title: Synthesis and pharmacokinetic profile of highly deuterated brecanavir analogs.
abstract: Several highly deuterated analogs of the HIV-1 protease inhibitor brecanavir have been prepared to study the effect of deuterium upon metabolic stability. The sites for deuterium incorporation were initially chosen to maximize the potential for a kinetic isotope effect; locations where C-H bond breaking is the rate limiting step. The analogs have been profiled in both in vitro and in vivo pharmacokinetic studies and the result will be described herein.
authors.affiliation: GlaxoSmithKline Research & Development, Infectious Diseases Therapeutic Area Unit, Five Moore Drive, Research Triangle Park, NC 27709, USA. emile.j.velthuisen@gsk.com
authors.forename: Emile J
authors.initials: EJ
authors.lastname: Velthuisen
authors.forename: Todd M
authors.initials: TM
authors.lastname: Baughman
authors.forename: Brian A
authors.initials: BA
authors.lastname: Johns
authors.forename: David P
authors.initials: DP
authors.lastname: Temelkoff
authors.forename: Jason G
authors.initials: JG
authors.lastname: Weatherhead
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D019540:Area Under Curve; D052117:Benzodioxoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D003903:Deuterium / Q000737:chemistry / Q000493:pharmacokinetics; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008657:Metabolic Clearance Rate; D008956:Models, Chemical; D015394:Molecular Structure; D051381:Rats
chemical_list: D052117:Benzodioxoles; D002219:Carbamates; D017320:HIV Protease Inhibitors; D003903:Deuterium; C512121:brecanavir