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The incubation mixture contained 50 mM Tris-HCl, 154 mM KCl, 5 mM MgCl2 and a NADPH regenerating system (1 mM NADP+, 5 mM isocitric acid, 1 unit\/mL isocitric dehydrogenase). The protein concentration was 0.2 mg\/mL and the final volume was 0.5 mL. Following a 10 min pre-incubation, the reaction was initiated by addition of the test compounds. After 0, 15, 30, 60, 90, 120, and 180 min., the reactions were terminated by transferring the subcellular fraction to 0.5 mL of stopping reagent containing an internal standard (13). The samples were centrifuged at 4000 g (4 \u00b0C, 15 min) and the supernatants were analyzed by HPLC-MS\/MS. Formation of the metabolites 11 and 12 was quantified vs. the internal standard, and the analyte peak area\/internal standard area is reported on the Y-axis."},{"key":"10.1016\/j.bmcl.2022.128879_b0050","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0009-2797(74)90128-8","article-title":"A similar \u2018intramolecularly controlled\u2019 study of the demethylation of p-trisdeuteromethoxyanisole has been reported in the literature before","volume":"9","author":"Foster","year":"1974","journal-title":"Chem.-Biol. Interact."},{"key":"10.1016\/j.bmcl.2022.128879_b0055","unstructured":"Recombinant human liver CYP2C19 (from BD Biosciences) isoenzymes were incubated with 1:1 10 \u00b5M mixtures of the protio and deuterio test compounds at 37 \u00b0C. The incubation mixture contained 50 mM Tris-HCl, 154 mM KCl, 5 mM MgCl2 and a NADPH regenerating system (1 mM NADP+, 1 unit\/mL isocitric dehydrogenase, 5 mM isocitric acid). The protein concentration was 0.5 mg\/mL and the final volume was 0.5 mL. Following a 10 min pre-incubation, the reaction was initiated by addition of the test compounds. After 0, 15, 30, 60, 90, 120, and 180 min. the reactions were terminated by transferring the subcellular fraction to 0.5 mL of stopping reagent containing internal standard. The incubations were carried out in triplicate. The samples were centrifuged at 4000 g (4 \u00b0C, 15 min) and the supernatants were analyzed by HPLC-MS\/MS. Formation of metabolites 11 and 12 was quantified vs. the internal standard 13, and the analyte peak area\/internal standard area is reported on the Y-axis."},{"key":"10.1016\/j.bmcl.2022.128879_b0060","unstructured":"These studies were performed in a similar manner as described in note 11 with recombinant human liver CYP3A4 isoenzymes (from BD Biosciences) instead of CYP2C19."},{"key":"10.1016\/j.bmcl.2022.128879_b0065","unstructured":"The KI values in Table 1 were measured at Eurofins Cerep (France) according to the protocols listed on their: https:\/\/www.eurofinsdiscoveryservices.com\/cms\/cms-content\/services\/in-vitro-assays\/. The only deviations from the standard protocols were that all experiments were performed using the same binding buffer (50 mM Tris-HCl (pH 7.4), 120 mM NaCl, 5 mM KCl, 5 mM MgCl2, 1 mM EDTA + protease inhibitors (1 \u00b5g\/mL leupeptin, 1 \u00b5M pepstatin A and 10 \u00b5g\/mL trypsin inhibitor))."},{"issue":"11","key":"10.1016\/j.bmcl.2022.128879_b0070","doi-asserted-by":"crossref","first-page":"e0206279","DOI":"10.1371\/journal.pone.0206279","article-title":"Deuterium isotope effects in drug pharmacokinetics II: Substrate-dependence of the reaction mechanism influences outcome for cytochrome P450 cleared drugs","volume":"13","author":"Sun","year":"2018","journal-title":"PLoS ONE"}],"container-title":["Bioorganic & Medicinal Chemistry Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0960894X22003559?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0960894X22003559?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T07:47:10Z","timestamp":1760773630000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0960894X22003559"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9]]},"references-count":23,"alternative-id":["S0960894X22003559"],"URL":"https:\/\/doi.org\/10.1016\/j.bmcl.2022.128879","relation":{},"ISSN":["0960-894X"],"issn-type":[{"value":"0960-894X","type":"print"}],"subject":[],"published":{"date-parts":[[2022,9]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Distal kinetic deuterium isotope effect: Phenyl ring deuteration attenuates N-demethylation of Lu AF35700","name":"articletitle","label":"Article Title"},{"value":"Bioorganic & Medicinal Chemistry Letters","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.bmcl.2022.128879","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2022 The Authors. 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