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

J Med Chem. 2005 May 5;48(9):3141-52. doi: 10.1021/jm0492094.

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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Reductase / antagonists & inhibitors*
  • Aldehyde Reductase / chemistry
  • Aldehyde Reductase / genetics
  • Animals
  • Cataract / drug therapy
  • Chronic Disease
  • Crystallography, X-Ray
  • Diabetes Complications / drug therapy*
  • Diabetes Complications / metabolism
  • Diabetes Complications / physiopathology
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / physiopathology
  • Humans
  • Indoleacetic Acids / chemical synthesis*
  • Indoleacetic Acids / pharmacokinetics
  • Indoleacetic Acids / pharmacology
  • Lens, Crystalline / metabolism
  • Male
  • Models, Molecular
  • Rats
  • Rats, Sprague-Dawley
  • Sciatic Nerve / metabolism
  • Sciatic Nerve / physiopathology
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology
  • Tissue Distribution

Substances

  • Indoleacetic Acids
  • Thiazoles
  • lidorestat
  • AKR1B1 protein, human
  • Aldehyde Reductase