ArticleChemMedChem2026
Sulfonylurea Bioisosteres of Sulfonic Acid in JFD 00458-Based ST6GAL1 Inhibitors Enhance Membrane Permeability.
Article in ChemMedChem, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Sialyltransferases catalyze the transfer of sialic acid to glycoconjugates within the Golgi apparatus, generating cell-surface sialoglycans that regulate cell-cell and immune communication. This process can be modulated by inhibiting α-2,6-sialyltransferase 1 (ST6GAL1), one of the most important sialyltransferases. Most β-galactoside ST6GAL1 inhibitors are polar CMP-Neu5Ac derivatives with limited membrane permeability, a limitation shared by the noncarbohydrate inhibitor JFD 00458. Here, we designed JFD 00458 analogs to improve permeability while maintaining ST6GAL1 inhibition and direct target engagement. Incorporation of sulfonic-acid bioisosteres, particularly sulfonylureas, improved passive permeability, as measured by parallel artificial membrane permeability assay, with the best analog reaching log(P_app [cm/s]) = -4.3. Potency was also improved in an expanded series of sulfonylureas, with the best inhibitor displaying an IC
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