Investigation of ketone warheads as alternatives to the nitrile for preparation of potent and selective cathepsin K inhibitors

Article abstract of DOI:10.1016/j.bmcl.2008.12.053

Amino ketone warheads were explored as alternatives to the nitrile group of a potent and selective cathepsin K inhibitor. The resulting compounds were potent and selective inhibitors of cathepsin K and these nitrile replacements had a significant effect o

Full text of DOI:10.1016/j.bmcl.2008.12.053

Bioorganic & Medicinal Chemistry Letters 19 (2009) 675–679
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Investigation of ketone warheads as alternatives to the nitrile for preparation
of potent and selective cathepsin K inhibitors
*
Michael J. Boyd , Sheldon N. Crane, Joël Robichaud, John Scheigetz, W. Cameron Black, Nathalie Chauret,
Qingping Wang, Frédéric Massé, Renata M. Oballa
Merck Frosst Centre for Therapeutic Research, Medicinal Chemistry, 16711 Trans Canada Hwy, PO Box 1005, Pointe-Claire-Dorval, Que., Canada H9R 4P8
a r t i c l e i n f o
a b s t r a c t
Article history:
Amino ketone warheads were explored as alternatives to the nitrile group of a potent and selective
cathepsin K inhibitor. The resulting compounds were potent and selective inhibitors of cathepsin K
and these nitrile replacements had a significant effect on metabolism and pharmacokinetics.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 28 October 2008
Revised 9 December 2008
Accepted 10 December 2008
Available online 24 December 2008
Keywords:
Cathepsin K
Ketone
Odanacatib
Osteoporosis is a condition where bone becomes weak and brit-
tle. Consequently, osteoporosis significantly increases the risk of
bone fractures. The condition is caused by an imbalance between
bone formation and bone resorption, and it is believed that the
lysosomal cysteine protease cathepsin K (Cat K) plays a key role
in the degradation of the bone matrix.1 More specifically, Cat K is
involved in the degradation of type I collagen, which is the major
organic component of the bone matrix.
In fact, several studies have shown that Cat K deficiency leads to
an increase in bone mineral density (BMD).2 As a consequence, it
has been hypothesized that Cat K inhibitors could be used for the
treatment of osteoporosis, and there has been considerable effort
directed towards the development of potent and selective Cat K
inhibitors over the last decade.3 Recently, two Cat K inhibitors4
have demonstrated reduction in bone resorption biomarkers and
an increase in BMD in the clinic.
active site, which are designated S1, S2, S3 in the C-terminal direc-
tion and S10, S20, S30 in the N-terminal direction of the scissile bond
(prime side). The X-ray crystal structure of an odanacatib-like
inhibitor bound to Cat K reveals several important inhibitor/pro-
tein interactions.5f The nitrile forms a hydrogen bond-stabilized
thioimidate intermediate with Cys 25. The leucine moiety interacts
with the hydrophobic S2 subsite and the biphenyl moiety with the
S3 subsite. Also of importance, are the hydrogen bond interactions
of the trifluroethylamine amide isostere with Gly 66. Furthermore,
odanacatib does not interact with the prime side of Cat K.
After the discovery of odanacatib, we decided to direct effort to-
wards the development of a structurally distinct series of revers-
ible inhibitors. Since ketones have been extensively used as
reversible Cat K inhibitors,4 we decided to investigate replacement
of the nitrile with previously reported cyclic ketone warheads.6c,d,9
Substitution on the a-aminoketone nitrogen could conceivably al-
Most reported inhibitors of Cat K contain electrophilic ‘war-
heads’ which covalently bind to the catalytic Cys 25 residue of
the enzyme. Several of these warheads, such as nitriles5 and ke-
tones,6 bind reversibly to this active site cysteine and thus have
the potential to be safer than earlier, irreversible inhibitors such
as vinyl sulfones and epoxides.7 Recently, we have reported the
development of the reversible, non-basic, potent and selective
Cat K inhibitor, odanacatib 1 (MK-0822) (Fig. 1).8
low interactions on the prime side of the scissile bond (Fig. 2). For
example, carbonyl/sulfonyl substitutions could lead to hydrogen
bond interactions with Trp 184 in S30, as well as hydrophobic inter-
actions with S20. These interactions are of particular interest,
F
CF3
H
Selective and potent inhibition of cathepsin K is achieved by
taking advantage of interactions with the six main subsites in the
N
N
N
H
O
MeSO2
* Corresponding author.
E-mail address: michael_boyd@merck.com (M.J. Boyd).
Figure 1. Odanacatib, 1.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.12.053

676
M. J. Boyd et al. / Bioorg. Med. Chem. Lett. 19 (2009) 675–679
because the nitrile essentially end caps the inhibitor rendering the
Gln 19
H2N
O
aforementioned interactions difficult to achieve with nitrile-based
inhibitors. Moreover, replacement of the nitrile would also likely
lead to inhibitors with distinct metabolic profiles.
Sulfonamides, carbamates, amides and ureas were prepared by
condensation of acid 210 (Scheme 1) with the appropriate Boc pro-
tected amino alcohol 3.6c,d The amine was then deprotected,
capped with an isocyanate, chloroformate or sulfonyl chloride,
and the alcohol was oxidized to the ketone under Swern condi-
tions. In cases where the Swern oxidation was sluggish, the reac-
tion was performed at ꢀ20 °C (instead of ꢀ78 °C).
S2
NH2
S1'
O
H2N
Cys 25
O
S3
F
F
H
F
F
O
S
Trp 184
N
H
N
H
H N
O
N
O
R
O
O
S
H
S2'
O
O
H2N
NH
Gly 66
N-Aryl compounds (32 and 33) could not be prepared by direct
arylation of intermediate 4. Attempts to arylate the nitrogen of 4
via palladium coupling or nucleophilic substitution failed under
various conditions. These conditions also failed with various pro-
tected intermediates of 3. Fortunately, fully protected intermediate
6 (prepared from 511 as shown in Scheme 1) was successfully ary-
lated under Hartwig arylation conditions12 to afford 8a. Compound
8b was prepared by aromatic nucleophilic substitution of 6 with 2-
fluorophenyl methyl sulfone. Acyclic amino ketone 31 was also
prepared in order to evaluate the importance of the restricted con-
formation of the cyclic amino ketones.
Our goal was to establish the structure–activity relationship be-
tween cyclic aminoketone ring size and nitrogen substitution (R
group). The SAR of the ketones prepared is shown in Table 1. Activ-
ity against Cat K was determined by measurement of the IC50 val-
ues against humanized rabbit cathepsin K5a and selectivity of the
inhibitors against human Cat L, B and S is also shown.
NH2
O
Asn 158
Figure 2. Hypothetical representation of ketone inhibitors in the Cat K active site.
F
F
F
F
OH
a,b
N
H
F
O
F
O
F
F
OH
2
H
S
N
O
N
H
+
OH
( )NnH
O
O
4
S
H2N
O
c,d
F
O
O
( )nN
In previously reported work by Marquis et al.,6c the pyridine-2-
sulfonamide group substitution on an azepanone produced a po-
tent inhibitor (34) (Table 1). The replacement of the nitrile of odan-
acatib with this moiety led to some loss of potency regardless of
the amino ketone ring size (9, 17, 19 vs odanacatib), with the
azepanone inhibitor the most potent. Separation of the diastereoi-
somers of compound 9 was performed by chiral HPLC and the po-
tency and selectivity profiles of separated isomers 10 and 11 are
shown in Table 1. Replacement of the pyridyl ring with a methyl
group (14), or replacement of the pyridine sulfonamide group with
a carbamate (15) led to loss of potency (8- and 27-fold, respec-
tively). Also noteworthy, compound 9 shows superior selectivity
against Cat L and S, when compared to compound 34.
The pyridine sulfonamide substitution in the pyrrolidinone ser-
ies (19) was 43 times less potent than its azepanone counterpart
(9). However, potency could be improved by replacement of the
pyridine sulfonamide group with short carbamates (22–24),
amides (25, 26) and ureas (27, 28). These compounds were of com-
parable potency to azepanone 9, with superior selectivity on Cat S,
especially with smaller R groups (22, 23, 26 and 27).
F
n=1,2,3
F
F
O
H
3
N
N
H
( )Nn
O
R
O
9-30
S
O
OH
N3
O
O
N
e-h
O
O
i
N
O
O
N
Cbz
R
N
H
N
5
6
7a,b
j,k
OH
a,d
H2N
32,33
N
R
8a,b
Piperidinones were also examined. In this case, both the pyri-
dine-2-sulfonamide (17) and ethyl carbamate (18) were tolerated,
although with a loss of potency (relative to 9 and 23). These com-
pounds were also less selective on Cat S, especially when compared
to the pyrrolidinone series (18 vs 23). Cyclic arylamines have also
been reported.11 Arylamines 32 and 33 were prepared, and had
comparable potency to other piperidinones, but selectivity was
essentially lost on Cat S and Cat B.
TBDPS
l,m
OH
O
H
H2N
NH2
H2N
O
N
O
a,n,d
F
F
F
F
O
H
N
N
H
HN
O
O
Consistent with the work by Marquis et al.6c the acyclic version
31 (Scheme 1) led to a loss of potency, suggesting that the re-
stricted conformation is important.
O
S
O
31
O
Pharmacokinetic experiments of selected compounds were per-
formed in rats.5g Animals were dosed at 2–5 mg/kg IV in 60% PEG
200. The measured half-lives (t1/2) and clearance rates (Cl) are
shown in Table 2. The half-lives and clearance rates of odanacatib
and 346c are also shown for comparison. Rat hepatocyte incuba-
tions were also performed and results are expressed as % inhibitor
remaining (by HPLC analysis) after a 2 h incubation.5g
Scheme 1. Synthesis of aminoketones. Reagents and conditions: (a) (2), HATU,
DIEA, DMF; (b) TFA, DCM; (c) isocyanate, chloroformate or sulfonyl chloride, (TEA or
pyridine), DCM; (d) (ClCO)2, DMSO, DCM, ꢀ78 to ꢀ20 °C; (e) TPP, H2O, THF,
Boc2O, TEA, MeOH; (g) 2,2-dimethoxypropane, CSA, acetone; (h) H2, Pd/C, MeOH; (i)
t-BuONa, CTC-Q-Phos, Pd(OAc)2, toluene, (for 7a, R = H), 2-fluorophenyl methyl
sulfone, Cs2CO3, DMF, (for 7b, R = SO2Me); (j) AcOH, H2O; (k) HCl, dioxane (8a,
D; (f)
D
D
R = H and 8b, R = SO2Me); (l) TBDPS-Cl, TEA, DMAP, DCM; (m) ClCO2Me,TEA, DCM;
(n) TBAF, AcOH, THF.

M. J. Boyd et al. / Bioorg. Med. Chem. Lett. 19 (2009) 675–679
677
Table 1
Potency and selectivity profiles of ketone Cat K inhibitors
F
F
F
F
O
H
N
N
H
NR
( )n
O
O
S
O
O
H
N
O
N
O
N
H
N
O
S
O
O
34
Compound
N
R
Hrab Cat K IC50 (nM)
Cat L/K
Cat S/K
Cat B/K
Odanacatib
9
0.2
2.0
10
1.8
2.6
159
16
54
33
5.7
9
85
>1000
939
>1000
681
984
>63
617
>185
236
621
>1000
118
158
16
604
861
403
197
>1000
40
300
45
54
35
33
8
114
46
179
22
10
>1000
>1000
>1000
>1000
>1000
50
>1000
>185
303
232
364
118
370
485
637
215
27
188
>1000
355
355
53
9
148
2
3
3
3
3
3
3
3
3
2
2
1
1
1
1
1
1
1
1
1
1
1
1
SO2-2-Pyr
SO2-2-Pyr
SO2-2-Pyr
SO2-2-Pyr-NO
SO2CH2Ph
SO2Me
COOEt
H
SO2-2-Pyr
COOEt
SO2-2-Pyr
SO2Me
10a
11a
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
27
27
313
159
304
185
29
H
9.8
4.3
1.6
3.9
2.9
4.2
7.3
7.3
15
68
45
8.3
6.9
0.16
COOMe
COOEt
COO-t-Bu
COPh
COMe
CONH2
CONHPh
CONHCH2Ph
CONHSO2Ph
14
604
104
104
36
>6
38
8
3.9
25
40
29
30
31
32
33
34
667
>147
152
101
91
2
2
Ph
Ph-2-SO2Me
1
14
>1000
a
Separated diastereoisomers of 9. Separation accomplished on an ADRH HPLC column with acetonitrile/0.1% formic acid (10 was the first eluting diastereoisomer).
Odanacatib has been shown to be metabolically robust.8 In rats
this compound has a t1/2 of 6 h, is cleared at a rate of 2 mL/min/kg
and is very stable in rat hepatocyte incubation experiments (Table
Table 2
Metabolism and pharmacokinetics
Compound
t1/2 (h)
% Inhibitor remaining
in rat hepatocytesa
Cl (mL/min/kg)
2). In contrast, azepanone 9 has a very short t1/2a. Although the ter-
minal t1/2b, was much longer (11 h), the clearance rate was high
(46 mL/min/kg). Previously reported 34, with the same warhead,
was also cleared quickly (t1/2 = 0.5 h, Cl = 50 mL/min/kg).6c
Pharmacokinetic experiments on separated diastereoisomers
10 and 11 were performed, and it was found that these compounds
rapidly re-equilibrated (<5 min) back to 9 in rat, indicating that the
34
0.54b
6
—
50b
2.0
46
24
43
40
53
67
17
Odanacatib8
96
56
—
15
11
20
—
9
0.6; 11c
0.6
17
19
22
23
26
31
1.3
2.8
2.1
1.2
a-keto stereocenter is not stable in vivo, even though compounds
1.1
—
with the same azepanone warhead had been reported to be stable
under neutral and acidic pH.6c It is also evident that 9 is signifi-
cantly more metabolized in rat hepatocytes than odanacatib (Table
2). In the hepatocyte incubations of 9, many small unidentified
metabolites were observed, none of which corresponded to pyri-
dine N-oxide 12 (Table 1), this despite the observation that com-
pound 34 undergoes metabolism through pyridine oxidation.13
Considering the metabolically robust nature of odanacatib, it
was proposed that heavy metabolism on the azepanone ring could
account for the metabolic liability of 9. On this basis, the smaller
ring versions 17 and 19 were prepared with the hope that they
would potentially have decreased metabolism. However, as shown
a
After 2 h incubation.
b
c
Ref. 6c.
Two half-lives were calculated since 9 clearly showed two long and distinct
and t1/2b, respectively.
phases, indicated here as t1/2
a
in Table 2, the smaller ring versions were also cleared rapidly and
showed decreased stability in hepatocytes. Acyclic compound 31,
carbamates (22, 23) and amides (26) all showed similar pharmaco-
kinetics to 9.
In order to better understand the clearance of the ketones, a
radiolabelled version of 22 was prepared from 358 as shown in

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M. J. Boyd et al. / Bioorg. Med. Chem. Lett. 19 (2009) 675–679
F
F
F
F
F
F
F
F
a
OEt
OEt
N
H
N
H
O
F
O
O
Br
B
O
F
F
F
35
36
OH
c,d
N
H
+
O
O
O S O
38
S
Br
F
O
Br
F
F
F
O
H
Br
b
N
N
H
37
N
O
O
S
O
O
Br
39
S
O
Br
e
Br
F
F
F
F
O
H
N
N
H
N
O
O
O
3H-22
O
S
O3
H
Scheme 2. 3H-22. Reagents and conditions: (a) bis(pinacolato)diboron, PdCl2(dppf), KOAc, DMF,
D
D
; (b) H2O2, Na2WO4ꢁ2H2O, NBu4HSO4, EtOAc; (c) PdCl2(dppf), NaHCO3, DMF,
; (d) LiOH, MeOH, THF, D
; (e) 3H2, TEA, Pd/C, THF.
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Oxidation (+16, 32, etc)
F
F
F
F
O
H
N
N
H
N
O
O
O
S
O
O
Cleavage
Figure 3. Metabolism of 22.
Scheme 2. A rat bile cannulation study was performed with 3H-22,
and LC/MS analysis of the bile indicated the presence of many
metabolites. Some of the more prominent metabolites were the re-
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sult of cleavage between the amide nitrogen and the a-keto stereo-
center, as well as oxidation on the pyrrolidinone (Fig. 3). Parent
was detected in low amounts (<5%), indicating that excretion oc-
curs mainly through metabolism.
In conclusion, ketone replacement of the nitrile of odanacatib
led to potent and selective inhibitors of cathepsin K (compounds
22 and 26). However, these inhibitors are rapidly cleared in rats,
presumably due to metabolism on the ketone moiety. Substitu-
tions on this cyclic ketone template could be explored to poten-
tially stabilize the inhibitors.
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