Linked Life Data

20843082

Source:http://linkedlifedata.com/resource/pubmed/id/20843082

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
40
pubmed:dateCreated
2010-10-7
pubmed:abstractText
In our efforts to discover neuronal isoform selective nitric oxide synthase (NOS) inhibitors, we have developed a series of compounds containing a pyrrolidine ring with two stereogenic centers. The enantiomerically pure compounds, (S,S) versus (R,R), exhibited two different binding orientations, with (R,R) inhibitors showing much better potency and selectivity. To improve the bioavailability of these inhibitors, we have introduced a CF(2) moiety geminal to an amino group in the long tail of one of these inhibitors, which reduced its basicity, resulting in compounds with monocationic character under physiological pH conditions. Biological evaluations have led to a nNOS inhibitor with a K(i) of 36 nM and high selectivity for nNOS over eNOS (3800-fold) and iNOS (1400-fold). MM-PBSA calculations indicated that the low pK(a) NH is, at least, partially protonated when bound to the active site. A comparison of rat oral bioavailability of the difluorinated compound to the parent molecule shows 22% for the difluorinated compound versus essentially no oral bioavailability for the parent compound. This indicates that the goal of this research to make compounds with only one protonated nitrogen atom at physiological pH to allow for membrane permeability, but which can become protonated when bound to NOS, has been accomplished.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1520-5126
pubmed:author
pubmed:issnType
Electronic
pubmed:day
13
pubmed:volume
132
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
14229-38
pubmed:dateRevised
2011-10-13
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Potent, highly selective, and orally bioavailable gem-difluorinated monocationic inhibitors of neuronal nitric oxide synthase.
pubmed:affiliation
Department of Chemistry and Biochemistry, Center for Molecular Innovation and Drug Discovery, Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural