ꢀ10-fold selective for cathepsin K).5 Their selectivity
versus cathepsin S was poor.
In summary, this report describes the design of a novel
hybrid ketone series of cathepsin K inhibitors based
on two previously disclosed cathepsin K inhibitor series.
Significant enhancements in oral exposure were realized
by eliminating two amide bonds and incorporating a
constrained P3 peptidomimetic fragment, while main-
taining the low nanomolar inhibitory activity of the ori-
ginal ketone versus cathepsin K. Further efforts to
improve the selectivity of this series versus other cathep-
sins via modifications to the P3 residue may prove
worthwhile.
These ketones exhibited good to excellent permeability
in an in vitro Madin-Darby canine kidney (MDCK) cell
permeation assay (PAPP = 68–340 nm/s), as shown in
Table 3.15 Furthermore, their solubility in fasted state-
simulated intestinal fluid (FS-SIF = 0.028–0.097 mg/
mL) at pH 6.8 was only slightly lower than that of
ketoamide 2 (FS-SIF 0.11mg/mL), which exhibited
good oral exposure.16 Encouraged by these predictors
of oral bioavailability, the iv and po pharmacokinetics
of several analogs were profiled in male Han Wistar rats.
As shown in Table 3, the compounds exhibited short ter-
minal elimination half-lives (t1/2 = 24–120 min) and
moderate to high clearances (Cl = 16–82 mL/min/kg),
similar to starting ketone 1 (t1/2 = 33 min, Cl = 33 mL/
min/kg). In contrast, the steady-state volumes of distri-
bution (VSS = 460–1800 mL/kg) on average resembled
the more moderate volume of starting ketoamide 2
(VSS = 1600 mL/kg) than ketone 1 (VSS = 710 mL/kg).
Encouragingly, the oral bioavailabilities (F = 20–100%)
of the hybrid ketones were all significantly better than
that of the starting ketone 1 (F = 3.2%), with the 4-pyr-
idyl derivative 3h (F = 100%) exhibiting similar oral and
intravenous exposure.
Acknowledgments
The authors thank Robert Marquis and Dennis
Yamashita for helpful discussions.
References and notes
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A model of the hybrid ketone 3c docked into the active
site of cathepsin K with the active site thiol of 25Cys
forming a covalent hemithioketal intermediate with the
ketone group of the inhibitor is shown in Figure 2. The
model of starting ketone 1 is included for comparison.
This model provides insight into the SAR of the hybrid
ketone series. The hemithioketal hydroxyl of ketone 3c
is stabilized by two hydrogen bonds to the side chain
of 19Gln, and the backbone amide of 25Cys, consistent
with other ketone co-crystal structures (e.g., 1BGO).
One face of the P1 n-butyl group of the norleucine-de-
rived inhibitor forms van der Waals interactions with
the S1 wall composed of 23Gly, 24Ser, 64Gly, and 65Gly.
Moreover, the carbamate NH and the carbamate car-
bonyl of the inhibitor are stabilized by two additional
hydrogen bonds between 161Asn and 66Gly in the peptide
backbone recognition site of the enzyme. Furthermore,
the P2 tert-butyl substituent of 3c forms significant
lipophilic interactions with the deep S2 pocket composed
of 67Tyr, 68Met, 134Ala, 163Ala, and 209Leu. Additional
interactions between the P3 phenyl moiety and the active
site trough as well as the S3 subsite formed by 60Asn,
61Asp, 65Gly, 66Gly, and 67Tyr further enhance binding
en0ergy. Finally, the pyridyl sulfonamide occupies the
S1 subsite with one of its sulfone oxygens forming a
10. Catalano, J. G.; Deaton, D. N.; Furfine, E. S.; Hassell, A.
M.; McFadyen, R. B.; Miller, A. B.; Miller, L. R.;
hydrogen bond with the indole NH of 184Trp. The hybrid

D. G. Barrett et al. / Bioorg. Med. Chem. Lett. 17 (2007) 22–27
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