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Bioinformatic, mutagenesis and drug metabolism work indicate that the cyclohexyl ring of PZQ is a key pharmacophore for activation of trematode TRPM<jats:sub>PZQ<\/jats:sub>, as well as serving as the primary site of oxidative metabolism which results in PZQ being a short\u2010lived drug. Based on our recent findings, the hydrophobic cleft in schistosome TRPM<jats:sub>PZQ<\/jats:sub> defined by three hydrophobic residues surrounding the cyclohexyl ring has little tolerance for polarity. Here we evaluate the <jats:italic>in\u2005vitro<\/jats:italic> and <jats:italic>in\u2005vivo<\/jats:italic> activities of PZQ analogues with improved metabolic stability relative to the challenge of maintaining activity on the channel. Finally, an estimation of the respective contribution to the overall activity of both the parent and the main metabolite of PZQ in humans is reported.<\/jats:p>","DOI":"10.1002\/cmdc.202300140","type":"journal-article","created":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T13:47:42Z","timestamp":1686059262000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Metabolism of (<i>R<\/i>)\u2010Praziquantel versus the Activation of a Parasite Transient Receptor Potential Melastatin Ion Channel"],"prefix":"10.1002","volume":"18","author":[{"given":"Lukas","family":"Friedrich","sequence":"first","affiliation":[{"name":"Global Research &amp; Development Merck Healthcare KGaA  Frankfurter Str. 250 64293 Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang\u2010Kyu","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Neurobiology and Anatomy Medical College of Wisconsin  Milwaukee WI 53226 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Ballard","sequence":"additional","affiliation":[{"name":"PB DMPK Consulting Ltd.  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