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

• Published in: Journal of medicinal chemistry Vol. 48; no. 9; pp. 3141 - 3152
• Main Authors: Van Zandt, Michael C, Jones, Michael L, Gunn, David E, Geraci, Leo S, Jones, J. Howard, Sawicki, Diane R, Sredy, Janet, Jacot, Jorge L, DiCioccio, A. Thomas, Petrova, Tatiana, Mitschler, Andre, Podjarny, Alberto D
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 05-05-2005
• Subjects: Aldehyde Reductase; Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - chemistry; Aldehyde Reductase - genetics; Animals; Biochemistry, Molecular Biology; Biological and medical sciences; Cataract; Cataract - drug therapy; Chronic Disease; Crystallography, X-Ray; Diabetes Complications; Diabetes Complications - drug therapy; Diabetes Complications - metabolism; Diabetes Complications - physiopathology; Diabetes Mellitus, Experimental; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - physiopathology; General and cellular metabolism. Vitamins; Humans; Indoleacetic Acids; Indoleacetic Acids - chemical synthesis; Indoleacetic Acids - pharmacokinetics; Indoleacetic Acids - pharmacology; Lens, Crystalline; Lens, Crystalline - metabolism; Life Sciences; Male; Medical sciences; Models, Molecular; Molecular biology; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Sciatic Nerve - metabolism; Sciatic Nerve - physiopathology; Structure-Activity Relationship; Thiazoles; Thiazoles - chemical synthesis; Thiazoles - pharmacokinetics; Thiazoles - pharmacology; Tissue Distribution; Endocrinopathy; Rat; Selectivity; Neuropathy; Prevention; Structure activity relation; Complication; Lidorestat; Chemical synthesis; Nervous system diseases; Cataract; Enzyme; Diabetes mellitus; Rodentia; Enzyme inhibitor; Benzothiazole derivatives; Triglyceride; In vitro; In vivo; Eye disease; Vertebrata; Chronic; Mammalia; Treatment; Animal; Aldehyde reductase; Oxidoreductases; Fluorine Organic compounds; Acetic acid; Indole derivatives; Antilipemic agent
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0492094

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 IC50 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 ED50'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 μg equiv/g, respectively, when dosed with [14C]lidorestat at 10 mg/kg po).