A metabolically stable tight-binding transition-state inhibitor of glyoxalase-I.
The design, synthesis, and enzyme kinetics evaluation of a transition-state inhibitor of glyoxalase-I is described. The union of the hydroxamic acid zinc-chelator with a urea isostere for the glu-cys amide bond led to a glutathione analog which retained inhibitory potency toward glyoxalase-I while possessing resistance toward gamma-glutamyltranspeptidase mediated breakdown. This compound is viewed as a potential lead for the development of second-generation glyoxalase-I inhibitors wherein, the problems pertaining to metabolism and selectivity are overcome.
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Swati S
SS
Center for Drug Design, Academic Health Center, and Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 8-123A WDH, 308 Harvard St SE, Minneapolis, MN 55455, USA.
Vince
Robert
R
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015394:Molecular Structure; D011485:Protein Binding
D004791:Enzyme Inhibitors; D007791:Lactoylglutathione Lyase; D005978:Glutathione