Discovery and structure-activity relationships of 6-(benzoylamino) benzoxaboroles as orally active anti-inflammatory agents

Article abstract of DOI:10.1016/j.bmcl.2013.08.096

Structure-activity relationships of 6-(benzoylamino)benzoxaborole analogs were investigated for the inhibition of TNF-α, IL-1β, and IL-6 from lipopolysaccharide stimulated peripheral blood mononuclear cells. Compound 1q showed potent activity against all three cytokines with IC₅₀ values between 0.19 and 0.50 μM, inhibited LPS-induced TNF-α and IL-6 elevation in mice and improved collagen-induced arthritis in mice. Compound 1q (AN4161) is considered to be a promising lead for novel anti-inflammatory agent with an excellent pharmacokinetic profile.

Full text of DOI:10.1016/j.bmcl.2013.08.096

Bioorganic & Medicinal Chemistry Letters 23 (2013) 5870–5873
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and structure–activity relationships of
6-(benzoylamino)benzoxaboroles as orally active
anti-inflammatory agents
a
a
a
b
Tsutomu Akama a, , Chen Dong , Charlotte Virtucio , Yvonne R. Freund , Daitao Chen ,
Matthew D. Orr b, Robert T. Jacobs a,b, Yong-Kang Zhang a, Vincent Hernandez a, Yang Liu a,
Anne Wu a, Wei Bu a, Liang Liu a, Kurt Jarnagin a, Jacob J. Plattner a
⇑
a Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA
b SCYNEXIS Inc., 3501 C Tricenter Boulevard, Durham, NC 27713, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Structure–activity relationships of 6-(benzoylamino)benzoxaborole analogs were investigated for the
Received 27 June 2013
Revised 21 August 2013
Accepted 26 August 2013
Available online 6 September 2013
inhibition of TNF-
cells. Compound 1q showed potent activity against all three cytokines with IC50 values between 0.19
and 0.50 M, inhibited LPS-induced TNF- and IL-6 elevation in mice and improved collagen-induced
arthritis in mice. Compound 1q (AN4161) is considered to be a promising lead for novel anti-
inflammatory agent with an excellent pharmacokinetic profile.
Ó 2013 Elsevier Ltd. All rights reserved.
a, IL-1b, and IL-6 from lipopolysaccharide stimulated peripheral blood mononuclear
l
a
Keywords:
Benzoxaborole
Structure–activity relationships
Anti-inflammatory
Cytokine
Tumor necrosis factor-alpha
Interleukin-1beta
Interleukin-6
Pharmacokinetics
Collagen-induced arthritis
The clinical success of various biologic therapeutics has demon-
strated that several cytokines are important therapeutic targets for
chronic inflammatory diseases. Therapeutics targeting tumor
We have focused our efforts on discovery of new therapeutic
agents by inclusion of boron into small molecule scaffolds. Using
the benzoxaborole and related scaffolds as novel drug pharmaco-
phores, we have discovered a number of novel anti-infective and
anti-inflammatory agents.4 As part of this research, we have cre-
ated a library of boron-containing compounds which has proven
to be productive in both biochemical and phenotypic assays. In
the course of our research to identify novel anti-inflammatory
agents, we sought inhibitors of the release of three pro-inflamma-
tory cytokines (TNF-a, IL-1b, and IL-6) from lipopolysaccharide
(LPS) stimulated peripheral blood mononuclear cells (PBMCs). Dur-
ing this screening campaign, we discovered compound 1a (Fig. 1),
which showed IC50 values of 2.1–7.2 lM against all three cyto-
kines. Previously we reported another series of benzoxaborole ana-
logs that polar substituents such as aminomethyl and carboxy
groups were essential components for their activity in inhibiting
cytokine release represented by AN3485 (Fig. 1).5 Since compound
1a is an uncharged and relatively hydrophobic molecule without
such polar groups, this scaffold could have a different mechanism
of action, which prompted us to explore the benzamide class. Here
we describe the in vitro SAR of 6-(benzoylamino)benzoxaborole
necrosis factor-a (TNF-a) are used to treat rheumatoid arthritis
(RA), psoriasis, inflammatory bowel disease, for example.1 Biolo-
gics targeting interleukin-1b (IL-1b) are approved for RA or cryop-
yrin-associated periodic syndrome and an interleukin-6 (IL-6)
receptor monoclonal antibody is approved for RA, Crohn’s disease,
and Castleman’s disease.1 Although biologics have been highly
effective and represent an important therapeutic advance, they
have a number of limitations, including administration by injec-
tion, high cost, and poor or partial efficacy in considerable numbers
of individuals.2 Thus there is a need for more convenient, lower
cost and effective medications.3 An orally or topically administered
small molecule which blocks multiple inflammatory cytokines
would meet the needs for ease of administration, lower cost and
potentially increased efficacy.
⇑
Corresponding author. Tel.: +1 650 543 7527; fax: +1 650 543 7660.
E-mail address: takama@anacor.com (T. Akama).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.08.096

T. Akama et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5870–5873
5871
OH
H
N
Cl
OH
OH
H
N
R
B
6
O
B
B
HCl
H2N
O
O
O
O
CF3
O
1a
AN3485
Figure 1. Chemical structures of compound 1a and AN3485.
F
1c
Cl
1d
Me
1e
1b
derivatives against the release of three cytokines, mouse pharma-
cokinetics, and in vivo activity of a selected compound (1q) against
the LPS-induced production of TNF-
induced arthritis model in mice.
a and IL-6 and collagen-
F3C
OCF3
1g
Ph
1h
OMe
The syntheses of 6-(benzoylamino)benzoxaborole analogs 1
and related analogs (3–5) are shown in Scheme 1. Reaction of 6-
aminobenzoxaborole (2)6 with benzoyl chlorides afforded the
benzamide products (1a–u)7 shown in Figure 2.8 Sulfonamide 3
and urea 48 were synthesized by treating 2 with sulfonyl chloride
and isocyanate, respectively. Benzylamine analog 5 was obtained
by alkylation of 2 with 2-trifluoromethylbenzyl bromide.
1i
F
1f
F
F
F3C
CF3
1L
CF3
1k
1j
CF3
1m
The compounds were tested for the inhibitory activity against
the release of the three cytokines, TNF-a, IL-1b, and IL-6 as summa-
CF3
Cl
F3C
F
rized in Table 1.5 The unsubstituted benzamide analog (1b) was
not active. Among the 20-monosubstituted derivatives (1a–h), the
trifluoromethyl analog (1a) was the only compound that showed
significant inhibition against three cytokines. Relocation of the tri-
fluoromethyl group of 1a to the 30- or 40-positions resulted in loss
of activity. Addition of fluoro group to the 60- (1k) enhanced the
potency against all three cytokines 6 to 12-fold, while the potency
was slightly diminished by the addition of either 40-fluoro (1L) or
50-fluoro (1m) substitution. Having a fluoro group at the 20-posi-
tion and a trifluoromethyl group at either 30- (1n), 40- (1o), or
50-position (1p) resulted in loss of activity. Addition of 50-chloro
decoration to 1k to afford the trisubstituted analog 1q provided
further improvement in potency compared to 1k and showed
F3C
F3C
F
F
F
CF3
1n
1o
1p
1q
CF3
Cl
F
F
CF3
Cl
CF3
1t
1r
1u
1s
Figure 2. Chemical structures of 6-(benzoylamino)benzoxaboroles 1b–u.
0.19–0.50 lM IC50 values against all three cytokines. Bis(trifluoro-
methyl) analogs (1r and 1s) showed similar levels of activity to 1a.
The 30-chloro-20-fluoro analog (1t) showed no activity, while the
Table 1
In vitro IC50 results of compounds against three cytokinesa
Compound
IC50
TNF-
(
a
l
M)
IC50
IL-1b
(
lM)
IC50
IL-6
(lM)
OH
H
N
R
B
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1L
1m
1n
1o
1p
7.2
2.1
>100
>10
4.4
>100
>10
O
>100
>100
>100
>100
36
>100
>100
>10
>100
1.2
13
28
99
>100
>100
0.50
10
O
1a-u
>100
>100
>100
>100
>100
>10
>100
0.18
3.2
>100
>100
>100
>100
>100
>10
>100
0.37
5.6
a
CF3
OH
H
N
B
b
c
S
O
OH
O
O
6
H2N
B
O
3
CF3
OH
H
N
H
2
11
8.2
N
B
>100
>100
>100
0.19
5.3
>100
>100
>100
0.32
8.3
O
d
O
4
1q
1r
1s
1t
1u
3
4
5
6.3
>100
15
>10
>10
>10
0.0070
0.017
1.0
2.0
>100
3.1
>10
>10
>10
4.4
0.0095
0.34
3.0
>100
4.9
>10
>10
CF3
OH
H
N
B
O
5
>10
Clobetasol
Dexamethasone
SB-203580
4.2
43%b
>10
Scheme 1. Synthesis of compounds 1a–u, 2–5. Reagents and conditions: (a)
corresponding benzoyl chloride, Et3N, DCM, 0 °C to rt (34%–95%); (b) 2-trif-
luoromethylbenzenesulfonyl chloride, pyridine, MeCN, rt (74%); (c) 2-trif-
luoromethylphenylisocyanate, MeCN, rt (58%); (d) 2-trifluoromethylbenzyl
bromide, NaHCO3, MeCN, rt (25%).
a
IC50 values are calculated from means of at least two experiments.
Inhibition% at 10 lM.
b

5872
T. Akama et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5870–5873
20-chloro-60-fluoro analog (1u) was similar in potency to 1a. In or-
der to investigate linkages other than amide, the sulfonamide (3),
urea (4), and benzylamino (5) analogs were synthesized and tested.
These three analogs lost activity compared to the corresponding
amide (1a). By comparison a corticosteroid, Clobetasol, showed
100
80
60
40
20
0
TNF-α
IL-6
very potent activity against TNF-
against IL-1b (4.4 M) and IL-6 (4.2
methasone, showed IC50 values of 17 and 9.5 nM against TNF-
and IL-1b, respectively, while it showed only 43% inhibition against
IL-6 at 10 M. A p38 MAP kinase inhibitor, SB-203580, was active
against TNF- and IL-1b with IC50 values of 1.0 and 0.34 M,
respectively, but not active against IL-6 (>10 M). Thus the most
a
(7.0 nM), but moderate activity
l
lM). Another steroid, dexa-
a
l
-20
-40
3
10
30
100
a
l
l
1q (mg/kg)
potent compound, 1q, showed an interesting breadth of activity
as compared to these anti-inflammatory agents.
Figure 3. Inhibition of LPS-induced TNF-a and IL-6 by compound 1q in mice.
Mouse pharmacokinetics were examined for the most potent
compound 1q.5 As shown in Table 2, compound 1q showed very
low clearance (41 mL/h/kg), low volume of distribution (410 mL/
kg), long terminal half life (7.85 h) after intravenous administra-
tion. Following oral administration at 4 mg/kg, 1q exhibited high
AUC (70.1 h mg/mL), long terminal half life (13.3 h), and excellent
bioavailability (71%).
15
vehicle
prednisolone, PO, QD, 3 mg/kg
1q, PO, Q2D, 30 mg/kg
10
5
Compound 1q was tested for the inhibition of LPS-induced TNF-
***
***
and IL-6 production in mice.9 Oral administration of 1q inhibited
***
***
a
***
***
the production of TNF-
manner as shown in Figure 3. Inhibition of TNF-
10 mg/kg and 80% at 30 mg/kg against TNF- , and Inhibition of
a
and IL-6 production in a dose dependent
**
*
a
was 60% at
a
IL-6 was 75% at 10 mg/kg and 95% at 30 mg/kg. The inhibitory
activity reached a plateau at 30 mg/kg and no further change
was observed when mice were treated with 100 mg/kg.
0
0
3
6
9
12
15
18
21
Day of drug administration
Compound 1q was also tested in a collagen-induced arthritis
model in mice in order to examine the ability of 1q to suppress
progression of chronic inflammatory disease.10 Clinical severity of
arthritis (arthritis index) in each paw was quantified based on a
scale of 0–4 (total maximum 16).11 When a total arthritis score
of a mouse reached 3.2, mice were randomly assigned to different
groups with 10 mice in each group (mice with score <2 or >6 were
excluded). Based on the low clearance and long half life, 1q was
dosed every other day, while positive control, prednisolone, was
given daily (3 mg/kg, PO). As shown in Figure 4, orally adminis-
tered 1q (30 mg/kg, Q2D for 20 days) significantly suppressed the
rate of disease progression. The average arthritis score of the vehi-
cle treated group increased 9.3, whereas 1q-treated group only in-
creased 3.0 during the 20 day period, which translated to 68%
inhibition of the disease development on day 20. Prednisolone
completely suppressed the disease progression throughout the
experiment. There were no significant differences in the body
weight between untreated control mice and either 1q or predniso-
lone treated groups.
Figure 4. Inhibition of collagen-induced arthritis by compound 1q and predniso-
lone in mice (N = 10 for each group, QD: once a day dosing; Q2D: every other day
dosing) ⁄p 0.05, ⁄⁄p 0.005,⁄⁄⁄p 0.001.
atropisomeric effect around the amide bond. A specific range of
the torsion angle between two aromatic rings due to the substitu-
ents at the 20-position seems to be important for the activity, since
compounds with a small group (such as proton) and a large one
(such as phenyl) were not active. Three analogs (3–5) with other
linkers than amide lost activity compared to the corresponding
amide (1a), suggesting the importance of the particular amide
linkage. The IC50 value of compound 1q against the growth of
LPS-stimulated PBMCs was >100 lM (by MTT assay), indicating
the activity against cytokine release was not due to cell growth
inhibition. Compound 1q affects T cell viability under certain con-
ditions;12 however, it does not explain the activity against the
cytokine release from LPS-stimulated PBMCs. The broad spectrum
profile was distinct from three reference compounds, clobetasol,
dexamethasone, and SB-203580, suggesting that the mechanism
of action of 1q is different from those of the reference compounds.
The possibility that 1q might act as an inhibitor of a kinase in TLR
pathways was addressed by screening of 1q in an in vitro kinase
assay panel. The activities of 39 kinases involved in TLR signaling
and inflammation pathways13 were tested. When tested at
Compound 1q showed sub-micro molar IC50 values against the
release of three cytokines from LPS-stimulated PBMCs. Compounds
showing potent activity possess a moderately bulky group, such as
trifluoromethyl and Cl, at the 20-position, indicating an
Table 2
In vivo mouse pharmacokinetics parameters of 1q
30
TAK1, TBK1, MAP3K8, MEK1/2, MKK4/6, p38
3/5, ERK1/2, IKK /b/ , AKT1/2/3, PI3 K /b/ /d, JNK1/2/3, JAK1/2/
3, PKCb, ROCK1/2 and PKA. Compound 1q did show 62% inhibition
of PKC at 30 M; however, an IC50 near 30 M would not account
l
M, 1q had no effect on the kinase activities of IRAK1/4,
IV (2 mg/kg) (n = 3)
a
/b/ /d, MAPKAPK2/
c
CL (mL/h/kg)
Vss (mL/kg)
AUC0-24h (h lg/mL)
41
a
e
a
c
410
43.4
7.85
a
l
l
Terminal t1/2 (h)
for the 200–500 nM in vitro activity or the in vivo efficacy ob-
served. Therefore, it is unlikely that 1q acts as a kinase inhibitor
PO (4 mg/kg) (n = 3)
Cmax (
lg/mL)
5.65
4.00
70.1
13.3
71
Tmax (h)
AUC0-24 h (h lg/mL)
Terminal t1/2 (h)
Bioavailability (%)
to mitigate TLR-mediated TNF-
pound 1q did not inhibit cyclooxygenases (COXs) 1 and 2 up to
25 M (data not shown), indicating that COXs are not the primary
target.
a, IL-1b and IL-6 production. Com-
l

T. Akama et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5870–5873
5873
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L.; Ji, J.; Kazmierski, W. M.; Tallant, M. D.; Wright, L. L.; Smith, G. K.; Crosby, R.
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Bioorg. Med. Chem. Lett. 2012, 22, 1299.
This class of compounds, the benzoxaborole-6-benzamides, is
also known to show antiprotozoal activity, especially against
Trypanosoma species such as Trypanosoma brucei (T. brucei) with
an unknown mechanism of action.8,14 The SAR for the inhibition
of cytokine release described here is different from the antiproto-
zoal activity reported for compounds 1a–d and 1L.8 Consequently,
the mechanisms of action are likely to be different between
cytokine release inhibition and antiprotozoal activity.
5. Akama, T.; Virtucio, C.; Dong, C.; Kimura, R.; Freund, Y.; Zhang, Y.-K.; Nieman,
J.; Sharma, R.; Lu, X.; Sales, M.; Singh, R.; Wu, A.; Fan, X.-Q.; Liu, L.; Jarnagin, K.;
Plattner, J. J. Bioorg. Med. Chem. Lett. 2013, 23, 1680.
6. Lennarz, W. J.; Snyder, H. R. J. Am. Chem. Soc. 1960, 82, 2172.
7. Synthesis of 3-chloro-2-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-
Compound 1q showed low clearance and excellent bioavailabil-
ity after oral dosing. Orally administered 1q inhibited LPS-stimu-
lated up-regulation of TNF-
a and IL-6 levels at a dose of 10 mg/
yl)-6-(trifluoromethyl)benzamide (1q):
A solution of 3-chloro-2-fluoro-6-
kg or higher. Compound 1q also significantly inhibited the increase
of the arthritis score in collagen-induced mouse arthritis model for
at least 20 days by oral dosing every other day. Although the mech-
anism of action of compound 1q is unclear, it is possible that the
oxaborole part is interacting with the biological target molecule
through a covalent type binding. Nevertheless, it does not neces-
sarily imply potential toxicity concerns.15 Reversibility of the inter-
actions between oxaboroles and biological targets has been shown
in several cases.16
Compound 1q (AN4161) is considered to be a promising lead for
development of a novel anti-inflammatory agent. Further struc-
tural optimization and studies on its mechanism of action and
in vivo efficacy are in progress.
trifluoromethyl-benzoic acid (25.0 g, 103 mmol) in thionyl chloride (100 mL)
was refluxed for 2 h to give a homogenous solution. After evaporating the
excess of thionyl chloride and drying the residue in vacuo, the crude acid
chloride was dissolved in DCM (250 mL). To the solution was added a solution
of 2 (15.2 g, 103 mmol) and triethylamine (43 mL, 309 mmol) in DCM dropwise
at 0 °C. The reaction mixture was stirred at room temperature overnight. The
reaction mixture was concentrated and diluted with ethyl acetate, and washed
with aqueous 1 M HCl, brine and concentrated. The resulting solution was
filtered and concentrated to give the desired product as a pale yellow solid
(26.8 g, 70.5%). ESI-MS (m/z): 374 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 4.96
(s, 2H), 7.4 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H),
7.97 (m, 1H), 8.1 (s, 1H), 9.3 (s, 1H), 10.9 (s, 1H); HPLC: 98.5% (254 nm).
8. Jacobs, R.; Plattner, J. J.; Nare, B.; Wring, S. A.; Chen, D.; Freund, Y.; Gaukel, E. G.;
Orr, M. D.; Perales, J. B.; Jenks, M.; Noe, R. A.; Sliger, J. M.; Zhang, Y.-K.; Cyrus, J.;
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We, A.; Bu, W.; Liu, L.; Feng, L.; Jarnagin, K.; Freund, Y. J. Pharm. Exp. Ther. 2013,
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A.; Liu, L.; Jarnagin, K.; Freund, Y. Society for Investigative Dermatology Annual
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