title: Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.
abstract: Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid aldose reductase inhibitors. The lead candidate, 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat, 9) inhibits aldose reductase with an IC(50) of 5 nM, while being 5400 times less active against aldehyde reductase, a related enzyme involved in the detoxification of reactive aldehydes. It lowers nerve and lens sorbitol levels with ED(50)'s of 1.9 and 4.5 mg/kg/d po, respectively, in the 5-day STZ-induced diabetic rat model. In a 3-month diabetic intervention model (1 month of diabetes followed by 2 months of drug treatment at 5 mg/kg/d po), it normalizes polyols and reduces the motor nerve conduction velocity deficit by 59% relative to diabetic controls. It has a favorable pharmacokinetic profile (F, 82%; t(1/2), 5.6 h; Vd, 0.694 L/kg) with good drug penetration in target tissues (C(max) in sciatic nerve and eye are 2.36 and 1.45 mug equiv/g, respectively, when dosed with [(14)C]lidorestat at 10 mg/kg po).
authors.affiliation: The Institute for Diabetes Discovery, LLC, 23 Business Park Drive, Branford, Connecticut 06405, USA. michael.vanzandt@ ipd-discovery.com
authors.forename: Michael C
authors.initials: MC
authors.lastname: Van Zandt
authors.forename: Michael L
authors.initials: ML
authors.lastname: Jones
authors.forename: David E
authors.initials: DE
authors.lastname: Gunn
authors.forename: Leo S
authors.initials: LS
authors.lastname: Geraci
authors.forename: J Howard
authors.initials: JH
authors.lastname: Jones
authors.forename: Diane R
authors.initials: DR
authors.lastname: Sawicki
authors.forename: Janet
authors.initials: J
authors.lastname: Sredy
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Jacot
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Dicioccio
authors.forename: Tatiana
authors.initials: T
authors.lastname: Petrova
authors.forename: Andre
authors.initials: A
authors.lastname: Mitschler
authors.forename: Alberto D
authors.initials: AD
authors.lastname: Podjarny
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D000818:Animals; D002386:Cataract / Q000188:drug therapy; D002908:Chronic Disease; D018360:Crystallography, X-Ray; D048909:Diabetes Complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007210:Indoleacetic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007908:Lens, Crystalline / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000378:metabolism / Q000503:physiopathology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D007210:Indoleacetic Acids; D013844:Thiazoles; C500848:lidorestat; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase