Linked Life Data

15056002

Source:http://linkedlifedata.com/resource/pubmed/id/15056002

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
8
pubmed:dateCreated
2004-4-1
pubmed:abstractText
In our efforts to develop orally active GPIIb-IIIa antagonists with improved pharmaceutical properties, we have utilized a novel 2,8-diazaspiro[4.5]decane scaffold as a template. We describe here our investigation of a variety of templates including spiropiperidinyl-gamma-lactams, spiropiperidinylimide, spiropiperidinylureas, and spiropiperidinylhydantoins. With the appropriate acidic and basic pharmacophores in place, each template yielded analogues with potent GPIIb-IIIa inhibitory activity. One of the compounds, 59 (CT50787), was also used to demonstrate for the first time the use of a pharmacological agent which is alphaIIbbeta3 specific to display biological activity in a lower species such as mouse and to extend bleeding times. Evaluation of the pharmacokinetic properties of selected compounds from each series in rat, dog, and cynomolgus monkey has led to the identification of 22 (CT51464), a double prodrug, with excellent pharmacokinetic properties. It exhibited good pharmacokinetic profile across species (F% = 33 (Cyno), 73 (dog), 22 (rat); t(1/2)(beta)() = 14.2 h (Cyno), 8.97 h (dog), 1.81 h (rat)). The biologically active form, 23 (CT50728), displayed inhibition of platelet aggregation in platelet rich plasma (PRP) with an IC(50) value of 53 nM in citrate buffer, 110 nM in PPACK anticoagulated PRP, and 4 nM in solid-phase GPIIb-IIIa competition binding assay (ELISA). Both 23 and 22 were stable in human liver microsomes, did not inhibit the P450 3A4 isozyme, and had low protein binding (18.22% for 23) and a desirable log P (0.45 +/- 0.06 for 22, and -0.91 +/- 0.32 for 23). It is predicted that the high oral bioavailability for these compounds in multiple species should translate into lower intra- and intersubject variability in man. The long plasma half-life of the lead is consistent with once or twice daily administration for chronic therapy. Analogue 22 (CT51464) thus appears to be a promising oral GPIIb-IIIa inhibitor with significantly improved pharmacokinetic properties over the previously described clinical candidates and may be found useful in the treatment of arterial occlusive disorders.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
8
pubmed:volume
47
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2037-61
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:15056002-Administration, Oral, pubmed-meshheading:15056002-Alkanes, pubmed-meshheading:15056002-Animals, pubmed-meshheading:15056002-Aza Compounds, pubmed-meshheading:15056002-Binding, Competitive, pubmed-meshheading:15056002-Biological Availability, pubmed-meshheading:15056002-Bleeding Time, pubmed-meshheading:15056002-Dogs, pubmed-meshheading:15056002-Humans, pubmed-meshheading:15056002-Hydantoins, pubmed-meshheading:15056002-Hydroxylamines, pubmed-meshheading:15056002-Lactams, pubmed-meshheading:15056002-Macaca fascicularis, pubmed-meshheading:15056002-Mice, pubmed-meshheading:15056002-Platelet Aggregation Inhibitors, pubmed-meshheading:15056002-Platelet Glycoprotein GPIIb-IIIa Complex, pubmed-meshheading:15056002-Prodrugs, pubmed-meshheading:15056002-Rats, pubmed-meshheading:15056002-Rats, Sprague-Dawley, pubmed-meshheading:15056002-Spiro Compounds, pubmed-meshheading:15056002-Structure-Activity Relationship, pubmed-meshheading:15056002-Urea
pubmed:year
2004
pubmed:articleTitle
Discovery of novel 2,8-diazaspiro[4.5]decanes as orally active glycoprotein IIb-IIIa antagonists.
pubmed:affiliation
Millennium Pharmaceuticals Inc., 256 E. Grand Avenue, South San Francisco, CA 94080, USA. mukund_mehotra@hotmail.com
pubmed:publicationType
Journal Article, In Vitro