Pyrazole-based cathepsin S inhibitors with arylalkynes as P1 binding elements

Article abstract of DOI:10.1016/j.bmcl.2009.09.014

A crystal structure of 1 bound to a Cys25Ser mutant of cathepsin S helped to elucidate the binding mode of a previously disclosed series of pyrazole-based CatS inhibitors and facilitated the design of a new class of arylalkyne analogs. Optimization of the

Full text of DOI:10.1016/j.bmcl.2009.09.014

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6131–6134
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Pyrazole-based cathepsin S inhibitors with arylalkynes as P1 binding elements
a
a
a
a
a
Michael K. Ameriks a, , Frank U. Axe , Scott D. Bembenek , James P. Edwards , Yin Gu , Lars Karlsson ,
*
Mike Randal b, Siquan Sun a, Robin L. Thurmond a, Jian Zhu a
a Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA
b Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2009
Revised 2 September 2009
Accepted 4 September 2009
Available online 10 September 2009
A crystal structure of 1 bound to a Cys25Ser mutant of cathepsin S helped to elucidate the binding mode
of a previously disclosed series of pyrazole-based CatS inhibitors and facilitated the design of a new class
of arylalkyne analogs. Optimization of the alkyne and tetrahydropyridine portions of the pharmacophore
provided potent CatS inhibitors (IC50 = 40–300 nM), and an X-ray structure of 32 revealed that the aryl-
alkyne moiety binds in the S1 pocket of the enzyme.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cathepsin
Protease
Alkyne
X-ray crystallography
Cathepsin S (CatS), a cysteine protease of the papain family, is
found in the lysosome of certain antigen-presenting cells. Through
proteolytic degradation of the invariant chain (Ii), a chaperone pro-
tein for major histocompatibility complex class II molecules
(MHCII), CatS plays a key role in facilitating antigen presentation
to CD4+ T-cells.1 Inhibition of CatS activity impedes the removal of
Ii from MHCII molecules, and may help to regulate immune hyperre-
sponsiveness by attenuating antigen presentation. Other pharmaco-
logically relevant activities have also been attributed to CatS.2 Most
CatS inhibitors have traditionally relied upon covalent modification
of the active site cysteine to achieve good activity, but recently sev-
eral noncovalent inhibitors have been disclosed as well.3–6
Two hydrogen bonds are observed between the oxamide of 1
and the backbone amide of Val162 as well as the side chain amide
of Asn161 in the S4 subsite of CatS.9 These interactions anchor the
We have previously reported potent noncovalent inhibitors of
human CatS characterized by a fused tetrahydropyrido-pyrazole
heterocycle.6 In order to elucidate the binding mode of this class
of compounds, a crystal structure of 1 bound to a Cys25Ser mu-
tant7 of cathepsin S was obtained (Fig. 1).8
P2
P5
Cl
N
CN
N
N
CH3
P1?
N
OH
N
O
P4
O
1
OCH3
hCatS = 120 nM
* Corresponding author.
E-mail address: mameriks@its.jnj.com (M.K. Ameriks).
Figure 1. Crystal structure of
Compound conformation is shown as an average of two enantiomers.
1 bound to a Cys25Ser mutant of cathepsin S.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.09.014

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M. K. Ameriks et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6131–6134
Table 1
tetrahydropyrido-pyrazole core of 1 in the S2 region and the aryl-
piperazine moiety in S5. Notably, ligand 1 differs from previously
reported CatS inhibitors in that it binds distal to the active site
and does not access the S1, S10, or S3 regions of the enzyme. How-
ever, further analysis reveals that the methyl group ortho to the
arylchloride in 1 is oriented towards the S1 pocket, suggesting that
a judicious choice of substituents at this position might provide ac-
cess to the active site. In this Letter, we describe the successful
implementation of this design strategy, and disclose a series of
arylalkyne analogs of 1 that bind in S1.
Effect of alkyne substitution on cathepsin S activitya
Cl
N
N
N
O
R
N
SO2CH3
Compound
R
CatS IC50 (lM)
At the onset, we targeted aryliodide 3 as a key synthetic inter-
mediate for introducing potential P1 groups through Pd-catalyzed
cross-couplings (Scheme 1). For ease of synthesis, a sulfonamide
was selected as a P4 group, and following our previously described
route, the tetrahydropyrido-pyrazole core 2 was assembled in
three steps from N-methanesulfonyl piperidone. Subsequent regio-
selective pyrazole alkylation, acetal hydrolysis, and reductive ami-
nation afforded the desired intermediate 3 in moderate yield. This
sequence allowed for removal of the chiral center in 1 and pro-
vided a potential late-stage opportunity to screen P5 binding ele-
ments. However, a morpholine ring was initially chosen as a
solubilizing replacement for the bulky arylpiperazine moiety in 1,
and was held constant to facilitate identification of a suitable P1
group. Based on molecular modeling for a variety of scaffolds, we
initially focused on alkyne linkers as it was anticipated that the
rigidity imposed by sp-hybridization would direct substituents to
the S1 pocket.
Using standard Sonogashira conditions, a small library of al-
kynes (4–11) was prepared from aryliodide 3 (Table 1). Preliminary
results proved discouraging as terminal acetylene 11 demon-
strated only micromolar inhibition of CatS. Appending a hetero-
atom onto the alkyne (4) failed to improve potency, as did the
introduction of linear, branched, or cyclic alkyl groups (5–7). How-
ever, direct attachment of aromatic rings provided a dramatic
improvement in potency, affording compounds (8–9) with sub-
micromolar inhibition of CatS. In fact, the phenyl-substituted al-
kyne 8 demonstrated a 10-fold improvement in enzymatic activity
4
5
6
7
8
9
10
11
CH2OH
n-Butyl
i-Butyl
Cyclohexyl
Phenyl
2-Thiophene
3-Thiophene
H
7.9
11
8.3
6.7
0.61
0.79
1.5
7.4
a
CatS IC50 values are the mean of n P 2 runs and determined as described pre-
viously.6a All IC50s were within a twofold range.
substituted arenes 12–20 could be prepared by either coupling
the parent aryliodide 3 with commercially available arylacetyl-
enes, or by introducing a terminal alkyne 11 through a standard
two-step sequence, followed by a second Sonogashira coupling
with a variety of aryliodides (Scheme 2).
CatS inhibition for a range of substituted arylalkynes is shown
in Table 2. The SAR of ortho- and meta-substituted arenes is quite
flat, as lipophilic (Cl, CH3), electron-donating (OCH3), and elec-
tron-withdrawing (CF3) groups all failed to significantly enhance
enzymatic potency relative to the unsubstituted arene 8. The intro-
duction of para-substituents, however, slightly improved activity.
Both electron-donating (OCH3, NH2) and electron-withdrawing
(CF3, CO2H) functionalities were tolerated, and the 4-chloro analog
18 consistently exhibited a threefold improvement in CatS inhibi-
tion (0.20 lM vs 0.61 lM for 8).
Further profiling of compound 18 revealed several promising
attributes (Fig. 2). In addition to inhibiting human CatS, 18 demon-
strated sub-micromolar inhibition of mouse CatS activity
(IC50 = 690 nM). This is encouraging because previous pyrazole-
based inhibitors displayed markedly reduced affinity for murine
CatS, making it difficult to test these compounds in in vivo disease
models.6a Furthermore, alkyne 18 exhibited exquisite selectivity
(0.6
lM vs 7.4 lM) compared to the unsubstituted alkyne 11.
In order to optimize the potency of phenylalkyne 8, we explored
the effect of substitution around the terminal aromatic ring. The
Cl
O
N
HN
I
d,e,f
a,b, c
Cl
N
N
N
SO2CH3
b,c
N
N
N
I
SO2CH3
O
2
Cl
Cl
I
N
a
SO2CH3
N
N
N
3
g
N
N
O
O
N
11
R
N
Cl
SO2CH3
SO2CH3
Cl
N
3
I
N
N
R1
N
d
R
O
R
N
N
R2
R3
O
N
SO2CH3
4-10
N
SO2CH3
Scheme 1. Reagents and conditions: (a) Morpholine, p-TSAꢀH2O (1–3%), benzene,
80 °C; (b) 4-Chloro-3-iodobenzoyl chloride, Et3N, CH2Cl2, 0 °C to rt; (c) H2NNH2,
EtOH (36%, three steps); (d) 2-(2-Bromoethyl)1,3-dioxolane, Cs2CO3, DMF (85%); (e)
1 N HCl, acetone, 55 °C; (f) Morpholine, Na(OAc)3BH, acetic acid, CH2Cl2 (60%, two
steps); (g) H–„–R, 10% Pd(PPh3)2Cl2, 10% CuI, Et3N, THF, rt (50–95%).
12-24
Scheme 2. Reagents and conditions: (a) 10% Pd(PPh3)2Cl2, 10% CuI, Et3N, THF (50–
95%); (b) Trimethylsilylacetylene, 10% Pd(PPh3)2Cl2, 10% CuI, Et3N, THF (91%); (c)
TBAF, THF (67%); (d) 10% Pd(PPh3)2Cl2, 10% CuI, Et3N, THF (50–70%).

M. K. Ameriks et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6131–6134
6133
Table 2
Cl
I
Effect of aryl substitution on cathepsin S activitya
O
N
Cl
HN
d,e,f
a,b,c
R1
N
N
N
R2
R3
N
Boc
N
Boc
26
O
N
SO2CH3
Cl
I
Compound
R1
R2
R3
CatS IC50 (lM)
N
g,h,i
N
N
8
12
13
14
15
16
17
18
19
20
21
22
23
24
H
Cl
CH3
CF3
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
CH3
CF3
OCH3
NH2
CO2H
Cl
0.61
0.72
1.1
0.87
0.55
0.70
1.5
0.20
0.28
0.28
0.48
0.43
0.51
0.32
O
N
Cl
Boc
H
N
27
Cl
CF3
H
H
H
H
H
H
Cl
N
N
O
Cl
N
R
O
H
H
H
H
28-33
Scheme 3. Reagents and conditions: (a) morpholine, p-TSAꢀH2O (1–3%), benzene,
80 °C; (b) 4-chloro-3-iodobenzoyl chloride, Et3N, CH2Cl2, 0 °C to rt; (c) H2NNH2,
EtOH (62%, three steps); (d) acrylonitrile, 1% aq NaOH, THF (72%); (e) DIBAL, CH2Cl2,
ꢁ78 °C to rt; (f) morpholine, Na(OAc)3BH, acetic acid, CH2Cl2 (51%, two steps); (g) 4-
Chloro-ethynylbenzene, 10% Pd(PPh3)2Cl2, 10% CuI, Et3N, THF (93%); (h) TFA, CH2Cl2
(92%); (i) RCOCl, pyridine, CH2Cl2 (75–95%), or RCO2H, EDC (polymer-bound),
CH2Cl2 (85%).
a
See Table 1 for details.
Cl
N
N
O
N
(31–32) hydrogen-bond acceptors failed to significantly enhance
CatS inhibition relative to sulfonamide 18, the introduction of an
oxamide moiety 33 provided a fivefold improvement in enzymatic
activity (IC50 = 40 nM, Table 3). Despite the modest enzymatic
activity observed for many of these sulfonamide replacements,
X-ray analysis of compound 32 bound to Cys25Ser CatS revealed
Cl
N
SO2CH3
18
hCatS = 200 nM; mCatS = 690 nM; hCatB, hCatF, hCatL > 20 µM
Rat PK (male Sprague-Dawley, n = 3):
the presence of two hydrogen bonds between the a-hydroxyamide
and the targeted S4 residues (PDB ID: 3IEJ, Fig. 3).7 Furthermore,
the crystal structure confirmed that the 4-chlorophenylalkyne
group in 32 resides in the S1 pocket, thus validating the molecular
modeling predictions that inspired our design strategy.
po, (10 mpk): Cmax = 0.53 µM; AUC = 48 µmol*h/L
iv, (2 mpk): t1/2 = 2h; Cl = 0.18 L/h; %F = 21
Figure 2. Profile of alkyne 18.
In conclusion, a crystal structure of 1 bound to a Cys25Ser mu-
tant of cathepsin S helped to elucidate the binding mode of a pre-
viously disclosed series of pyrazole-based CatS inhibitors and
facilitated the design of a new class of arylalkyne analogs. Optimi-
zation of the alkyne and tetrahydropyridine portions of the phar-
macophore provided potent CatS inhibitors (IC50 = 40–300 nM),
for CatS over the closely related cathepsins B, F, and L (>100-fold),
and also reached systemic circulation following oral dosing in rats
(%F = 21). However, despite their encouraging enzymatic potency,
all of the alkynes shown in Table 2 failed to demonstrate any activ-
ity in a secondary cellular assay measuring Ii degradation in hu-
man JY cells (data not shown).
Table 3
In order to further optimize the enzymatic activity of the alkyne
series, sulfonamide replacements on the tetrahydropyridine nitro-
gen were investigated (Scheme 3). The N-Boc tetrahydropyridine
26 could be prepared in an identical manner to the N-methanesulfo-
nyl analog described earlier. Due to the poor stability of the Boc
group under the acidic conditions used for the acetal hydrolysis,
an alternate route to the P5 morpholine linker was developed. Con-
jugate addition of pyrazole 26 to acrylonitrile and subsequent nitrile
reduction afforded an aldehyde, which was immediately subjected
to a reductive amination with morpholine to yield iodide 27. Intro-
duction of 4-chloro-ethynylbenzene under Sonogashira conditions,
followed by removal of the Boc group, provided the free tetrahydro-
pyridine, which was acylated with commercially available carbox-
ylic acids or acid chlorides to generate the targeted alkynes 28–33.
Based on the crystal structure of 1 bound to CatS, it was antic-
ipated that the incorporation of a P4 group with two hydrogen-
bond acceptors would improve potency by interacting with both
Asn161 and Val162. Although heterocyclic (28–30) and acyclic
Effect of N-substitution on cathepsin S activitya
Cl
N
N
N
O
Cl
N
R
O
Compound
R
CatS IC50 (lM)
28
29
30
31
32
33
2-Pyridyl
2-Furanyl
( )-2-Tetrahydrofuranyl
CH2OAc
CH2OH
C(O)OCH3
0.14
0.33
0.31
0.28
0.22
0.04
a
See Table 1 for details.

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Figure 3. Crystal structure of 32 bound to a Cys25Ser mutant of CatS.
5. For examples of non-covalent cathepsin S inhibitors, see: (a) Chatterjee, A. K.;
Liu, H.; Tully, D. C.; Guo, J.; Epple, R.; Russo, R.; Williams, J.; Roberts, M.;
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B. T.; Tumanut, C.; Li, J.; Spraggon, G.; Hornsby, M.; Chang, J.; Tuntland, T.;
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4799.
7. The serine mutant of cathepsin S demonstrated improved stability over the
parent cysteine protease under the conditions used for crystallography. See:
Turkenberg, J. P.; Lamers, M. B. A. C.; Brzozowski, A. M.; Wright, L. M.;
Hubbard, R. E.; Sturt, S. L.; Williams, D. H. Acta Crystallogr., Sect. D 2002,
D58, 451.
and an X-ray structure of 32 confirmed that the arylalkyne moiety
binds in the S1 pocket of the enzyme.
Acknowledgment
The authors thank deCODE biostructures, Inc. for obtaining the
crystal structure of compound 32.
References and notes
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8. The crystal structure of compound 1 could not be uploaded into the PDB because
structure factors were not provided by Sunesis Pharmaceuticals, presumably
because they were note required for submission into the PDB at the time this
structure was solved (2003).
9. The electron density for the methyl group in oxamide
1 could not be
observed, so it is not clear which oxygen of the oxamide forms a H-bond
with Asn161.