Discovery of [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acids as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications

Bioorg Med Chem Lett. 2009 Apr 1;19(7):2006-8. doi: 10.1016/j.bmcl.2009.02.037. Epub 2009 Feb 12.

Abstract

Efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acid aldose reductase inhibitors. The lead candidate, [6-methyl-3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acid example 16, inhibits aldose reductase with an IC50 of 8 nM, while being inactive against aldehyde reductase (IC50>100 microM), a related enzyme involved in the detoxification of reactive aldehydes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / chemical synthesis*
  • Acetates / chemistry
  • Acetates / pharmacology*
  • Aldehyde Reductase / antagonists & inhibitors*
  • Aldehyde Reductase / metabolism
  • Benzothiazoles / chemical synthesis*
  • Benzothiazoles / chemistry
  • Benzothiazoles / pharmacology
  • Catalytic Domain
  • Chronic Disease
  • Computer Simulation
  • Crystallography, X-Ray
  • Diabetes Complications / drug therapy
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Inhibitory Concentration 50

Substances

  • (6-methyl-3-(4,5,7-trifluorobenzothiazol-2-ylmethyl)pyrrolo(2,3-b)pyridin-1-yl)acetic acid
  • Acetates
  • Benzothiazoles
  • Enzyme Inhibitors
  • Aldehyde Reductase