Linked Life Data

19013076

Source:http://linkedlifedata.com/resource/pubmed/id/19013076

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
24
pubmed:dateCreated
2008-11-25
pubmed:abstractText
Recent studies demonstrated that inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity could be a new strategy to indirectly affect nitric oxide (NO) formation by elevating N(omega)-methylated L-arginine (NMMA, ADMA) levels. This approach is an alternate strategy for the treatment of diseases associated with increased NO-concentrations. To date, three classes of potent inhibitors are known: (1) pentafluorophenyl sulfonates (IC(50)=16-58 microM, PaDDAH), which are also inhibitors for the arginine deiminase; (2) the most potent inhibitors are based on indolylthiobarbituric acid (IC(50)=2-17 microM, PaDDAH), which were identified by virtual modelling; and (3) L-arginine analogs, whose best representative is N(omega)-(2-methoxyethyl)-L-arginine (IC(50)=22 microM, rat DDAH). Based on these known structures, we aimed to develop inhibitors for the human DDAH-1 with improved potency and better relative selectivity for DDAH-1 over NOS. Particularly, the binding pocket of the guanidine-moiety was investigated by screening differently substituted guanidines, amidines and isothioureas in order to collect information on possible binding modes in the active site. All substances were tested in a plate-reader format and HPLC assay and several potent inhibitors were identified with K(i)-values varying from 2 to 36 microM, with N(5)-(1-iminobut-3-enyl)-L-ornithine (L-VNIO) being the most potent inhibitor of the human DDAH-1 so far described. Besides these potent inhibitors alternate substrates for hDDAH-1 were identified as well.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1464-3391
pubmed:author
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
16
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
10205-9
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Structure-activity relationship of novel and known inhibitors of human dimethylarginine dimethylaminohydrolase-1: alkenyl-amidines as new leads.
pubmed:affiliation
Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, Christian-Albrechts-University of Kiel, Gutenbergstrasse 76-78, D-24118 Kiel, Germany.
pubmed:publicationType
Journal Article