home
***
CD-ROM
|
disk
|
FTP
|
other
***
search
/
Shareware Overload Trio 2
/
Shareware Overload Trio Volume 2 (Chestnut CD-ROM).ISO
/
dir26
/
med9408a.zip
/
M9480084.TXT
< prev
next >
Wrap
Text File
|
1994-08-09
|
3KB
|
45 lines
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).