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

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 chroni...

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Veröffentlicht in:	Journal of medicinal chemistry 2003-06, Vol.46 (12), p.2283-2286
Hauptverfasser:	Mylari, Banavara L, Armento, Sandra J, Beebe, David A, Conn, Edward L, Coutcher, James B, Dina, Michael S, O'Gorman, Melissa T, Linhares, Michael C, Martin, William H, Oates, Peter J, Tess, David A, Withbroe, Gregory J, Zembrowski, William J
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Aldehyde Reductase - antagonists & inhibitors Aldehyde Reductase - chemistry Animals Biological and medical sciences 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 General and cellular metabolism. Vitamins Humans Hypoglycemic Agents - chemical synthesis Hypoglycemic Agents - chemistry Hypoglycemic Agents - pharmacology Lens, Crystalline - drug effects Lens, Crystalline - enzymology Medical sciences Permeability Pharmacology. Drug treatments 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
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Beschreibung
Zusammenfassung:	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 ED90 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).
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm034065z