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.
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.
Van Zandt
Michael C
MC
The Institute for Diabetes Discovery, LLC, 23 Business Park Drive, Branford, CT 06405, USA. michael.vanzandt@ipd-discovery.com
Doan
Brian
B
Sawicki
Diane R
DR
Sredy
Janet
J
Podjarny
Alberto D
AD
D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D002908:Chronic Disease; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D048909:Diabetes Complications / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50
C541283:(6-methyl-3-(4,5,7-trifluorobenzothiazol-2-ylmethyl)pyrrolo(2,3-b)pyridin-1-yl)acetic acid; D000085:Acetates; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D000449:Aldehyde Reductase