title: Evaluation and optimization of antifibrotic activity of cinnamoyl anthranilates.
abstract: 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-beta-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.
authors.affiliation: School of Chemistry, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Zammit
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Cox
authors.forename: Renae M
authors.initials: RM
authors.lastname: Gow
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gilbert
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Williams
mesh_terms: D000818:Animals; D002109:Caffeic Acids / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D002934:Cinnamates / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D003094:Collagen / Q000037:antagonists & inhibitors; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000473:pathology*; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D062367:ortho-Aminobenzoates / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C546971:3-methoxy-4-propargyloxycinnamoyl anthranilate; D002109:Caffeic Acids; D002934:Cinnamates; D062367:ortho-Aminobenzoates; D003094:Collagen; C012293:tranilast