title: Accessing Drug Metabolites via Transition-Metal Catalyzed C-H Oxidation: The Liver as Synthetic Inspiration.
abstract: Can classical and modern chemical C-H oxidation reactions complement biotransformation in the synthesis of drug metabolites? We have surveyed the literature in an effort to try to answer this important question of major practical significance in the pharmaceutical industry. Drug metabolites are required throughout all phases of the drug discovery and development process; however, their synthesis is still an unsolved problem. This Review, not intended to be comprehensive or historical, highlights relevant applications of chemical C-H oxidation reactions, electrochemistry and microfluidic technologies to drug templates in order to access drug metabolites, and also highlights promising reactions to this end. Where possible or appropriate, the contrast with biotransformation is drawn. In doing so, we have tried to identify gaps where they exist in the hope to spur further activity in this very important research area.
authors.affiliation: Pfizer Inc., Worldwide Medicinal Chemistry, Cardiovascular, Metabolic, and Endocrine Diseases (CVMED), 558 Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Julien
authors.identifier: 0000-0001-5879-2491
authors.initials: J
authors.lastname: Genovino
authors.affiliation: Columbia University, Department of Chemistry and Neurotechnology Center, 3000 Broadway MC3101, New York, NY, 10027, USA.
authors.forename: Dalibor
authors.initials: D
authors.lastname: Sames
authors.affiliation: Novartis Institutes for Biomedical Sciences (NIBR), Global Discovery Chemistry (GDC), 181 Massachusetts Avenue, Cambridge, MA, 02139, USA.
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Hamann
authors.affiliation: Novartis Institutes for Biomedical Sciences (NIBR), Global Discovery Chemistry (GDC), 100 Technology Square, Cambridge, MA, 02139, USA. btoure@relaytx.com.
authors.forename: B Barry
authors.identifier: 0000-0001-5225-7594
authors.initials: BB
authors.lastname: Touré
mesh_terms: D001688:Biological Products / Q000737:chemistry / Q000378:metabolism; D002244:Carbon / Q000737:chemistry; D002384:Catalysis; D055664:Electrochemical Techniques; D006859:Hydrogen / Q000737:chemistry; D046210:Microfluidic Analytical Techniques; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D028561:Transition Elements / Q000737:chemistry*
chemical_list: D001688:Biological Products; D004364:Pharmaceutical Preparations; D028561:Transition Elements; D002244:Carbon; D006859:Hydrogen
keywords: C−H functionalization; biotransformation; chemotransformation; drug discovery; drug metabolites