3a2,4a2-Bis-difluoromethoxycinnamoylanthranilate (FT061): An orally-active antifibrotic agent that reduces albuminuria in a rat model of progressive diabetic nephropathy

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...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-12, Vol.23 (24), p.6868-6873
Main Authors: Williams, Spencer, Zammit, Steven, Cox, Alison, Shackleford, David, Morizzi, Julia, Zhang, Yuan, Powell, Andrew, Gilbert, Richard, Krum, Henry, Kelly, Darren
Format: Article
Language:English
Subjects:
Catechol
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Summary: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-I2-stimulated production of collagen in cultured renal mesangial cells (approx 50% at 3 mu M). When dosed orally at 20 mg/kg to male Sprague Dawley rats, FT061 exhibited a high bioavailability (73%), Cmax of 200 mu M and Tmax 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.
ISSN:0960-894X
DOI:10.1016/j.bmcl.2013.09.100