6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.06.072

6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile analogues were identified as potent and selective cathepsin S inhibitor against both purified enzyme and in human JY cell based cellular assays. This core has a very stable thio-trapping nitrile war-head in comparison with the well reported pyrimidine-2-carbonitrile cysteine cathepsin inhibitors. Compound 47 is also very potent in in vivo mouse spleenic Lip10 accumulation assays.

Full text of DOI:10.1016/j.bmcl.2010.06.072

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4350–4354
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6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S inhibitors
a
a
a
a
a
Jiaqiang Cai a, , Mark Baugh , Darcey Black , Clive Long , D. Jonathan Bennett , Maureen Dempster ,
Xavier Fradera a, Jonathan Gillespie a, Fiona Andrews a, Sylviane Boucharens a, John Bruin a,
Kenneth S. Cameron a, Iain Cumming a, William Hamilton a, Philip S. Jones a, Allard Kaptein b,
Emma Kinghorn a, Maurice Maidment a, Iain Martin a, Ann Mitchell a, Zoran Rankovic a, John Robinson a,
Paul Scullion a, Joost C. M. Uitdehaag b, Paul Vink b, Paul Westwood a, Mario van Zeeland b,
Leon van Berkom c, Martijn Bastiani c, Tommi Meulemans c
*
a Merck Research Laboratories, MSD, Newhouse, Lanarkshire ML1 5SH, United Kingdom
b Merck Research Laboratories, MSD, 5340BH Oss, The Netherlands
c Mercachem B.V. Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile analogues were identified as potent and selective
cathepsin S inhibitor against both purified enzyme and in human JY cell based cellular assays. This core
has a very stable thio-trapping nitrile war-head in comparison with the well reported pyrimidine-2-car-
bonitrile cysteine cathepsin inhibitors. Compound 47 is also very potent in in vivo mouse spleenic Lip10
accumulation assays.
Received 14 May 2010
Revised 11 June 2010
Accepted 12 June 2010
Available online 17 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cathepsin S
1H-Imidazo[4,5-c]pyridine-4-carbonitrile
Lip10
Eleven members of the cathepsin family cysteine proteases
have been identified in the human genome (cathepsins B, C, H, F,
K, L, O, S, V, W and X).1 Two of these, cathepsins K and S have been
the subject of extensive effort in the pharmaceutical industry.1–3
Cathepsin S is highly expressed in antigen presenting cells and
plays a major role in the degradation of the invariant peptide chain
associated with the major histocompatibility complex and affects
antigen presentation. Selective cathepsin S inhibitors should then
be useful therapeutics for autoimmune disorders, for example,
rheumatoid arthritis (RA) and multiple sclerosis (MS). More re-
cently cathepsin S has also been indicated for neuropathic pain.4
Several cathepsin K inhibitors have progressed into human clinical
trials for osteoporosis5 but as yet there are no reports of any
cathepsin S inhibitors in advanced stages of human clinical trials.
Several different cathepsin S inhibitor chemotypes have been re-
ported in the literature, most of which contain some kind of pep-
tide feature within the molecule and pose some challenges in
terms of pharmacokinetic property optimization.2
These compounds differ from other reported aryl nitrile cys-
teine protease inhibitors where the nitrile war-head is flanked be-
tween two electron-negative aromatic nitrogen atoms and has
relatively high reactivity towards nucleophiles. These 2-phenyl-
9H-purine-6-carbonitrile compounds however still suffer from a
war-head reactivity issue in our glutathione based war-head sta-
bility NMR assay.19 Although the pyridine-2-carbonitrile based
compounds are stable towards nucleophiles, such as glutathione,
we were unable to optimize their cathepsin S inhibitory activity
to better than 10 nM.
In this Letter, we report a novel series of 6-phenyl-1H-[4,5-
c]pyridine-4-carbonitrile based selective cathepsin S inhibitors 3.
These new inhibitors are equivalent to a hybrid between structures
18
1 and 2 and they combined both ‘transition state stabilization’
(Fig. 2a) and ‘in situ double activation’19 ( Fig. 2b) in the same
molecule.
The initial 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile
compounds were synthesized according to Scheme 1. N-Nitration
of the commercially available 4-amino-2,6-dichloropyridine 4 fol-
lowed by a sulfuric acid promoted rearrangement gives compound
5 in high yield. Treatment of compound 5 with copper(I) cyanide in
NMP at 180 °C for 15–20 min selectively displaces the 2-position
chloride to give 4-amino-6-chloro-3-nitropyridine-2-carbonitrile
6 in 80% yield. Suzuki coupling of 6 with boronic acids or esters
gives compound 7. Reduction of the nitro group by means of
Several groups have reported6–17 heteroaryl nitrile based human
cathepsin K and S inhibitors. Recently, we reported 2-phenyl-9H-
purine-6-carbonitrile18 and 6-phenyl-pyridine-2-carbonitrile19 as
selective human cathepsin S inhibitors (Fig. 1).
* Corresponding author. Tel.: +44 1698736133; fax: +44 1698736187.
E-mail address: jiaqiang.cai@merck.com (J. Cai).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.072

J. Cai et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4350–4354
4351
Table 1
CN
CN
N
Cathepsin S and K inhibitory activity
N
N
F3C
N
F3C
O
CN
N
H
N
O
N
N
IC50 (nM)a,b
O
2
1
F3C
N
H
Compd
hCat S IC50: 29nM
hCat K IC50: >10000nM
hCat S IC50: 3.9nM
hCat K IC50: 1072nM
R
R
Cat S
3.9
Cat K
CN
N
N
CN
N
1072
F3C
N
N
N
H
O
F3C
N
H
CN
R
O
N
3
1660
>10,000
F3C
O
Figure 1. 9H-Purine-6-carbonitrile 1, pyridine-2-carbonitrile
cathepsin S inhibitors and their hybrid 1H-imidazo[4,5-c]pyridine-4-carbonitrile 3.
2 based selective
9
10
H
MeO
EtO
1047
339
25
1995
8511
8310
11
12
13
14
15
16
17
HO(CH2)2O
n-PrO
HO(CH2)3O
BenzylO
EtNH
145
200
63
676
105
3236
2818
7762
2691
>10,000
>10,000
>10,000
H+
Cys
Cys S
N
N
S
N
H
N
H
N
F3C
F3C
N
H
N
AcNH
a
b
a
For assay conditions see Ref. 6.
Compounds inactive against human cathepsin B and L.
b
Figure 2. (a) Transition state stabilization through hydrogen bond between
thioimidate NH and N7 purine nitrogen; (b) electrostatic interaction between SH
proton and pyridine ring nitrogen makes nitrile war-head more electrophilic and
cysteine thiol more nucleophilic.
CN
CN
CN
N
N
N
N
N
N
b
N
a
F3C
O
F3C
O
N
F3C
O
N
H
( )n
( )n
Cl
CN
Cl
c
NO2
NH2
NO2
NH2
N
a, b
Br
R
N
N
N
R
11
18
Cl
Cl
Cl
NH2
19: n=1, RRN=mopholine
20: n=1, RRN=Me2N
21: n=2, RRN=morpholine
22: n=2, RRN=Me2N
6
5
4
CN
CN
NH2
NH2
NO2
NH2
N
N
d
e
F3C
R
F3C
Scheme 2. Reagents and conditions. (a) bromoethanol/bromopropanol, betaine,
THF, 4 h; (b) amine, DMF, 120 °C, 5 min.
R
7
8
CN
N
N
f
F3C
sess its nitrile war-head stability with the intention to further im-
prove the activity. Computer aided docking studies suggest that N1
and C2 attachments should be exposed to the solvent and have lit-
tle or no impact on activity. To validate this theory early in the pro-
ject a series of N1- and C2- substituted analogues (data not shown)
of compound 11 were synthesized. The selected N1 substituted
compounds were synthesized according to Scheme 2. Mitsunobu
coupling of 2-bromoethanol or 3-bromopropanol with compound
11 provided intermediates 18 which were then treated with pri-
mary or secondary amines to give the desired products 19–22. It
is worth noting that there are no war-head related side products
detected when intermediate 18 was heated with 10 equiv of pri-
mary or secondary amines at temperature as high as 120 °C in
DMF for 40 min. This indicates that the nitrile group of this 1H-imi-
dazo[4,5-c]pyridine-4-carbonitrile core has good stability towards
nucleophiles.
N
H
R
9-17
Scheme 1. Reagents and conditions. (a) HNO3/H2SO4, 0 °C, 3 h; (b) H2SO4, 100 °C,
1 h; (c) CuCN, NMP, 180 °C, 15–20 min; (d) Pd2(DBA)3, K3PO4, (c-Hex)3P, dioxane–
H2O, 100 °C, 3 h; (e) Pd/C/H2, EtOAc, 1 h; (f) CH(OEt)3, Yt(OTf)3 (cat), MeCN, 90 °C,
30 min.
hydrogenation gives the bisaniline product which is then ring-
closed with triethyl orthoformate catalyzed by ytterbium triflate
to give the desired final products 9–17. Results of this study are
shown in Table 1.
Although 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile
appeared to be less potent than the corresponding purine ana-
logues (compound 11 vs purine compound in Table 1), the imidaz-
ole ring of compound 11 contributed
a
66-fold activity in
The biological results of compounds 19–22 are shown in
Table 2. As expected all compounds exhibited cathepsin S inhibi-
tory activity within half a log unit of compound 11. It is noticeable
however that all these weakly basic compounds are less selective
towards cathepsin K. Unfortunately these compounds had only
modest cellular activity against the degradation of invariant chain
measured by accumulation of cathepsin S substrate Lip10 in the
human JY cells.
In order to improve cellular activity, we then focused on
increasing the interactions with the S2 pocket.19 Compounds with
the expanded P2 motif were synthesized according to Scheme 3
and 4.
comparison with the corresponding pyridine based compound
(11 vs pyridine compound in the Table 1). The reasons for this con-
tribution can be explained by the binding to the S1 pocket, as
shown later by an X-ray structure analysis, as well as an intramo-
lecular H-bonding induced stabilization of the transition state.18
Among the first nine compounds synthesized, the ethoxyl com-
pound 11 appeared to be the most potent. Longer chain (13) or
other non-oxygen based compounds (16, 17) have lower activity.
Having established the 6-phenyl-1H-[4,5-c]pyridine-4-carboni-
trile as a scaffold for selective human cathepsin S inhibition, our
next objective was to synthesize a water soluble compound to as-

4352
J. Cai et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4350–4354
Table 2
CN
CN
N
N
Activity against human cathepsin S and K and cellular activity in human JY cells
a
N
N
N
N
F3C
( )n
F3C
a
Compd
IC50 (ki) (nM)
Lip10b,20 IC50 (nM)
HO
O
O
( )n
Ms
O
Cat S
Cat K
30, 31
40, 41
CN
19
20
21
22
37 (9.1)
32 (13.8)
35
1660 (603)
447 (302)
513
>10,000
854
na
N
N
N
b
F3C
R
N
( )n
O
27 (14.5)
270 (339)
260
R
42-47
a
For assay conditions see Ref. 6.
Measured by western blot using human B lymphoblastoid cells, 500,000/ml,
b
Scheme 4. Reagents and conditions. (a) MsCl, DIPEA, NMP, rt, 1 h; (b) amine, DMF,
120 °C, 10–40 min.
mouse anti-CD74 Pin. One monoclonal antibody, 50% of the maximum activity of
LHVS in the same assay as IC50; na = not available.
Table 3
Activity against human cathepsin S and K and cellular activity in human JY cells
N-Methylation of compound 6 gives compound 23 in high yield.
Reduction of the nitro group with stannous chloride provides the
bisaniline intermediate 24. Compound 25 was obtained in high
yield by heating compound 24 in triethyl orthoformate at 90 °C
for an hour using ytterbium triflate as a catalyst. Independently,
alkylation of the phenol 26 gives the intermediate 27 which was
then converted to boronic ester 28 by applying standard palladium
chemistry. Suzuki coupling between the intermediates 25 and 28
afforded the final compounds 29–36. Compounds 37–39 were syn-
thesized using the above route where the secondary amine was
protected by a Boc group. The Boc protecting group was then final-
ly removed using trifluoroacetic acid in a mixed solvent of DCM
and acetonitrile (v/v 10–30%) in nearly quantitative yield. The
by-product N-t-butyl acetamide is easily removed by washing
the final solid TFA salt product with 1:1 EtOAc: Et2O. The use of
acetonitrile as a co-solvent is essential to stop t-butyl cation re-
lated side reactions by the in situ ‘Ritter’ reaction. Only 25–50%
yield of product can be obtained without acetonitrile as co-solvent
in the cases of compounds 37–39. The use of acetonitrile as a co-
solvent could offer a generic solution for all Boc/t-butyl ester de-
protections where t-butyl cation trapping is necessary to replace
the widely used phenols or thiols. The alcohols 30 and 31 were fur-
ther modified to give compounds 42–47 via the methanesulfonate
intermediates 40 and 41, respectively (Scheme 4). Biological re-
sults from this optimization are shown in Table 3.
CN
N
N
a,b
IC50 (ki) (nM)
F3C
Lip10c,20 (nM)
N
Compd
R
R
Cat S
Cat K
29
30
31
EtO
HO(CH2)2
HO(CH2)3
40
71
24
1259
3162
1071
na
na
na
N
O
32
33
34
20 (3)
12.6
10
2291
853
na
N
N
O
O
>10,000
>10,000
na
35
36
11
2042
2512
267
N
N
O
O
7.8 (1.6)
1420
O
HN
37
38
39
42
43
316
891
na
na
9
O
O
14.1
8.3 (2)
209
240
HN
HN
178
O
N
5888
1175
na
na
O
HN
O
7.8
N
O
N
O
In comparison with compound 11, the N1-methyl derivative 29
is only slightly less active against human cathepsin S. Although
selectivity against cathepsin K is reduced, it was selected as a
new starting point for P2 optimization as this N1-methyl substi-
tuted imidazopyridine is potentially more permeable. As reported
in our previous publication,19 the extended P2 region is very
accommodative for a variety of functional groups, e.g. hydroxyl
44
45
41 (7.7)
28
776
871
84
89
N
O
N
O
46
47
9.5
468
331
106
63
N
N
O
7.2 (2.9)
N
a
b
c
For assay conditions see Ref. 6.
Compounds inactive against human cathepsin B and L.
na = not available; measured by western blot using human B lymphoblastoid
cells, 500,000/ml, mouse anti-CD74 Pin. One monoclonal antibody, 50% of the
maximum activity of LHVS in the same assay as IC50
.
CN
CN
CN
CN
NH2
NH
a
NO2
NH
NO2
NH2
b
N
N
c
N
N
N
d
N
Cl
Cl
Cl
Cl
25
24
6
23
(31), pyridine residues (32–35), amides (36). The basic nitrogen
is also well tolerated in this region as long as a minimum distance
between this basic nitrogen and the imidazopyridine core is main-
tained, for example, compound 39 is more active than compound
37 and 44 better than 42. However, when the pka of the basic nitro-
gen is reduced to lower than assay pH (5.5), such as compound 43
(pka <4), the cathepsin S inhibitory activity is unaffected. Although
compound 44 has very similar cathepsin S inhibitory activity as
compound 20, its cellular activity against Lip10 degradation is in-
creased by 10-fold. An x-ray structure of compound 46 bound to
human cathepsin S was obtained (Fig. 3). The Cys25 thiol formed
a covalent bond with the nitrile war-head with the formation of
a flat thioimidate which is co-planar with the imidazopyridine
ring. The imidazole ring binds to the shallow S1 pocket with the
N3 nitrogen atom well setup for an intramolecular hydrogen bond
+
O
F3C
HO
Br
F3C
Br
e
F3C
B
O
R
R
O
O
26
27
28
f
CN
CN
N
N
N
N
N
g
N
HN
O
F3C
( )n
F3C
+
N
R
O
O
H
29-36
37-39
100%
Scheme 3. Reagents and conditions. (a) MeI, K2CO3, MeCN, reflux, 4 h; (b) SnCl2,
EtOH, 40 min; (c) CH(OEt)3, Yt(OTf)3, 90 °C, 1 h; (d) 3-iodopropanol or 2-bromo-
ethanol, K2CO3, MeCN, reflux, 4 h; (e) PdCl2(DPPF), KOAc, dioxane, 100 °C; (f)
Pd2(DBA)3, K3PO4, (c-Hex)3P, dioxane–H2O, 100 °C, 3 h; (g) TFA–DCM–MeCN, rt,
20 min.

J. Cai et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4350–4354
4353
Table 4
Nitrile war-head reactivity with glutathione measured by 1H NMR in 1:1 D2O–CD3OD
at 20 °C at pD 7.5
Compd
Concentration (mM)
T1/2
Inhibitor
GSH
CN
N
N
N
F3C
O
1.15
1.24
1.25
7.22
<15 min
>100 h
>100 h
N
N
CN
F3C
O
7.06
7.06
N
N
CN
Figure 3. X-ray structure of compound 46 bound to human cathepsin s enzyme,
solved at 2.1 Å resolution (PDB code: 3N4C).
N
N
N
F3C
O
N
N
CN
N
O
F3C
O
N
Table 5
N
Pharmacokinetic parameters (iv 2 mg/kg; po 10 mg/kg, gelatin mannitol) and mouse
cathepsin S inhibitory activity
48
hCat S IC50: 661nM
Compd
Cl (mL/min/kg)
Vss (L/kg)
F (%)
Mouse Cat S (IC50, nM)
hCat K IC50: >10000nM
32
44
47
10
327
28
0.7
58
2.0
54
58
9
2.6
2.6
2.5
Figure 4.
O
Cl
Cl
a
b
CHO
O
O
N
N
N3
N3
2500000
16
14
12
10
8
O
Cl
Cl
49
50
51
Cl
Cl
Cl
2000000
1500000
1000000
500000
0
d, e
c
O
O
N
N
N
N
N
N
O
N
O
Cl
Cl
Cl
H
54
53
52
CN
CN
N
g
f
6
N
O
F3C
O
N
Cl
N
4
48
55
2
Scheme 5. Reagents and conditions. (a) NaOMe, MeOH, rt, 24 h; (b) Mesitylene,
165 °C, 1 h; (c) MeI, DMF, K2CO3, rt, 2 h; (d) LiOH, THF–H2O, rt, 2 h; (e) quinoline, Cu,
185 °C, 3 h; (f) CuCN, Pd(DBA)2, DPPF, dioxane, 100 °C, 3 h; (g) boronic ester (28),
Pd2(DBA)3, K3PO4, (c-Hex)3P, dioxane–H2O, 100 °C, 3 h.
0
Vehicle
0.3 mg/kg 1 mg/kg
3 mg/kg
10 mg/kg
Figure 5. C57Bl/6 (18–25 g) mice were dosed by gavage with vehicle (0.5% gelatin,
5% mannitol in water) or 0.3–30 mg/kg compound 47. Blood and spleen were
collected at 4 h time point after dosing. Spleens were lysed in 1% Triton X-100, the
supernatants collected and measured for protein concentration. Protein/lane
with the newly formed thioimidate NH group. The important CF3
group is buried inside the S2 pocket interacting with methionine
residue. The O-CH2 has hydrophobic interactions with Val162
and the middle CH2 with Phe70. The three CH2 groups attached
to the internal piperazine nitrogen atom are well positioned to
interact with Phe211. The protonated external piperazine nitrogen
may have ionic interactions with the glutamic acid residue Glu115
which is immediately outside the S2 pocket.
The N3 nitrogen of 1H-imidazo[4,5-c]pyridine-4-carbonitrile is
important, although not critical, for its cathepsin S inhibitory activ-
ity. Compounds 48 (Fig. 4) was synthesized (Scheme 5) and it is 85
times less active than the corresponding analogue 36 of Table 3. An
intramolecular hydrogen bond formation in the transition states
probably best explains these results, although nitrile activation
through the electron withdrawing of the N3 nitrogen may also
contribute.
(0.5 lg) of each sample was subjected to SDS–PAGE followed by Western blotting
using 0.5 mg/ml rat anti-mouse CD74 mAb (clone In-1, Fitzgerald Industries); Liplo
level: bar chart; free compound plasma level: line chart.
1H-imidazo[4,5-c]pyridine-4-carbonitrile appears to be very stable
towards glutathione with a half life (T1/2) well over 100 h in
comparison with the corresponding pyrimidine-2-carbonitrile
compound of less than 15 min. 1H-Imidazo[4,5-c]pyridine-4-car-
bonitrile should be chemically stable enough to pursue further.
Selected compounds 32, 44 and 47 were evaluated for
pharmacokinetic properties with male Wistarrats. The PKresults to-
gether with their mouse cathepsin S inhibitory activity are listed in
Table 5. These compounds possess modest to good oral bioavailabil-
ity. The most basic compound, 44, has a plasma clearance (327 mL/
min/kg), much higher than the rat hepatic blood flow and a large dis-
tribution volume (58 L/kg). The high clearance and distribution vol-
ume suggest a rapid tissue distribution after dosing. All compounds
have low nanomolar mouse cathepsin S inhibitory activity and com-
pound 47 has an in vitro Lip10 IC50 of 6.5 nM using splenocytes iso-
lated from mouse spleens (BD Falcon cell strainers).
To further assess the nitrile war-head stability, compound 46
and a few other compounds from the pyrimidine-2-carbonitrile19
and pyridine-carbonitrile19 series were tested in a NMR based sta-
bility assay. The results are shown in Table 4. The nitrile group in

4354
J. Cai et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4350–4354
G.; Nonomura, K.; Tanabe, K.; Fukaya, H.; Kosaka, T.; Snell, C. R.; Hallet, A.
In vivo pharmacodynamic effect of compound 47 was examined
Bioorg. Med. Chem. Lett. 2008, 18, 3959.
by measuring the accumulation of Lip10 in the spleen of C57Bl/6
mice by western blot after oral dosing. After 4 h compound 47
was shown to significantly induce Lip10 accumulation in the
spleen at doses as low as 0.3 mg/kg (Fig. 5). The lower than Lip10
IC50 free compound level in plasma suggests that this compound
might be sequestered in the lysosome. Further analysis showed
that compound level is ꢀ50-fold greater in spleen than in the
plasma.
In summary, 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carboni-
trile core was identified as a good scaffold for cathepsin S inhibition.
This core offers much improved nitrile war-head stability in com-
parison with other arylnitrile based cathepsin S and K inhibitors.
The optimized compounds have good cellular activity in human JY
cells measured by cathepsin S substrate Lip10 accumulation.
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