3′,4′-Bis-difluoromethoxycinnamoylanthranilate (FT061): An orally-active antifibrotic agent that reduces albuminuria in a rat model of progressive diabetic nephropathy

Article abstract of DOI:10.1016/j.bmcl.2013.09.100

Cinnamoylanthranilates including tranilast have been identified as promising antifibrotics that can reduce fibrosis occurring in the kidney during diabetes, thereby delaying and/or preventing kidney dysfunction. Structure-activity relationships aimed at improving potency and metabolic stability have led to the discovery of FT061. This compound, which bears a bis-difluoromethoxy catechol, attenuates TGF-β-stimulated production of collagen in cultured renal mesangial cells (approx 50% at 3 μM). When dosed orally at 20 mg/kg to male Sprague Dawley rats, FT061 exhibited a high bioavailability (73%), C_max of 200 μM and T_max of 150 min, and a half-life of 5.4 h. FT061 reduced albuminuria when orally dosed in rats at 200 mg kg/day in a late intervention study of a rat model of progressive diabetic nephropathy.

Full text of DOI:10.1016/j.bmcl.2013.09.100

Bioorganic & Medicinal Chemistry Letters 23 (2013) 6868–6873
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
30,40-Bis-difluoromethoxycinnamoylanthranilate (FT061): An
orally-active antifibrotic agent that reduces albuminuria in a rat
model of progressive diabetic nephropathy
a
b
c
c
Spencer J. Williams a, , Steven C. Zammit , Alison J. Cox , David M. Shackleford , Julia Morizzi ,
⇑
Yuan Zhang b, Andrew K. Powell c, Richard E. Gilbert d, Henry Krum e, Darren J. Kelly b,
⇑
a School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia
b Department of Medicine, University of Melbourne, St. Vincent’s Hospital, Fitzroy, VIC 3065, Australia
c Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia
d Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada
e Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Cinnamoylanthranilates including tranilast have been identified as promising antifibrotics that can
reduce fibrosis occurring in the kidney during diabetes, thereby delaying and/or preventing kidney dys-
function. Structure–activity relationships aimed at improving potency and metabolic stability have led to
the discovery of FT061. This compound, which bears a bis-difluoromethoxy catechol, attenuates TGF-b-
Received 5 August 2013
Accepted 30 September 2013
Available online 8 October 2013
stimulated production of collagen in cultured renal mesangial cells (approx 50% at 3
orally at 20 mg/kg to male Sprague Dawley rats, FT061 exhibited a high bioavailability (73%), Cmax of
200 M and Tmax of 150 min, and a half-life of 5.4 h. FT061 reduced albuminuria when orally dosed in rats
lM). When dosed
Keywords:
Chronic kidney disease
T1D
Juvenile diabetes
Fluorination
l
at 200 mg kg/day in a late intervention study of a rat model of progressive diabetic nephropathy.
Ó 2013 Elsevier Ltd. All rights reserved.
Diabetic nephropathy (DN) develops in approximately 30% of
subjects with type 1 diabetes. Control of hypertension, blood sugar
levels, and albuminuria through the use of ACE inhibitors are key
strategies in attenuating the progressive decline in renal function
in patients with DN.1 While tight glycaemic and blood pressure
control are important in delaying the progression of nephropathy
there is a need to treat the underling fibrosis that leads to end or-
gan failure.2 Pro-fibrotic growth factors including platelet-derived
growth factor (PDGF), connective tissue growth factor (CTGF), and
transforming growth factor b (TGF-b) have been identified as cyto-
kines that stimulate the deposition of collagen in the kidney.3–5
It has been estimated that some 45% of all deaths in the devel-
oped world may have an underlying pathology of aberrant fibro-
sis.6 However, this mode of action has only recently been
targeted explicitly in the clinic, with the approval of perfenidone
for idiopathic pulmonary fibrosis.7 Tranilast (1), a cinnamoylanth-
ranilate, has been used in Japan and South Korea for over 20 years
to treat allergic disorders, hypertrophic scars and scleroderma
(Fig. 1A). Tranilast inhibits pro-fibrotic growth factors including
TGF-b,8,9 PDGF,9 and CTGF,10 and thus is an antifibrotic agent.
Structure–activity relationships of cinnamoylanthranilates have
led to the development of several analogs including FT011 (2)
and FT023 (3).11 FT011 prevents collagen synthesis in TGF-b and
PDGF-BB stimulated mesangial cells in vitro.12 In an advanced
model of DN, the streptozotocin-diabetic Ren-2 rat, FT011 reduced
albuminuria, glomerulosclerosis and tubulointerstitial fibrosis.12
Reflecting the ability of FT011 to inhibit the action of locally-active
growth factors involved in fibrosis, FT011 also attenuates cardiac
remodeling and dysfunction in experimental diabetic cardiomyop-
athy.13 The related compound FT023 significantly attenuated the
increased heart weight:bodyweight ratio in diabetic Ren-2 rats,
and attenuated diastolic dysfunction.14 Further, FT011 treatment
attenuates Armanni–Ebstein lesions (a key morphological feature
of DN) in a rat model of diabetes.15 Recently, FT011 has entered
into clinical development for the treatment of DN.
The PRESTO (prevention of restenosis with tranilast and its out-
comes) study sought to use tranilast to prevent adverse clinical
events including re-stenosis for patients undergoing stent-based
and stent-free coronary revascularization.16 At the highest doses
of tranilast, a range of reversible abnormalities were identified
including hyperbilirubinemia, increased alanine aminotransferase
(ALT)/serum glutamic pyruvic transaminase (SGPT), decline in
hemoglobin, and increased serum creatinine.17 The molecular
bases of these issues are incompletely understood; however, it ap-
pears that hyperbilirubinemia is especially prevalent within
patients with Gilbert’s syndrome, in which carriers express lower
⇑
Corresponding authors.
E-mail addresses: sjwill@unimelb.edu.au (S.J. Williams), dkelly@medstv.unimelb.
edu.au (D.J. Kelly).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.09.100

S. J. Williams et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6868–6873
6869
A
B
R
O
O
O
MeO
MeO
N
H
N
H
CO2H
CO2H
MeO
1
tranilast
2
R = H, FT011
3 R = CH3, FT023
O
UGT1A1
MeO
MeO
N
1
H
O
O
OH
tranilast glucuronide
O
OH
OH
HO2C
O
CYP2C9
O
MeO
HO
N
H
UGT1A1
MeO
HO
N
H
O
O
CO2H
OH
N-3 glucuronide
O
4 N-3
OH
OH
HO2C
Figure 1. (A) Tranilast and analogs; (B) major metabolic pathways of tranilast in humans.
than normal levels of UGT1A1.18,19 Tranilast undergoes Phase I
metabolism to the demethylated derivative N-3 (4), and both trani-
last and N-3 undergo phase II glucuronidation catalyzed by
UGT1A1 (Fig. 1B).20 Consequently, tranilast-induced hyperbilirubi-
nemia appears to result from inhibition of bilirubin-metabolism by
glucuronosyltransferase UGT1A1 through competition by tranilast
and N-3, with N-3 representing a more effective substrate and thus
a more effective UGT1A1 inhibitor than tranilast.20 The goal of this
work was to identify derivatives of tranilast modified to increase
potency and prevent the formation of the hyperbilirubinemia-pro-
moting metabolite N-3. Herein we report the realization of these
aims through the development of the antifibrotic agent 10c
(FT061).
Our initial synthetic efforts were directed at modifying the cat-
echol portion of the tranilast structure. Previous work leading to
the development of FT011 and FT023 revealed key structure–activ-
ity relationships, namely that (i) increasing the size of substituents
on the catechol oxygens enhances antifibrotic activity; (ii) conver-
sion of the carboxylic acid to an amide or its removal results in
reduction of antifibrotic activity; and (iii) saturation of the double
bond leads to a complete loss of antifibrotic activity.11 Difluorome-
thoxy and trifluoromethoxy groups have previously been high-
lighted as metabolically-stable replacements for methoxy
groups.21–24 We therefore investigated the effect of the introduc-
tion of fluoroalkyl groups into the tranilast structure, while main-
taining the acid and double bond functionalities.
K2CO3 and methyl chlorodifluoroacetate in DMF,26 or better, sodium
chlorodifluoroacetate and K2CO3 in DMF/H2O,27 affording 12, 13, 17
and 18 (Scheme 1B and C). Propargylation of 13 using propargyl bro-
mide/K2CO3 afforded 14.
Antifibrotic activity was assessed in cultured mesangial cells by
evaluating the ability of each compound to reduce the incorpora-
tion of [3H]-proline into collagen upon TGF-b stimulation.11,12,28
For initial screening purposes, compounds were studied at
concentrations of 10 and 30 lM in triplicate. Chart 1 reveals that
replacement of the 4-methoxy groups of tranilast (1) with a 4-
difluoromethoxy group (10a) resulted in a significant enhance-
ment of activity. Introduction of a 5-methoxy substituent to afford
10b gave an enhancement of activity over 10a. An even greater ef-
fect was seen for replacement of both methoxy groups with difluo-
romethoxy groups (10c, FT061). Joining the two groups as a
difluoromethylene substituent (10d) resulted in a complete loss
of activity. Extension of these results to incorporate a 2-propynyl
substituent, present in FT011,11 gave an even more potent deriva-
tive 10e, indicating that previously established structure–activity
results apply to this series.11 The structure–activity relationships
established in this set of compounds extends to a trifluoromethyl
group (10f). Additional potent antifibrotic agents were identified
through incorporation of 4-tetrafluoroethoxy (10g) or 3-fluoro-4-
trifluoromethoxy (10h) groups, although significant cellular toxic-
ity was observed at higher doses of these two compounds.
Among this series of compounds, FT061 (10c) was highlighted
owing to the expectation of being metabolically inert at both posi-
tions of the catechol, and through possessing limited cellular tox-
icity in the cell based screen. Additional SAR investigations of
FT061 were performed investigating more significant modifica-
tions of the cinnamoylanthranilate core (Scheme 2). 12 was con-
verted to the vinylsulfonate 18 by Horner–Wadsworth–Emmons
extension with (EtO)2POCH2SO3Et, and thence the sulfonamide
Compounds were synthesized by two main routes. Direct amidation
of anthranilic acids 5 and 6 with Meldrum’s acid or 2,2,5-trimethyl-1,3-
dioxane-4,6-dione afforded the carboxyacetamidobenzoic acids 7, 8
and 9. Knoevenagel reaction of 7, 8 or 9 and various benzaldehydes
provided the substituted cinnamoyl anthranilates 10a–h and 19a,b
(Scheme 1A).25 The benzaldehydes were either commercially avail-
able, or were obtained by difluoromethylation of 11, 15 or 16 by

6870
S. J. Williams et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6868–6873
R
A
O
R
R
R1
R2
O
b
a
N
H
HO2C
H2N
N
H
X
CO2H
R1
R2
CHO
CO2H
X
CO2H
R3
10a-h, 19a,b
7
5
R,X = H
8 R,X = Br
R =H, X = CH3
R = H
R3
6 R = Br
9
B
C
HO
CHO
HF2CO
HF2CO
CHO
CHO
HF2CO
HO
CHO
HF2CO
O
CHO
c
c
d
+
HO
11
12
13
14
MeO
HO
CHO
MeO
HF2CO
R
R
15
17
R = H
R = H
16 R = OMe
18 R = OMe
Scheme 1. Synthesis of cinammoylanthranilate derivatives. Reagents and conditions: (a) Meldrum’s acid or 2,2,5-trimethyl-1,3-dioxane-4,6-dione, toluene, reflux, 3 h; (b)
piperidine, toluene, reflux, 30 min; (c) ClF2CO2Me, K2CO3, DMF or ClF2CO2Na, K2CO3, DMF/H2O; (d) propargyl bromide, K2CO3, CH3CN, 16 h.
acetophenone 22, Horner–Emmons-Wadsworth extension gave
23, and finally 19f, by HBTU coupling with anthranilic acid.
Chart 2 reveals that introduction of a substituent on the B ring
(19a), or methyl substitution of the a-(19b) or b-positions (19f) of
O
R1
R2
N
H
CO2H
R3
the double bond, resulted in an enhancement of activity, although
this was offset by increased cellular toxicity. Replacement of the
amide linkage with a sulfonamide linkage and removal of the car-
boxylate (19c) resulted in a complete loss of activity. Conversion of
the carboxylic acid group to an aniline (19d) also yielded an in-
crease in activity. Interestingly, the cyclopropyl derivative 19e also
possessed significant ability to inhibit collagen synthesis.
To better characterize the antifibrotic activity of the most prom-
ising compounds, more detailed inhibition profiles were deter-
mined for FT061 (10c), 10a and 19e at a range of concentrations.
Figure 2 reveals that 10a has only a minor improvement in antifib-
rotic activity relative to tranilast, however both FT061 and 19e
were significantly more active.
The major routes of tranilast metabolism in humans involve
direct glucuronidation, and demethylation of O4 followed by glucu-
ronidation or sulfation.20,29 The susceptibility of FT061 to CYP450-
mediated metabolism was examined in human liver microsomes
in the presence of NADPH. While minimal loss of FT061 over the
60 min incubation was indicative of good metabolic stability, the
presence of a putative+16 product was detected, consistent with
monooxygenation. Metabolite identification of urine and plasma
samples collected during pharmacokinetic studies of FT061 (vide in-
fra) confirmed susceptibility of FT061 to glucuronidation.
The in vivo pharmacokinetic profile of FT061 was compared
with that of tranilast in Sprague Dawley (SD) rats following intra-
venous (IV) and oral administration, and the results are shown in
Tables S1 and S2 (see Supplementary data) and Figure 3. Relative
to tranilast, the IV pharmacokinetics of FT061 were characterized
by a longer half-life, lower plasma clearance and lower volume of
distribution. The differences in plasma clearance and volume of
distribution of the two compounds most likely reflect differences
in the plasma protein binding since the unbound intrinsic clear-
ance and unbound volume of distribution between the two
R1
R2
R3
Compound
number
Inhibition (%)
at 10 µM
at 30 µM
1
(tranilast)
2
OMe
OMe
OMe
H
H
H
15
40
2-propynyl
F2HCO
20-50
55-70
(FT011)
10a
MeO
MeO
20
24
60
70
80
10b
F2HCO MeO
10c
F2HCO
F2HCO
H
100
(FT061)
10d
-OCF2O-
H
H
H
H
H
-
0
10e
2-propynyl F2HCO
73
92
84
55
100
10f
F3CO
MeO
HF2CCF2O
F3CO
100
10g
H
F
damageda
damageda
10h
adamaged = significant proportion of stressed cells beginning to detach.
Chart 1. Inhibitory activities for cinnamoylanthranilates on TGF-b stimulated
production of collagen synthesis in cultured mesangial cells.
19c. Malonate extension of 12 to the cinnamate 20, conversion to
the acid chloride and finally reaction with phenylenediamine
afforded 19d. Cyclopropanation of 20 with CH2N2 and Pd(OAc)2
afforded 21, which was converted to 19e via the acid chloride.
MeMgCl addition to 12 followed by PCC oxidation gave

S. J. Williams et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6868–6873
6871
O
O
HF2CO
HF2CO
S
HF2CO
HF2CO
SO3Et
HF2CO
HF2CO
CHO
a
b
d
N
H
19c
12
18
O
O
HF2CO
HF2CO
HF2CO
HF2CO
c
N
H
OH
NH2
20
19d
e
g
O
O
HF2CO
HF2CO
HF2CO
HF2CO
f
N
H
OH
CO2H
CO2H
19e
21
23
O
O
O
HF2CO
HF2CO
HF2CO
HF2CO
HF2CO
HF2CO
h
i
N
H
OH
19f
22
Scheme 2. Preparation of FT061 analogs. Reagents and conditions: (a) (EtO)2POCH2SO3Et, BuLi, THF, ꢀ78 °C; (b) (i) Bu4NI, acetone, 16 h, (ii) Ph3P, SO2Cl2, 16 h, (iii) aniline,
pyridine, 4 h; (c) malonic acid, piperidine, pyridine, 120 °C, 16 h; (d) (i) (COCl)2, cat. DMF, CH2Cl2, 1 h (ii) 1,2-phenylenediamine, pyridine, CH2Cl2, 16 h; (e) (i) H2SO4, MeOH,
16 h, (ii) CH2N2, Pd(OAc)2, CH2Cl2, (iii) NaOH, MeOH, 16 h; (f) (i) (COCl)2, DMF, CH2Cl2, 2 h, (ii) anthranilic acid, pyridine, 16 h; (g) (i) MeMgCl, THF, 2 h, (ii) PCC, CH2Cl2, 16 h;
(h) (i) (EtO)2POCH2CO2Et, NaH, THF, 16 h, (ii) 1 M aq NaOH, EtOH, 16 h; (i) HBTU, Et3N, CH3CN, 72 h.
Compound
number
Structure
Inhibition (%) at
10 µM
30 µM
Br
O
a
F2HCO
F2HCO
19a
N
H
100
damaged
CO2H
O
F2HCO
a
a
N
H
19b
19f
100
100
damaged
damaged
CH3
CO2H
CO2H
F2HCO
CH3
O
F2HCO
F2HCO
N
H
O
S
O
F2HCO
F2HCO
a
N
19c
0
damaged
H
O
F2HCO
F2HCO
N
H
19d
19e
57
70
79
90
NH2
O
F2HCO
F2HCO
N
H
CO2H
a
Damaged = Significant proportion of stressed cells beginning to detach.
Chart 2. Inhibitory activities for compounds on TGF-b stimulated production of collagen synthesis in cultured mesangial cells.

6872
S. J. Williams et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6868–6873
125
tranilast (1)
FT061 (10c)
125
100
75
50
25
0
100
75
50
25
0
–
+
3µM 10µM
30µM 100µM
–
+
3µM
10µM
30µM
100µM
125
100
75
50
25
0
125
100
75
50
25
0
10a
19e
*
–
+
3µM 10µM
30µM 100µM
–
+
3µM 10µM
30µM 100µM
Figure 2. Dose–response histograms of inhibition of TGF-b stimulated [3H]-proline incorporation in mesangial cells by tranilast (1), FT061 (10c), 10a, and 19e measured at
concentrations of 3, 10, 30 and 100
Error bars indicate standard error.
l
M. Inhibition values were determined in triplicate. (+) and (ꢀ) refer to the absence and presence of stimulation by the cytokine TGF-b.
plasma exposure (AUC) and maximum plasma concentration
(Cmax) following oral administration of FT061 were 4- and 1.7-fold
higher respectively, than the values observed for tranilast.
To assess the renal and liver toxicity of FT061, Sprague–Dawley
rats were treated with FT061 at doses of 50, 100, 200, 400 and
1000 mg/kg/d by gavage twice daily for two weeks. At the end of
the study serum was collected to assess liver and renal function.
Plasma levels of creatinine, urate, ALT and bilirubin from treated
rats were similar to control rats (see Supplementary data).
The ability of FT061 to reduce albuminuria was assessed in a rat
model of DN12 (Fig. 4). Hypertensive (m-Ren2)27 rats were ex-
posed to streptozotocin, a drug that is cytotoxic towards pancreatic
islet cells, to induce diabetes. Eight weeks post-streptozotocin
treatment, animals were treated with 200 mg/kg/d FT061 by oral
gavage for eight weeks. At 16 weeks, a 24 h urine collection was as-
sayed for albuminuria by radioimmunoassay. Untreated rats
Figure 3. Plasma concentrations following administration of tranilast (diamonds)
or FT061 (squares) to male SD rats. (A) Intravenous administration of a 5 mg/kg
solution. (B) Oral administration of 20 mg/kg suspension. Levels of drug were
quantified in blood plasma by LC–MS. For full details see Supplementary data.
Figure 4. FT061 reduces albuminuria in
a late intervention study. Albumin
excretion rate (AER) was measured after 16 weeks of experimental diabetes in a
streptozotocin-treated hypertensive (m-Ren2)27 rat model. Treatment with FT061
commenced 8 weeks after streptozotocin injection, and continued for 8 weeks. Data
are expressed as geometric mean SEM. ⁄p <0.01 when compared to controls, #p
<0.05 when compared to diabetic rat.
compounds are similar (see Supplementary data). Tranilast and
FT061 both exhibited high oral bioavailability; however, the

S. J. Williams et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6868–6873
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developed significant albuminuria that was attenuated by oral
administration of FT061. In contrast, tranilast attenuates albumin-
uria only when administered at higher doses of 400 mg/kg/day.30
In conclusion a structure–activity study undertaken to identify
tranilast derivatives with altered metabolism led to the discovery
of FT061. FT061 is an orally-active and metabolically-stable
antifibrotic agent that attenuates albuminuria in a rat model of
progressive diabetes. FT061 features replacement of the metaboli-
cally labile methyl groups of the catechol of tranilast with
bis-difluoromethoxy groups. This work extends previous struc-
ture–activity relationship studies11 exploring the antifibrotic prop-
erties of tranilast to delineate further structural contributors to the
antifibrotic properties of this class. FT061 is straightforward to syn-
thesize, is a potent antifibrotic agent, appears well-tolerated in
rats, and is resistant to deactivating metabolism and thus deserves
further study as an agent to ameliorate the pathological effects of
fibrosis.
Acknowledgments
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We thank the Australian Research Council and National Health
and Medical Research Council for financial support. R.E.G., H.K.,
S.Z., S.J.W. and D.J.K. declare competing interests as shareholders
in Fibrotech Therapeutics Ltd.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.
09.100.
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