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

Abstract

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 20mg/kg to male Sprague Dawley rats, FT061 exhibited a high bioavailability (73%), Cmax of 200 μM and Tmax of 150 min, and a half-life of 5.4h. 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.