The Synthesis of the Glucuronide Metabolite of UK-157,147 Using Immobilised Uridine 5′-Diphosphoglucuronyl Transferase and Traditional Organic Chemistry Techniques (Imidate Method)

Abstract

UK-157,147 (systematic name (3S,4R)-[6-(3-hydroxyphenyl)sulfonyl]-2,2,3-trimethyl-4-(2-methyl-3-oxo-2,3-dihydropyridazin-6-yloxy)-3-chromanol), a potent potassium channel opener designed for rapid systemic clearance, is metabolised in vivo to a glucuronide metabolite. A standard of this metabolite of UK-157,147 was required for biological testing to confirm the absence of pharmacological activity and assay development. The glucuronide conjugate of UK-157,147 was initially synthesised using a bioreactor containing immobilised microsomes as a source of uridine 5-diphosphoglucuronyl transferase (E.C.2.4.1.17). At a later date, larger amounts of the glucuronide metabolite were synthesised by traditional organic chemistry techniques using the imidate method. The identity of the chemically and biocatalytically produced glucuronide conjugate sample was proven by LC-MS and LC-NMR-MS.