Evaluation and optimization of antifibrotic activity of cinnamoyl anthranilates

A panel of cinnamoyl anthranilates were investigated for their antifibrotic activity through their ability to reduce collagen formation stimulated by the cytokine transforming growth factor-β. The most active compound was shown to reduce albuminuria in a hypertensive rat model of progressive type II diabetes. Tranilast is an anti-inflammatory drug in use for asthma and atopic dermatitis. In studies over the last decade it has been revealed that tranilast can reduce fibrosis occurring in the kidney during diabetes, thereby delaying and/or preventing kidney dysfunction. We report a structure–activity study aimed at optimizing the antifibrotic activity of tranilast. A series of cinnamoyl anthranilates were prepared and assessed for their ability to prevent TGF-β-stimulated production of collagen in cultured renal mesangial cells. We reveal derivatives with improved potency and reduced cellular toxicity relative to tranilast. 3-Methoxy-4-propargyloxycinnamoyl anthranilate reduces albuminuria in a rat model of progressive diabetes, and thus has potential as an innovative treatment for diabetic nephropathy.