1232007-52-1Relevant academic research and scientific papers
Metal-Binding Pharmacophore Library Yields the Discovery of a Glyoxalase 1 Inhibitor
Perez, Christian,Barkley-Levenson, Amanda M.,Dick, Benjamin L.,Glatt, Peter F.,Martinez, Yadira,Siegel, Dionicio,Momper, Jeremiah D.,Palmer, Abraham A.,Cohen, Seth M.
supporting information, p. 1609 - 1625 (2019/02/14)
Anxiety and depression are common, highly comorbid psychiatric diseases that account for a large proportion of worldwide medical disability. Glyoxalase 1 (GLO1) has been identified as a possible target for the treatment of anxiety and depression. GLO1 is a Zn2+-dependent enzyme that isomerizes a hemithioacetal, formed from glutathione and methylglyoxal, to a lactic acid thioester. To develop active inhibitors of GLO1, fragment-based drug discovery was used to identify fragments that could serve as core scaffolds for lead development. After screening a focused library of metal-binding pharmacophores, 8-(methylsulfonylamino)quinoline (8-MSQ) was identified as a hit. Through computational modeling and synthetic elaboration, a potent GLO1 inhibitor was developed with a novel sulfonamide core pharmacophore. A lead compound was demonstrated to penetrate the blood-brain barrier, elevate levels of methylglyoxal in the brain, and reduce depression-like behavior in mice. These findings provide the basis for GLO1 inhibitors to treat depression and related psychiatric illnesses.
From sensors to silencers: Quinoline- and benzimidazole-sulfonamides as inhibitors for zinc proteases
Rouffet, Matthieu,De Oliveira, Cesar Augusto F.,Udi, Yael,Agrawal, Arpita,Sagi, Irit,McCammon, J. Andrew,Cohen, Seth M.
supporting information; experimental part, p. 8232 - 8233 (2010/08/05)
Derived from the extensive work in the area of small molecule zinc(II) ion sensors, chelating fragment libraries of quinoline- and benzimidazole- sulfonamides have been prepared and screened against several different zinc(II)-dependent matrix metalloproteinases (MMPs). The fragments show impressive inhibition of these metalloenzymes and preferences for different MMPs based on the nature of the chelating group. The findings show that focused chelator libraries are a powerful strategy for the discovery of lead fragments for metalloprotein inhibition.
