Linked Life Data

8352384

Source:http://linkedlifedata.com/resource/pubmed/id/8352384

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
1993-9-16
pubmed:abstractText
A new, orally-active inhibitor of dihydrofolic acid reductase (DHFR), PS-15 (N-(3-(2,4,5-trichlorophenoxy)propyloxy)-N'-(1-methylethyl)- imidocarbonimidic diamide hydrochloride), has significant activity against drug-resistant Plasmodium falciparum. It is not cross-resistant with other inhibitors of DHFR (e.g., pyrimethamine and cycloguanil). Although it bears similarities to proguanil, PS-15 represents a new antifolate class of drugs that we have named oxyguanils or hydroxylamine-derived biguanides. This compound displays intrinsic antimalarial activity and also is metabolized in vivo to WR99210, an extremely active triazine inhibitor of DHFR. When tested in vitro against drug-resistant clones of P. falciparum, PS-15 was more active than proguanil, and the putative metabolite, WR99210, was more active than the proguanil metabolite cycloguanil. The drug is also more active as well as less toxic than proguanil when administered orally to mice infected with P. berghei. When administered orally to Aotus monkeys infected with multidrug-resistant P. falciparum, PS-15 was more active than either proguanil or WR99210. In 1973, WR99210 underwent clinical trials for safety and tolerance in volunteers. The trials showed gastrointestinal intolerance and limited bioavailability; further development of the drug was abandoned. Because PS-15 has intrinsic antimalarial activity, is not cross-resistant with other DHFR inhibitors, and can be metabolized to WR99210 in vivo, oral administration of this new drug should circumvent the shortcomings and retain the advantages found with both proguanil and WR99210.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0002-9637
pubmed:author
pubmed:issnType
Print
pubmed:volume
49
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
121-6
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:year
1993
pubmed:articleTitle
PS-15: a potent, orally active antimalarial from a new class of folic acid antagonists.
pubmed:affiliation
Pharmaceutical Systems Inc., Gaithersburg, Maryland.
pubmed:publicationType
Journal Article, Comparative Study