Document 0084
 DOCN  M9480084
 TI    Synthesis, oral bioavailability determination, and in vitro evaluation
       of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy)ethyl]adenine
       (PMEA).
 DT    9410
 AU    Starrett JE Jr; Tortolani DR; Russell J; Hitchcock MJ; Whiterock V;
       Martin JC; Mansuri MM; Bristol-Myers Squibb Company, Wallingford,
       Connecticut; 06492-7660.
 SO    J Med Chem. 1994 Jun 10;37(12):1857-64. Unique Identifier : AIDSLINE
       MED/94293304
 AB    A series of phosphonate prodrugs were evaluated in an attempt to
       increase the oral bioavailability of the anti-HIV agent
       9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; 1). The majority of the
       bis(alkyl ester) and bis(alkyl amide) prodrugs were prepared by alcohol
       or amine displacement of dichlorophosphonate 2. Basic hydrolysis of the
       bis(esters) or bis(amides) provided the corresponding monoesters or
       monoamides. Synthesis of bis[(acyloxy)alkyl] phosphonates 10a-c was
       accomplished by alkylation of PMEA with the appropriate chloromethyl
       ether in the presence of N,N'-dicyclohexylmorpholinecarboxamidine. The
       systemic levels of PMEA following oral administration of a PMEA prodrug
       to rats were determined by measuring the concentration of PMEA in the
       urine for 48 h after administration of the prodrug. The oral
       bioavailability of PMEA employing this method was determined to be 7.8%.
       Oral dosing with bis(alkyl) phosphonates 3a,b resulted in apparent
       absorption of the prodrugs (> or = 40%), although neither of the esters
       were completely cleaved to liberate the parent phosphonate PMEA. The
       mono(alkyl esters) 7a-e and 8a,b exhibited poor oral bioavailability (<
       or = 5%). Phosphonamides 5, 6, and 9 were unstable under acidic
       conditions and provided levels of PMEA comparable to the parent compound
       after oral administration. Bis[(acyloxy)alkyl] phosphonates 10a-c
       demonstrated significantly improved oral bioavailabilities of 17.6%,
       14.6%, and 15.4%, respectively. When evaluated in vitro against HSV-2,
       (acyloxy)alkyl phosphonates 10a-c were greater than 200-fold more active
       than PMEA.
 DE    Adenine/*ANALOGS & DERIVATIVES/CHEMICAL SYNTHESIS/PHARMACOLOGY/
       PHARMACOKINETICS  Animal  Antiviral Agents/*CHEMICAL
       SYNTHESIS/PHARMACOLOGY/  PHARMACOKINETICS  Biological Availability  Male
       Prodrugs/*CHEMICAL SYNTHESIS/PHARMACOLOGY/PHARMACOKINETICS  Rats
       JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).