Chemical synthesis and characterization of conjugates of a novel catechol-O-methyltransferase inhibitor.
BIA 3-202, 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenylethanone 3, is a novel, reversible, and tight-binding peripheral inhibitor of the enzyme catechol-O-methyltransferase (COMT), which is currently under clinical evaluation for the treatment of Parkinson's disease as an adjunct to current L-Dopa/peripheral decarboxylase inhibitor therapy. Chemically pure, well-characterized reference standards of conjugates of 3 were required for investigation of the routes of metabolism in several animal species (including humans) and for pharmacokinetic studies. The lack of suitable literature precedents for efficient, regioselective synthesis of nitrocatechol conjugate metabolites prompted us to develop efficient and highly selective chemical preparations of O-glucuronide and O-sulfate conjugates of 3 such that multigram quantities of excellent purity can now be conveniently synthesized. It is anticipated that these procedures could be applied to the synthesis of conjugates of other COMT inhibitors, also based on the 3-nitrocatechol pharmacophore.
Learmonth
David A
DA
Laboratory of Chemistry, Department of Research and Development, BIAL, 4745-457 S. Mamede do Coronado, Portugal. david.learmouth@bial.com
Freitas
Ana P
AP
D000098:Acetophenones; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000737:chemistry; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000138:chemical synthesis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D012015:Reference Standards
D000098:Acetophenones; D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; C433466:nebicapone