- Metal-Binding Pharmacophore Library Yields the Discovery of a Glyoxalase 1 Inhibitor
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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.
- 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.
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p. 1609 - 1625
(2019/02/14)
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- Novel Sulfonaminoquinoline Hepcidin Antagonists
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The present invention relates to novel hepcidin antagonists, pharmaceutical compositions comprising them and the use thereof as medicaments for the use in the treatment of iron metabolism disorders, such as, in particular, iron deficiency diseases and anemias, in particular anemias in connection with chronic inflammatory diseases.
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Page/Page column 136
(2012/09/05)
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- Chromofluorescent indicator for intracellular Zn2+/Hg 2+ dynamic exchange
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(Chemical Equation Presented) (Figure Presented) The fluorescence of NABQ increases remarkably in the presence of Zn2+ and is quenched by Hg2+. As shown by confocal imaging, NABQ-Zn2+ can penetrate cells, where the bound Zn2+ is exchanged for Hg 2+. This results in the concomitant export of Hg2+ from the cells, showing that NABQ can act as a Zn2+ carrier and as a Hg2+ extracting agent in living cells.
- Lee, Jeong Won,Jung, Hyo Sung,Kwon, Pil Seung,Kim, Jong Wan,Bartsch, Richard A.,Kim, Youngmee,Kim, Sung-Jin,Kim, Jong Seung
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supporting information; scheme or table
p. 3801 - 3804
(2009/07/01)
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- The synthesis of azacrown ethers with quinoline-based sidearms as potential zinc(II) fluorophores
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Two novel fluorophores, 12 and 13, composed of diaza-18-crown-6 ligands containing two quinoline-based sidearms which are structurally similar to Zn(II) fluorophores TSQ (1) and Zinquin (2) were synthesized as potential Zn(II) fluorophores by reductive amination of 8-benzenesulfonamido-2-quinoline carboxaldehyde 6 and 8-benzenesulfonamido-6-quinolyloxyacetate-2-carboxaldehyde 11 with diaza-18-crown-6 using sodium triacetoxyborohydride (NaBH(OAc)3) as the reducing agent. Preliminary photophysical properties of ligands 12 and 13 show that they possess the properties necessary to be effective chemosensors for Zn2+. The solid state structure of 12 is also reported.
- Xue, Guoping,Bradshaw, Jerald S,Dalley, N.Kent,Savage, Paul B,Izatt, Reed M,Prodi, Luca,Montalti, Marco,Zaccheroni, Nelsi
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p. 4809 - 4815
(2007/10/03)
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