β-Substituted cyclohexanecarboxamide cathepsin K inhibitors: Modification of the 1,2-disubstituted aromatic core

Article abstract of DOI:10.1016/j.bmcl.2007.03.028

Further SAR study around the central 1,2-disubstituted phenyl of the previously disclosed Cat K inhibitor (-)-1 has demonstrated that the solvent exposed P2-P3 linker can be replaced by various 5- or 6-membered heteroaromatic rings. While some potency loss was observed in the 6-membered heteroaromatic series (IC₅₀ = 1 nM for pyridine-linked 4 vs 0.5 nM for phenyl-linked (±)-1), several inhibitors showed a significantly decreased shift in the bone resorption functional assay (10-fold for pyridine 4 vs 53-fold for (-)-1). Though this shift was not reduced in the 5-membered heteroaromatic series, potency against Cat K was significantly improved for thiazole 9 (IC₅₀ = 0.2 nM) as was the pharmacokinetic profile of N-methyl pyrazole 10 over our lead compound (-)-1.

Full text of DOI:10.1016/j.bmcl.2007.03.028

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3146–3151
b-Substituted cyclohexanecarboxamide cathepsin K
inhibitors: Modification of the 1,2-disubstituted aromatic core
Joe¨l Robichaud,a,* Christopher I. Bayly,a W. Cameron Black,a Sylvie Desmarais,a
a
a
a
a
a
´
´ ´
´
ˆ
Serge Leger, Frederic Masse, Daniel J. McKay, Renata M. Oballa, Julie Paquet,
M. David Percival,a Jean-Franc¸ois Truchon,a Gregg Wesolowskib and Sheldon N. Cranea
aMerck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, Que., Canada H9H 3L1
bMerck Research Laboratories, West Point, PA 19486, USA
Received 10 November 2006; revised 21 December 2006; accepted 12 March 2007
Available online 15 March 2007
Abstract—Further SAR study around the central 1,2-disubstituted phenyl of the previously disclosed Cat K inhibitor (ꢀ)-1 has
demonstrated that the solvent exposed P2–P3 linker can be replaced by various 5- or 6-membered heteroaromatic rings. While some
potency loss was observed in the 6-membered heteroaromatic series (IC50 = 1 nM for pyridine-linked 4 vs 0.5 nM for phenyl-linked
( )-1), several inhibitors showed a significantly decreased shift in the bone resorption functional assay (10-fold for pyridine 4 vs 53-
fold for (ꢀ)-1). Though this shift was not reduced in the 5-membered heteroaromatic series, potency against Cat K was significantly
improved for thiazole 9 (IC50 = 0.2 nM) as was the pharmacokinetic profile of N-methyl pyrazole 10 over our lead compound (ꢀ)-1.
Ó 2007 Elsevier Ltd. All rights reserved.
Bone tissue remodeling is a dynamic process involving
multiple biological pathways wherein bone resorption
is mediated by highly specialized cells called osteoclasts.
After tightly binding to the bone surface, these osteo-
clasts create an acidic lacuna into which the lysosomal
cysteine protease cathepsin K (Cat K) is secreted and ef-
fects cleavage of type I collagen (i.e., the main protein
constituent of bone).1 The elucidation of this biological
mechanism has rendered it an attractive target for the
development of new anti-resorptive therapies for bone
diseases such as osteoporosis.2
F
F
P3
P1
H
P2
N
N
MeS
O
P2-P3
phenyl linker
(-)-1
Figure 2. The average structure resulting from 100 ps MD studies of
(ꢀ)-1in Cat K is shown. The P2–P3 phenyl linker is solvent exposed,
while P2 goes deeply in the S2 pocket and P3 forms lipophilic
interactions. Dashed line shows a steric contact between ligand and
active site.
Figure 1. Exploring the SAR around the 1,2-disubstituted P2–P3
linker.
Keywords: Cathepsin K; Osteoporosis; Inhibitor; Cyclohexanecarbox-
amide; Nitrile warhead; Modeling; Bone resorption.
Our ongoing research in this field has already led to the
disclosure of SAR for several series of Cat K inhibitors
bearing a P2 leucine side chain.3 We recently reported a
*
Corresponding author. Tel.: +1 514 428 3665; e-mail:
joel_robichaud@merck.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.03.028

J. Robichaud et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3146–3151
3147
new, structurally distinct series wherein this P2 leucine
side chain was replaced with a b-substituted cyclohexyl
moiety (see Fig. 1).4 These efforts led to the identifica-
tion of the potent and selective inhibitor (ꢀ)-1 possess-
ing a 1,2-disubstituted phenyl linking the P2–P3
portion of the molecule. The P3 SAR was found to be
different from other nitrile warhead based inhibitors in
that a basic group in P3 was not required for sub-nano-
molar potency, but rather a thiomethyl ether in P3 was
preferred. In addition, the gem-difluoro substitution of
the cyclohexyl in P2 was found to be critical to achieve
a good pharmacokinetic profile.
the P2–P3 aromatic linker is solvent-exposed (see
Fig. 2), we surmised that the introduction of polarity
in this region would be tolerated and that modifications
around this core might succeed in reducing the observed
shift.
We began our SAR in the 6-membered heteroaromatic
rings (see Table 1) by synthesizing the three isomeric
pyridines 2, 3, and 4. The 3- and 4-pyridyl substituted
compounds 3 and 4 showed slight erosion in potency
against Cat K (IC50 = 1 nM) while maintaining an excel-
lent selectivity profile against other cathepsins. More
important, however, is the fact that pyridines 3 and 4
showed a significant decrease in the observed shift
(18- and 10-fold, respectively) in the bone resorption
functional assay. The 3-pyridyl N-oxide 5 afforded a sig-
nificant loss in potency (IC50 = 5 nM) without maintain-
ing the improved shift in the functional assay (15-fold).
The two isomeric pyridones 6 and 7 displayed profiles
similar to that of the pyridine N-oxide 5 (IC50 = 8 and
4 nM, respectively) where the shift in the bone resorption
We now report further SAR based on inhibitor (ꢀ)-1
where the 1,2-disubstituted phenyl ring is replaced with
5- and 6-membered heteroaromatic rings. Part of our
strategy was to reduce the >50-fold loss of potency of
(ꢀ)-1 in the functional bone resorption assay as com-
pared to the enzyme assay.4 We reasoned that our inhib-
itors’ high lipophilic nature might be partly responsible
for this shift. Since modeling studies demonstrated that
Table 1. Inhibition of Cat K with 6-membered heteroaromatic compounds
F
F
H
N
MeS
N
O
X
Z
Y
Ar
Compounda
hrab Cat
b
K IC50 (nM)
rab Cat K
b
IC50 (nM)
Cat Lc/CatK
CatBc/CatK
Cat Sc/CatK
Bone res
d
IC50 (nM)
Shift
(fold)e
(ꢀ)-1
( )-1
0.3
0.5
0.3
0.5
780
880
>36,000
>120,000
940
1100
16
38
53
76
2f
3
2
1
1
2
1
1
260
520
540
>5000
>10,000
>10,000
450
720
850
58
18
10
29
18
10
N
N
4
N
5
6
5
8
5
6
460
430
>2000
>1250
480
310
75
84
15
14
N
O
O
N
H
7
4
5
410
1200
540
20
4
N
O
H
a All compounds in the 5- and 6-membered heteroaromatic series were synthesized and evaluated as racemic mixtures.
b IC50 values represent an average of at least n = 2 and variation was within 2-fold. Humanized rabbit (hrab) Cat K was utilized, see Ref. 5 for
conditions.
c Human enzyme was used for these assays, see Ref. 6 for conditions.
d See Ref. 6 for assay conditions.
e Shift is calculated by dividing the potency obtained in the bone resorption assay over the potency observed in the enzyme assay using rab Cat K.
f Pyridine 2 contains a CFH2 group in P3 instead of a CH3 on the sulfur atom.

3148
J. Robichaud et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3146–3151
assay (14- and 4-fold, respectively) was likewise reduced
in comparison with biaryl (ꢀ)-1. These results support
our hypothesis that the high lipophilic character of
inhibitors such as (ꢀ)-1 has a negative impact on the
shift observed in the functional assay.
The pharmacokinetic profile in rats (PO: 5 mg/kg, IV:
1 mg/kg) of the 3-pyridyl analog 3 was assessed
(F = 65%, T1/2 = 1.0 h, AUC = 8.6 lM h) but was found
to be somewhat inferior to that of the biaryl analog (ꢀ)-1
(F = 39%, T1/2 = 3.5 h, AUC = 18.5 lM h).
While all of the compounds generated in the 6-mem-
bered heteroaromatic linked series succeeded in decreas-
ing the observed shift in the functional bone resorption
assay, none of them were as potent as ( )-1. Molecular
dynamics calculations suggested that the replacement of
the 6-membered heteroaromatic linker with a 5-mem-
bered ring would reduce steric contact of the inhibitor
with the side of the S2 pocket (dashed line in Figs. 2
and 3), while increasing the angle of the bond vector
reaching towards S3, thereby also reducing the steric
interaction between the SMe group and the S3 pocket.
In addition, the dihedral angle between the 5-membered
heteroaromatic ring and the phenyl ring in P3 is smaller
than the corresponding dihedral angle in (ꢀ)-1. The net
effect of these changes would be to allow the inhibitors
to sit closer to the surface of the enzyme and thereby en-
hance their potency.
In line with this rationale, the central 1,2-disubstituted
phenyl ring of ( )-1 (see Table 2) was replaced with a
5-membered benzyl-substituted triazole to afford com-
pound 8. And while inhibitor 8 again showed very little
shift in the functional assay (4-fold), there was a 10-fold
loss in potency in the enzymatic assay (IC50 = 2 nM).
Hypothesizing that the bulky benzyl group was
Figure 3. Superposition of average structures from 100 ps MD
trajectories of compound (ꢀ)-1 with compound 9 in the Cat K active
site. The dashed line shows steric contact between compound 9 and the
˚
active site. Overall 9 sits just over 0.3 A deeper into the active site.
Table 2. Inhibition of Cat K with 5-membered heteroaromatic compounds
F
F
H
N
MeS
N
O
Z
X
Y
Ar
Compounda
hrab Cat K
b
IC50 (nM)
hrab Cat K
b
IC50 (nM)
Cat Lc/CatK
Cat Bc/CatK
Cat Sc/CatK
Bone Res
d
IC50 (nM)
Shift (fold)e
(ꢀ)-1
( )-1
0.3
0.5
0.3
0.5
780
880
>36,000
>120,000
940
1100
16
38
53
76
8
2
9
350
270
730
1 400
14 990
9 500
180
380
490
33
17
41
4
170
103
N
BnN
N
N
S
9
0.2
0.4
0.1
0.4
N
10
N
a All compounds 5- and 6-membered heteroaromatic series were synthesized and evaluated as racemic mixtures.
b IC50 values represent an average of at least n = 2 and variation was within 2-fold. Humanized rabbit (hrab) Cat K was utilized, see Ref. 5 for
conditions.
c Human enzyme was used for these assays, see Ref. 6 for assay conditions.
d See Ref. 6 for assay conditions.
e Shift is calculated by dividing the potency obtained in the bone resorption assay over the potency observed in the enzyme assay using rab Cat K.

J. Robichaud et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3146–3151
3149
detrimental to the potency of 8, debenzylation was at-
tempted under standard conditions but failed to provide
us with the debenzylated triazole.
synthesis of triazole 8, pyridines 2, 3, and 4, pyridine
N-oxide 5, and pyridones 6 and 7).
The synthesis of the 3-pyridyl analog 3 began with com-
mercially available 3-bromopyridine 11 which was
deprotonated with LDA and quenched with DMF to af-
ford aldehyde 12 (see Scheme 1). Wittig reaction with
Et3N as base afforded the key pyruvate ester 13 which
was hydrolyzed to the corresponding pyruvate acid 15
in two steps. Treatment of 15 with methyl vinyl ketone
under basic conditions yielded 16 via a Robinson annu-
lation type reaction. Alcohol elimination under acidic
conditions provided the a,b-unsaturated enone which
was then reduced with activated zinc dust to ketone 17
(predominantly as the cis isomer). Difluorination of
the ketone 17 with DAST yielded the desired difluoro
analog 18,7 which was cross-coupled with 4-(methyl-
thio)benzeneboronic acid and equilibrated to the more
thermodynamically stable trans isomer 19 under basic
conditions. Hydrolysis of the ester 19 followed by cou-
pling with aminoacetonitrile provided the final com-
pound 3.
The 2-methyl thiazole 9 was prepared and succeeded
in achieving sub-nanomolar potency against Cat K
(IC50 = 0.2 nM), being even more potent than our
lead compound ( )-1 (IC50 = 0.5 nM). This result lent
support to our modeling hypothesis. On the other
hand, the observed shift in the functional assay for
inhibitor 9 worsened (170-fold) and so did the selec-
tivity profile of 9 against other cathepsins. While the
N-methyl-substituted pyrazole 10 again displayed sub-
nanomolar potency against Cat K (IC50 = 0.4 nM)
along with an improved selectivity profile against
Cat L and S, the shift in the functional assay re-
mained high (103-fold).
We surmise that the lack of improvement in the func-
tional assay shift with these 5-membered heteroaromatic
inhibitors is due to their high lipophilicity in comparison
with the pyridine/pyridone compounds. In contrast,
however, with the 6-membered heteroaromatic series,
the pharmacokinetic profile in rats (PO: 10 mg/kg, IV:
5 mg/kg) of the N-methyl pyrazole analog 10
(F = 100%, T1/2 = 4.6 h, AUC = 28.9 lM h) was found
to be superior to that of our lead compound (ꢀ)-1
(F = 39%, T1/2 = 3.5 h, AUC = 18.5 lM h).
The sequence leading to the pyridine N-oxide 5 and the
corresponding pyridones 6 and 7 began with the equili-
bration of 18 under basic conditions followed by N-oxi-
dation with m-CPBA to afford compound 21 (see
Scheme 2). The usual sequence involving Suzuki cross-
coupling, hydrolysis, and amide coupling then afforded
N-oxide 5. Treatment of 22 with trifluoroacetic anhy-
dride afforded a mixture of two isomeric pyridones
(23) which were hydrolyzed and coupled as above to af-
ford the two isomeric pyridones 6 and 7 after separation
by flash chromatography.
Given that the SAR modifications all centered on the
core of the inhibitors, each new heterocyclic compound
had to be synthesized in a separate fashion. Two general
strategies were employed to synthesize these inhibitors.
The first utilized a Diels–Alder approach (for the syn-
thesis of thiazole 9 and pyrazole 10). The second em-
ployed a base-catalyzed addition of methyl vinyl
ketone onto a properly functionalized pyruvic acid
derivative which underwent concomitant intramolecular
cyclization to afford the cyclohexane-substituted het-
eroaromatic core (this approach was utilized for the
The synthesis of pyrazole 10 (see Scheme 3) began with
the commercially available aldehyde 24 which was con-
verted to the a,b-conjugated carboxylic acid 25 via a
Knoevenagel condensation. The Diels–Alder reaction
of 25 with butadiene in a stainless steel bomb at
OR'
O
R
OR
O
Br
b
e
Br
O
OH
OH
16
Br
N
11, R = H
a
N
12, R = CHO
13, R = Et, R' = Et
14, R = H, R' = Et
15, R = H, R' = H
c
N
O
d
F
F
f, g, h
F
F
MeS
R
i
j, k
OMe
OMe
O
Br
O
Br
O
19, R = OMe
20, R = OH
3, R = NHCH2CN
l
m
N
17
18
N
N
Scheme 1. Synthesis of the pyridine analog 3. Reagents and conditions: (a) n-BuLi, i-Pr2NH, THF, then DMF, ꢀ78 °C ! rt, 1.5 h, 45%; (b)
Ph3P@C(OEt)CO2Et, CHCl3, 18 h, 90%; (c) NaOH, MeOH, rt, 18 h; (d) HCl, 1,4-dioxane, 110 °C, 1.5 h, 46% (two steps); (e) methyl vinyl ketone,
MeOH, NaOH, 0 °C ! rt, 2 h, 56%; (f) H2SO4, H2O, 60 °C, 18 h, 96%; (g) Zn*, AcOH/Py/H2O (6:3:1), rt, 1 h, 74%; (h) CH2N2, Et2O, 100%; (i)
DAST, TsOH, CH2Cl2, rt ! 40 °C, 18 h, 58% (traces of alkenes); (j) 4-(methylthio)benzeneboronic acid, PdCl2(dppf)ÆCH2Cl2, aq 2 M Na2CO3,
DMF, 90 °C, 18 h, 56%; (k) NaH, MeOH, 75 °C; (l) aq 2M LiOH, MeOH, 60 °C, 18 h, 87%; (m) PyBOP, aminoacetonitrile hydrochloride, Et3N,
DMF, 3 h, 82%.

3150
J. Robichaud et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3146–3151
F
F
F
F
F
F
H
N
MeS
OMe
OMe
MeS
18
O
Br
O
O
a, b
c
d, e
N
22
5
N
O
N
O
N
O
f
21
F
F
F
F
F F
H
H
N
MeS
OMe
MeS
N
MeS
+
O
O
O
O
O
g, h
N
N
23
6
7
O
N
O
N
N
H
H
H
Scheme 2. Synthesis of pyridine N-oxide 5 and pyridones 6 and 7. Reagents and conditions: (a) NaH, MeOH, 80 °C, 3 h, 68%; (b) m-CPBA, CH2Cl2,
rt, 45 min, 66%; (c) 4-(methylthio)benzeneboronic acid, PdCl2(dppf)ÆCH2Cl2, aq 2 M Na2CO3, DMF, 85 °C, 18 h, 89%; (d) aq 2M LiOH, 75 °C, 18 h,
93%; (e) PyBOP, aminoacetonitrile hydrochloride, Et3N, DMF, 18 h, 44%; (f) TFAA, Et3N, THF, 0 °C ! rt, 2 h, 100%; (g) same conditions as (d),
95%; (h) same conditions as (e), 4% for 6 and 6% for 7.
O
R
R
Br
OH
O
N
b
c
Br
O
N
N
N
Br
27, R = I
28, R = H
24, R = CHO
25, R = CH=CHCO2H
a
26
N
d
N
e
F
F
F
F
OH
MeS
R
OMe
OMe
f, g
h
O
Br
O
N
N
Br
O
N
N
31, R = OMe
32, R = OH
10, R = NHCH2CN
N
N
i
j
30
29
Scheme 3. Synthesis of the pyrazole analog 10. Reagents and conditions: (a) malonic acid, pyrrolidine, pyridine, 100 °C, 2 h, 97%; (b) Butadiene,
MePh, 200 °C, stainless steel bomb, 24 h, 90%; (c) I2, KI, NaHCO3, CH2Cl2/H2O, 0 °C ! rt, 18 h, 59%; (d) Bu3SnH, AIBN, PhH, 80 °C, 1.5 h, 92%;
(e) MeONa, MeOH, 0 °C ! rt, 18 h, 96%; (f) Jones’ oxidation, Me2CO, 0 °C ! rt, 0.5 h, 85%; (g) DAST, CH2Cl2, 0 °C ! rt, 2 h, 38% (26%
alkenes + 12% SM); (h) 4-(methylthio)benzeneboronic acid, PdCl2(dppf)ÆCH2Cl2, aq. 2M Na2CO3, DMF, 90 °C, 3 h, 33%; (i) aq 2M LiOH, THF/
MeOH (2:1), rt, 18 h, 100%; (j) aminoacetonitrile hydrochloride, HATU; i-Pr2NEt, DMF, rt, 18 h, 96%.
200 °C afforded the desired cycloadduct 26 in good
yield (90%). Iodolactonization yielded 27 which was
de-iodinated under radical conditions to afford the bicy-
clic lactone 28. Cleavage of the lactone 28 with NaOMe
provided 29 which was oxidized with Jone’s reagent and
difluorinated using DAST to afford compound 30. Suzuki
cross-coupling of heteroaryl bromide 30 with 4-methyl-
thiobenzeneboronic acid yielded compound 31 which
was hydrolyzed to the corresponding carboxylic acid
32 and coupled with aminoacetonitrile to afford the final
compound 10.
heteroaromatic rings. This approach was first based on
the rationale that the P2–P3 phenyl linker is solvent-ex-
posed in the inhibitor–enzyme complex and that the
incorporation of polarity in this region of our lipophilic
inhibitors would be tolerated and could potentially de-
crease the magnitude of the shift observed in the bone
resorption functional assay. While inhibitors in the pyr-
idine/pyridone series succeeded in decreasing this shift,
none of these achieved the sub-nanomolar potency of
our lead compound ( )-1.
Second, it was hypothesized that replacing the 6-mem-
bered ring with a 5-membered ring would allow for tigh-
ter binding of the inhibitor with the active site and
potentially improve potency. This strategy enabled us
to identify the thiazole analog 9 (IC50 = 0.2 nM) that
showed superior potency over our lead inhibitor ( )-1
(IC50 = 0.5 nM). While the 5-membered heteroaromatic
inhibitors were still highly shifted in the functional
All other reported compounds were prepared analo-
gously, using either of the two routes shown above, with
minor modifications.
In this report, we have disclosed further SAR demon-
strating that the P2–P3 1,2-disubstituted phenyl linker
of 1 can be replaced with various 5- and 6-membered

J. Robichaud et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3146–3151
3151
J.; Seeman, E.; Wasnich, R. D. Am. J. Med. 1993, 94, 646;
(b) Blair, H. C.; Athanasou, N. A. Histol. Histopathol.
2004, 19, 189.
assay, the potent and selective pyrazole analog 10 dis-
played an improved pharmacokinetic profile over our
lead compound (ꢀ)-1. Based on our findings we are cur-
rently exploring strategies to incorporate additional
polarity into the 5-membered heteroaromatic-linked ser-
ies, and identify a cyclohexanecarboxamide based Cat K
inhibitor that exhibits an acceptable shift (610-fold) in
our functional assay. The results of these investigations
will be reported in due course.
3. (a) Black, W. C.; Bayly, C. I.; Davis, D. I.; Desmarais, S.;
´
´
Falgueyret, J.-P.; Leger, S.; Li, C. S.; Masse, F.; McKay,
D. J.; Palmer, J. T.; Percival, M. D.; Robichaud, J.; Tsou,
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´
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´
´
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D.; Rodan, S. B.; Percival, M. D. J. Med. Chem. 2001, 44,
94.
7. Small amounts of the isomeric fluoroalkenes were produced
along with 18 but were removed via chromatography in the
subsequent steps.