title: Novel prodrug approach for tertiary amines: synthesis and preliminary evaluation of N-phosphonooxymethyl prodrugs.
abstract: The synthesis and preliminary evaluation of a novel prodrug approach for improving the water solubility of drugs containing a tertiary amine group are reported. The prodrug synthesis involves a nucleophilic substitution reaction between the parent tertiary amine and a novel derivatizing reagent, di-tert-butyl chloromethyl phosphate, resulting in formation of the quaternary salt. The tertiary butyl groups are easily removed under acidic conditions with trifluoroacetic acid giving the N-phosphonooxymethyl prodrug in the free phosphoric acid form, which can subsequently be converted to the desired salt form. The synthesis was successfully applied to a model compound (quinuclidine) and to three tertiary amine-containing drugs (cinnarizine, loxapine, and amiodarone). The prodrugs were designed to undergo a two-step bioreversion process. The first step was an enzyme-catalyzed rate-determining dephosphorylation followed by spontaneous chemical breakdown of the N-hydroxymethyl intermediate to give the parent drug. Selected prodrugs were shown to be substrates for alkaline phosphatase in vitro. A preliminary in vivo study confirmed the ability of the cinnarizine prodrug to be rapidly and completely converted to cinnarizine in a beagle dog following iv administration.
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, Kansas 66047, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Krise
authors.forename: J
authors.initials: J
authors.lastname: Zygmunt
authors.forename: G I
authors.initials: GI
authors.lastname: Georg
authors.forename: V J
authors.initials: VJ
authors.lastname: Stella
mesh_terms: D000469:Alkaline Phosphatase / Q000737:chemistry; D000588:Amines / Q000737:chemistry*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002936:Cinnarizine / Q000737:chemistry*; D004285:Dogs; D006801:Humans; D007275:Injections, Intravenous; D007700:Kinetics; D008152:Loxapine / Q000737:chemistry*; D008297:Male; D010920:Placenta / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011812:Quinuclidines / Q000737:chemistry; D012995:Solubility
chemical_list: D000588:Amines; D011355:Prodrugs; D011812:Quinuclidines; D002936:Cinnarizine; D000469:Alkaline Phosphatase; D008152:Loxapine