title: Synthesis of [(3) H], [(13) C3 , (15) N], and [(14) C]SCH 900567: an inhibitor of TNF-α (tumor necrosis factor alpha) converting enzyme (TACE).
abstract: SCH 900567 is a specific inhibitor of tumor necrosis factor-alpha converting enzyme and is a potential candidate for the treatment of rheumatoid arthritis. [(3) H]SCH 900567 was synthesized to support the initial drug metabolism and pharmacokinetics studies. Stable isotope-labeled [(13) C3 , (15) N]SCH 900567 was requested by the bioanalytical group as an internal standard for Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method development as well as by the drug metabolism and pharmacokinetics group for a potential microdose study. [(13) C3 , (15) N]SCH 900567 is synthesized via a linear sequence of seven steps from commercially available materials in 2.6% overall yield. [(14) C]SCH 900567 was needed for a quantitative whole body autoradiography studies and was prepared from unlabeled Active Pharmaceutical Ingredient (API) via hydrolysis of the hydantoin moiety followed by rebuilding the hydantoin ring using potassium [(14) C]cyanate to give the desired product in 42.8% overall yield. Activation of the hydantoin moiety of SCH 900567 to achieve hydrolysis followed by derivatization of the resulting amino acid to avoid decarboxylation during cyclization is also discussed.
authors.affiliation: Merck Research Laboratories, 126 E. Lincoln Avenue, PO Box 2000, Rahway, NJ, USA, 07065.
authors.forename: Sumei
authors.initials: S
authors.lastname: Ren
authors.forename: David
authors.initials: D
authors.lastname: Hesk
authors.forename: Paul
authors.initials: P
authors.lastname: McNamara
authors.forename: David
authors.initials: D
authors.lastname: Koharski
authors.forename: Scott
authors.initials: S
authors.lastname: Borges
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D002250:Carbon Radioisotopes / Q000737:chemistry; D006827:Hydantoins / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D054833:Isoindoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D009590:Nitrogen Radioisotopes / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D014316:Tritium / Q000737:chemistry
chemical_list: D002250:Carbon Radioisotopes; D006827:Hydantoins; D054833:Isoindoles; D009590:Nitrogen Radioisotopes; D019275:Radiopharmaceuticals; C000599883:SCH 900567; D014316:Tritium; D051722:ADAM Proteins; D000072198:ADAM17 Protein
keywords: 3H; TACE; hydantoin; stable isotope label