title: Aryl ester prodrugs of cyclic HPMPC. I: Physicochemical characterization and in vitro biological stability.
abstract: OBJECTIVE
  The chemical, enzymatic, and biological stabilities and physical properties of a series of salicylate and aryl ester prodrugs of the antiviral agent, cyclic HPMPC, were evaluated to support the selection of a lead compound for clinical development.
  
  
  METHODS
  Chemical stabilities of the prodrugs in buffered solutions at 37 degrees C were determined. Stability was also studied in the presence of porcine liver carboxyesterases (PLCE) at pH 7.4 and 25 degrees C. Tissue stabilities were examined in both human and dog intestinal homogenates, plasmas and liver homogenates. Prodrug and product concentrations were determined by reverse phase HPLC.
  
  
  RESULTS
  Chemical degradation of the prodrugs resulted in the formation of both cyclic HPMPC and the corresponding HPMPC monoester. Chemical stability was dependent on the orientation of the exo-cyclic ligand; the equatorial isomers were 5.4- to 9.4-fold more reactive than the axial isomers. In the presence of PLCE, the salicylate prodrugs cleaved exclusively to give cyclic HPMPC and not the HPMPC monoester. In plasma, but not intestinal or liver homogenates, the salicylate esters of cyclic HPMPC cleaved readily with a rate dependent on the chain length of the alkyl ester substituent.
  
  
  CONCLUSIONS
  The carboxylate function on the salicylate prodrugs of cyclic HPMPC provides an additional handle to chemically modify the lipophilicity, solubility and the biological reactivity of the prodrug. In tissue and enzymatic studies, the major degradation product is cyclic HPMPC. The salicylate ester prodrugs are attractive drug candidates for further in vivo evaluation.
authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
authors.forename: R
authors.initials: R
authors.lastname: Oliyai
authors.forename: J P
authors.initials: JP
authors.lastname: Shaw
authors.forename: C M
authors.initials: CM
authors.lastname: Sueoka-Lennen
authors.forename: K C
authors.initials: KC
authors.lastname: Cundy
authors.forename: M N
authors.initials: MN
authors.lastname: Arimilli
authors.forename: R J
authors.initials: RJ
authors.lastname: Jones
authors.forename: W A
authors.initials: WA
authors.lastname: Lee
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000097:blood / Q000737:chemistry* / Q000378:metabolism; D001769:Blood / Q000378:metabolism; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D004285:Dogs; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D007413:Intestinal Mucosa / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000378:metabolism; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000097:blood / Q000737:chemistry* / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D012459:Salicylates / Q000378:metabolism; D012995:Solubility; D013237:Stereoisomerism; D013552:Swine; D013997:Time Factors
chemical_list: D000998:Antiviral Agents; D008024:Ligands; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011355:Prodrugs; D012459:Salicylates; D003596:Cytosine; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase; D000077404:Cidofovir