Design and synthesis of highly potent and selective (2-arylcarbamoyl-phenoxy)-acetic acid inhibitors of aldose reductase for treatment of chronic diabetic complications.
Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective (2-arylcarbamoyl-phenoxy)-acetic acid aldose reductase inhibitors. The compound class features a core template that utilizes an intramolecular hydrogen bond to position the key structural elements of the pharmacophore in a conformation, which promotes a high binding affinity. The lead candidate, example 40, 5-fluoro-2-(4-bromo-2-fluoro-benzylthiocarbamoyl)-phenoxyacetic acid, inhibits aldose reductase with an IC(50) of 30 nM, while being 1100 times less active against aldehyde reductase, a related enzyme involved in the detoxification of reactive aldehydes. In addition, example 40 lowers nerve sorbitol levels with an ED(50) of 31 mg/kg/d po in the 4-day STZ-induced diabetic rat model.
The Institute for Diabetes Discovery, LLC, 23 Business Park Drive, Branford, CT 06405, USA. michael.vanzandt@ipd-discovery.com
Michael C
MC
Van Zandt
Evelyn O
EO
Sibley
Erin E
EE
McCann
Kerry J
KJ
Combs
Brenda
B
Flam
Diane R
DR
Sawicki
Al
A
Sabetta
Anne
A
Carrington
Janet
J
Sredy
Eduardo
E
Howard
Andre
A
Mitschler
Alberto D
AD
Podjarny
D019342:Acetic Acid / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002908:Chronic Disease; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013012:Sorbitol / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D013012:Sorbitol; D000449:Aldehyde Reductase; D019342:Acetic Acid