Bioorganic & Medicinal Chemistry Letters
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 ,
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Yuan Zhang b, Andrew K. Powell c, Richard E. Gilbert d, Henry Krum e, Darren J. Kelly b,
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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
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Corresponding authors.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.