Metal-Binding Pharmacophore Library Yields the Discovery of a Glyoxalase 1 Inhibitor

• Published in: Journal of medicinal chemistry Vol. 62; no. 3; pp. 1609 - 1625
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.02.2019; Amer Chemical Soc
• Subjects: Aminoquinolines - chemistry; Aminoquinolines - therapeutic use; Animals; Antidepressive Agents - chemistry; Antidepressive Agents - therapeutic use; Brain - metabolism; Chemistry, Medicinal; Depression - drug therapy; Drug Discovery; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - therapeutic use; Female; Humans; Lactoylglutathione Lyase - antagonists & inhibitors; Life Sciences & Biomedicine; Male; Mice; Molecular Structure; Pharmacology & Pharmacy; Pyruvaldehyde - metabolism; Science & Technology; Small Molecule Libraries - chemistry; Small Molecule Libraries - therapeutic use; Structure-Activity Relationship; Sulfonamides - chemistry; Sulfonamides - therapeutic use; I INHIBITORS; OVEREXPRESSION; OXIDATIVE STRESS; PATHWAY; GLYCATION; REGULATE ANXIETY; IDENTIFICATION; FLUOXETINE; ZINC; METHYLGLYOXAL
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b01868

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.