title: 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.
authors.affiliation: School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: sjwill@unimelb.edu.au.
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Williams
authors.forename: Steven C
authors.initials: SC
authors.lastname: Zammit
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Cox
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.forename: Julia
authors.initials: J
authors.lastname: Morizzi
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Powell
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
mesh_terms: D000284:Administration, Oral; D000419:Albuminuria / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000933:Antifibrinolytic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002109:Caffeic Acids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000150:complications / Q000378:metabolism; D004195:Disease Models, Animal; D006207:Half-Life; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C000589842:3',4'-bis(difluoromethoxycinnamoylanthranilate); D000933:Antifibrinolytic Agents; D002109:Caffeic Acids; D062367:ortho-Aminobenzoates; D003094:Collagen; C012293:tranilast
keywords: Chronic kidney disease; Fluorination; Juvenile diabetes; T1D