title: 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.
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.
authors.affiliation: The Institute for Diabetes Discovery, LLC, 23 Business Park Drive, Branford, CT 06405, USA. michael.vanzandt@ipd-discovery.com
authors.forename: Michael C
authors.initials: MC
authors.lastname: Van Zandt
authors.forename: Brian
authors.initials: B
authors.lastname: Doan
authors.forename: Diane R
authors.initials: DR
authors.lastname: Sawicki
authors.forename: Janet
authors.initials: J
authors.lastname: Sredy
authors.forename: Alberto D
authors.initials: AD
authors.lastname: Podjarny
mesh_terms: 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
chemical_list: 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