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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
1
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pubmed:dateCreated |
2007-1-4
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pubmed:abstractText |
The metabolism of our prototypical thrombin receptor antagonist 1, Ki = 2.7 nM, was studied and three major metabolites (2, 4, and 5) were found. The structures of the metabolites were verified independently by synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a Ki = 11 nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activity was sustained with 60% inhibition observed at 24 h post-dose. Compound 4 was highly active in functional assays and showed excellent oral bioavailability in rats and monkeys. Compound 4 showed a superior rat enzyme induction profile relative to compound 1, allowing it to replace compound 1 as a development candidate.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:Agans-FantuzziJacquelineJ,
pubmed-author:AhnHo-SamHS,
pubmed-author:AltonKevinK,
pubmed-author:BoykowGeorgeG,
pubmed-author:BryantMatthewM,
pubmed-author:ChackalamannilSamuelS,
pubmed-author:ChintalaMadhuM,
pubmed-author:ClasbyMartin CMC,
pubmed-author:CzarnieckiMichaelM,
pubmed-author:DollerDarioD,
pubmed-author:EagenKeithK,
pubmed-author:FosterCarolynC,
pubmed-author:GreenleeWilliamW,
pubmed-author:HsiehYunshengY,
pubmed-author:KaoGraceG,
pubmed-author:LauJaniceJ,
pubmed-author:OrrV BVB,
pubmed-author:PalamandaJairamJ,
pubmed-author:Smith-TorhanAprilA,
pubmed-author:TsaiHsinganH,
pubmed-author:YanXiaX
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pubmed:issnType |
Print
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pubmed:day |
11
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pubmed:volume |
50
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
129-38
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pubmed:meshHeading |
pubmed-meshheading:17201416-Animals,
pubmed-meshheading:17201416-Biological Availability,
pubmed-meshheading:17201416-Cytochrome P-450 Enzyme System,
pubmed-meshheading:17201416-Furans,
pubmed-meshheading:17201416-Heterocyclic Compounds, 3-Ring,
pubmed-meshheading:17201416-Humans,
pubmed-meshheading:17201416-Macaca fascicularis,
pubmed-meshheading:17201416-Microsomes, Liver,
pubmed-meshheading:17201416-Platelet Aggregation,
pubmed-meshheading:17201416-Platelet Aggregation Inhibitors,
pubmed-meshheading:17201416-Pyridines,
pubmed-meshheading:17201416-Radioligand Assay,
pubmed-meshheading:17201416-Rats,
pubmed-meshheading:17201416-Receptors, Thrombin,
pubmed-meshheading:17201416-Stereoisomerism,
pubmed-meshheading:17201416-Structure-Activity Relationship
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pubmed:year |
2007
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pubmed:articleTitle |
Metabolism-based identification of a potent thrombin receptor antagonist.
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pubmed:affiliation |
Central Nervous System and Cardiovascular Chemical Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
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pubmed:publicationType |
Journal Article,
In Vitro
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