       Document 0075
 DOCN  M9580075
 TI    Synthesis and in vivo evaluation of prodrugs of
       9-[2-(phosphonomethoxy)ethoxy]adenine.
 DT    9506
 AU    Serafinowska HT; Ashton RJ; Bailey S; Harnden MR; Jackson SM; Sutton D;
       SmithKline Beecham Pharmaceuticals, Epsom, Surrey, U.K.
 SO    J Med Chem. 1995 Apr 14;38(8):1372-9. Unique Identifier : AIDSLINE
       MED/95248518
 AB    A number of esters and amides of the anti-HIV nucleotide analogue
       9-[2-(phosphonomethoxy)-ethoxy]adenine (1) have been synthesized as
       potential prodrugs and evaluated for oral bioavailability in mice.
       Dialkyl esters 17-20 were prepared via a Mitsunobu coupling of alcohols
       8-11 with 9-hydroxypurine 12 whereas (acyloxy)alkyl esters 25-33 and
       bis-[(alkoxycarbonyl)methyl] and bis(amidomethyl) esters 34-39 were
       obtained by reaction of 1 with a suitable alkylating agent.
       Phosphonodichloridate chemistry was employed for the preparation of
       dialkyl and diaryl esters 42-65, and bis(phosphonoamidates) 66 and 67.
       Following oral administration to mice, most of the dialkyl esters 17-20
       were well-absorbed and then converted to the corresponding monoesters,
       but minimal further metabolism to 1 occurred. Bis[(pivaloyloxy)methyl]
       ester 25 displayed an oral bioavailability of 30% that was 15-fold
       higher than the bioavailability observed after dosing of 1. Methyl
       substitution at the alpha carbon of the bis[(pivaloyloxy)methyl] ester
       25 (33) increased the oral bioavailability of 1 to 74%. Some of the
       diaryl esters also showed improved absorption properties in comparison
       with that of 1. In particular, the crystalline hydrochloride salt of
       diphenyl ester 55 was well-absorbed and efficiently converted to the
       parent compound with an oral bioavailability of 50%. On the basis of
       these results as well as the physicochemical properties of the prodrugs
       and their stability in mouse duodenal contents, the hydrochloride salt
       of diphenyl ester 55 was identified as the preferred prodrug of 1.
 DE    Adenine/*ANALOGS & DERIVATIVES/CHEMICAL SYNTHESIS/PHARMACOLOGY/
       PHARMACOKINETICS  Animal  Antiviral Agents/*CHEMICAL
       SYNTHESIS/PHARMACOLOGY/  PHARMACOKINETICS  Biological Availability
       Female  Intestinal Absorption  Mice  Mice, Inbred BALB C
       Prodrugs/*CHEMICAL SYNTHESIS/PHARMACOLOGY/PHARMACOKINETICS  JOURNAL
       ARTICLE

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

