Linked Life Data

2754699

Source:http://linkedlifedata.com/resource/pubmed/id/2754699

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
8
pubmed:dateCreated
1989-9-7
pubmed:abstractText
Potential oral prodrugs of the antiherpesvirus acyclonucleoside 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]guanine (1, BRL 39123) have been synthesized and evaluated for bioavailability of 1 in the blood of mice. Reduction of 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-amino-6-chloropurine (13) using ammonium formate and 10% palladium on carbon afforded the 2-aminopurine 14, which was hydrolyzed to the monoacetate 15 and to 2-amino-9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]purine (5). The 2-aminopurine 5 was subsequently converted to additional monoester (17, 21-23) and diester (16, 24) derivatives and to its di-O-isopropylidene derivative 18. Both 5 and its esters (14-17, 21, 22) and also 18 were well absorbed after oral administration and converted efficiently to 1, the diacetyl (14) and dipropionyl (16) esters providing concentrations of 1 in the blood that were more than 15-fold higher than those observed after dosing either 1 or its esters (25-27). Some 6-alkoxy-9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]purines (8-10), the preparation of which has been reported previously, also showed improved absorption properties, but their conversion to 1 was less efficient than for the 2-aminopurine derivatives. On the basis of these results and subsequent experiments involving determinations of rates of conversion to 1 in the presence of rat and human tissue preparations, 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-aminopurine (14, BRL 42810) was identified as the preferred prodrug of 1. Oral bioavailability studies in healthy human subjects confirmed 14 as an effective prodrug, and this compound is now being evaluated in clinical trials.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:volume
32
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1738-43
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed:year
1989
pubmed:articleTitle
Prodrugs of the selective antiherpesvirus agent 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]guanine (BRL 39123) with improved gastrointestinal absorption properties.
pubmed:affiliation
Beecham Pharmaceuticals Research Division, Biosciences Research Centre, Epsom, Surrey, U.K.
pubmed:publicationType
Journal Article