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Selective GH inhibitors are sought to better understand their functions and assess the therapeutic potential of modulating their activities. Iminosugars are a promising class of GH inhibitors but typically lack the selectivity required to accurately perturb biological systems. Here, we describe a concise synthesis of iminosugar inhibitors of <jats:italic>N<\/jats:italic>\u2010acetyl\u2010\u03b1\u2010galactosaminidase (\u03b1\u2010NAGAL), the GH responsible for cleaving terminal \u03b1\u2010<jats:italic>N<\/jats:italic>\u2010acetylgalactosamine residues from glycoproteins and other glycoconjugates. Starting from non\u2010carbohydrate precursors, this modular synthesis supported the identification of a potent (490\u2005nM) and \u03b1\u2010NAGAL selective (\u223c200\u2010fold) guanidino\u2010containing derivative DGJNGuan. To illustrate the cellular activity of this new inhibitor, we developed a quantitative fluorescence image\u2010based method to measure levels of the Tn\u2010antigen, a cellular glycoprotein substrate of \u03b1\u2010NAGAL. Using this assay, we show that DGJNGuan exhibits excellent inhibition of \u03b1\u2010NAGAL within cells using patient derived fibroblasts (EC<jats:sub>50<\/jats:sub>=150\u2005nM). Moreover, in\u2005vitro and in cell assays to assess levels of lysosomal \u03b2\u2010hexosaminidase substrate ganglioside GM2 show that DGJNGuan is selective whereas DGJNAc exhibits off\u2010target inhibition both in\u2005vitro and within cells. DGJNGuan is a readily produced and selective tool compound that should prove useful for investigating the physiological roles of \u03b1\u2010NAGAL.<\/jats:p>","DOI":"10.1002\/chem.202300982","type":"journal-article","created":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T22:44:54Z","timestamp":1684795494000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Potent and Selective Cell\u2010Active Iminosugar Inhibitors of Human \u03b1\u2010<i>N<\/i>\u2010Acetylgalactosaminidase (\u03b1\u2010NAGAL)"],"prefix":"10.1002","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9580-7533","authenticated-orcid":false,"given":"Roger A.","family":"Ashmus","sequence":"first","affiliation":[{"name":"Department of Chemistry Simon Fraser University  8888 University Drive Burnaby British Columbia V5A 1S6 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