title: The synthesis of a tritium, carbon-14, and stable isotope-labeled cathepsin C inhibitors.
abstract: As part of a medicinal chemistry program aimed at developing a highly potent and selective cathepsin C inhibitor, tritium, carbon-14, and stable isotope-labeled materials were required. The synthesis of tritium-labeled methanesulfonate 5 was achieved via catalytic tritiolysis of a chloro precursor, albeit at a low radiochemical purity of 67%. Tritium-labeled AZD5248 was prepared via a 3-stage synthesis, utilizing amide-directed hydrogen isotope exchange. Carbon-14 and stable isotope-labeled AZD5248 were successfully prepared through modifications of the medicinal chemistry synthetic route, enabling the use of available labeled intermediates.
authors.affiliation: Pharmaceutical Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Allen
authors.affiliation: Pharmaceutical Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge, UK.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Bragg
authors.affiliation: Respiratory, Inflammation, and Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Gothenburg, Sweden.
authors.forename: Moya
authors.initials: M
authors.lastname: Caffrey
authors.affiliation: Pharmaceutical Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Gothenburg, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ericsson
authors.affiliation: Pharmaceutical Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hickey
authors.affiliation: Pharmaceutical Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Gothenburg, Sweden.
authors.forename: Lee P
authors.initials: LP
authors.lastname: Kingston
authors.affiliation: Pharmaceutical Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Gothenburg, Sweden.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Elmore
mesh_terms: D001713:Biphenyl Compounds / Q000737:chemistry*; D002250:Carbon Radioisotopes / Q000737:chemistry; D020789:Cathepsin C / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D008698:Mesylates / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D014316:Tritium / Q000737:chemistry*
chemical_list: C000607639:AZD5248; D001713:Biphenyl Compounds; D002250:Carbon Radioisotopes; D015853:Cysteine Proteinase Inhibitors; D008698:Mesylates; D019275:Radiopharmaceuticals; D014316:Tritium; C045880:methanesulfonic acid; D020789:Cathepsin C
keywords: carbon-13; carbon-14; cathepsin C; dipeptidyl peptidase I; tritium