A highly selective, non-hydantoin, non-carboxylic acid inhibitor of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran- 2-sulfonyl)-2-H-pyridazin-3-one

J Med Chem. 2003 Jun 5;46(12):2283-6. doi: 10.1021/jm034065z.

Abstract

We report here on the discovery path that led to a structurally unprecedented non-hydantoin, non-carboxylic acid aldose reductase inhibitor, 24, which shows remarkably potent oral activity in normalizing elevated sorbitol levels and, more significantly, fructose levels in the sciatic nerve of chronically diabetic rats, with ED(90) values of 0.8 and 3 mpk, respectively. It is well absorbed in rats (oral bioavailability, 98%) and has a long plasma t(1/2) (26 +/- 3 h).

MeSH terms

  • Administration, Oral
  • Aldehyde Reductase / antagonists & inhibitors*
  • Aldehyde Reductase / chemistry
  • Animals
  • Biological Availability
  • Caco-2 Cells
  • Combinatorial Chemistry Techniques
  • Crystallography, X-Ray
  • Diabetes Mellitus, Experimental / metabolism*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Fructose / blood
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology
  • Lens, Crystalline / drug effects
  • Lens, Crystalline / enzymology
  • Permeability
  • Pyridazines / chemical synthesis*
  • Pyridazines / chemistry
  • Pyridazines / pharmacology
  • Rats
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / enzymology
  • Sorbitol / blood
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis*
  • Sulfones / chemistry
  • Sulfones / pharmacology

Substances

  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Pyridazines
  • Sulfones
  • Fructose
  • Sorbitol
  • Aldehyde Reductase
  • 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H-pyridazin-3-one