title: Synthesis of mevalonate- and fluorinated mevalonate prodrugs and their in vitro human plasma stability.
abstract: The mevalonate pathway is essential for the production of many important molecules in lipid biosynthesis. Inhibition of this pathway is the mechanism of statin cholesterol-lowering drugs, as well as the target of drugs to treat osteoporosis, to combat parasites, and to inhibit tumor cell growth. Unlike the human mevalonate pathway, the bacterial pathway appears to be regulated by diphosphomevalonate (DPM). Enzymes in the mevalonate pathway act to produce isopentenyl diphosphate, the product of the DPM decarboxylase reaction, utilize phosphorylated (charged) intermediates, which are poorly bioavailable. It has been shown that fluorinated DPMs (6-fluoro- and 6,6,6-trifluoro-5-diphosphomevalonate) are excellent inhibitors of the bacterial pathway; however, highly charged DPM and analogs are not bioavailable. To increase cellular permeability of mevalonate analogs, we have synthesized various prodrugs of mevalonate and 6-fluoro- and 6,6,6-trifluoromevalonate that can be enzymatically transformed to the corresponding DPM or fluorinated DPM analogs by esterases or amidases. To probe the required stabilities as potentially bioavailable prodrugs, we measured the half-lives of esters, amides, carbonates, acetals, and ketal promoieties of mevalonate and the fluorinated mevalonate analogs in human blood plasma. Stability studies showed that the prodrugs are converted to the mevalonates in human plasma with a wide range of half-lives. These studies provide stability data for a variety of prodrug options having varying stabilities and should be very useful in the design of appropriate prodrugs of mevalonate and fluorinated mevalonates.
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, IL, United States.
authors.forename: Soosung
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, IL, United States.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, IL, United States.
authors.forename: J C
authors.initials: JC
authors.lastname: Jacobs
authors.affiliation: Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States.
authors.forename: Masaya
authors.initials: M
authors.lastname: Yamaguchi
authors.affiliation: Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States.
authors.forename: Samira
authors.initials: S
authors.lastname: Dahesh
authors.affiliation: Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, United States.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Leyh
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, IL, United States. Electronic address: Agman@chem.northwestern.edu.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000900:Anti-Bacterial Agents / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D006845:Hydrocarbons, Fluorinated; D011355:Prodrugs; D008798:Mevalonic Acid
keywords: 6,6,6-Trifluoromevalonate; 6-Fluoromevalonate; Mevalonate; Plasma stability; Prodrugs