Linked Life Data

8164261

Source:http://linkedlifedata.com/resource/pubmed/id/8164261

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
8
pubmed:dateCreated
1994-5-24
pubmed:abstractText
The syntheses, biological evaluations, and structure-activity relationships of a series of 4,5-bis-(4-methoxyphenyl)-2-substituted-thiazoles as potent antiplatelet agents with vasodilatory activity are described. 2-Guanidino-4,5-bis(4-methoxyphenyl)thiazole (3), designed from two parent compounds (itazigrel and timegadine), showed inhibitory activity of malondialdehyde (MDA, IC50 = 31 microM) production which is formed from the cyclooxygenase (CO)-catalyzed oxygenation of arachidonic acid in the synthesis of prostanoids in platelets, with vasodilatory activity (ED50 = 2.0 microM). Further structure-activity relationship studies on 3 culminated in the preparation of 4,5-bis(4-methoxyphenyl)-2-[(1-methylpiperazin-4-yl)carbonyl]thiaz ole (10a, FR122047) which exhibited potent inhibitory activity on MDA synthesis in vitro (IC50 = 0.088 microM) and platelet aggregation in guinea pigs ex vivo (100% inhibition even 6 h after 1.0 mg/kg administration) with vasodilatory activity in vitro (ED50 = 6.2 microM). Moreover, 10a demonstrated no ulcerogenesis effect in rats even at 100 mg/kg dosage (safety margin in rats is more than 70 while that of aspirin is only 1.2) in spite of its potent CO inhibition (IC50 = 0.43 microM14), while the use of aspirin, a CO inhibitor and the most popular thromboembolic drug, is restricted by the side effect. Pharmacokinetic studies on 10a have revealed that 10a is detectable in platelet-rich plasma but not in platelet-poor plasma 1 day after oral administration, which indicates that 10a tends to be localized in platelets. This property could be responsible for its low toxicity and reduction of side effects in clinical studies.
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
15
pubmed:volume
37
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1189-99
pubmed:dateRevised
2003-11-14
pubmed:meshHeading
pubmed:year
1994
pubmed:articleTitle
Antiplatelet agents based on cyclooxygenase inhibition without ulcerogenesis. Evaluation and synthesis of 4,5-bis(4-methoxyphenyl)-2-substituted-thiazoles.
pubmed:affiliation
New Drug Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan.
pubmed:publicationType
Journal Article