Synthesis, platelet aggregation inhibitory activity, and in vivo antithrombotic activity of new 1,4-dihydropyridines

A series of 1,4-dihydropyridines (DHP) bound to 1,2-benzisothiazol-3-ones were synthesized and evaluated for their ability to inhibit platelet aggregation induced by collagen in human platelet-rich plasma (PRP) and to protect mice against experimental thrombosis. The results showed that the compound...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1988-10, Vol.31 (10), p.1886-1890
Main Authors: Sunkel, Carlos E, Fau de Casa-Juana, Miguel, Cillero, Francisco Javier, Priego, Jaime G, Ortega, M. Pilar
Format: Article
Language:English
Subjects:
Animals
Cats
Chemistry
Collagen - pharmacology
Dihydropyridines - chemical synthesis
Dihydropyridines - pharmacology
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms
Humans
Kinetics
Male
Mice
Nitrendipine - pharmacology
Organic chemistry
Platelet Aggregation - drug effects
Preparations and properties
Rats
Rats, Inbred Strains
Structure-Activity Relationship
Thrombosis - prevention & control
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Summary:A series of 1,4-dihydropyridines (DHP) bound to 1,2-benzisothiazol-3-ones were synthesized and evaluated for their ability to inhibit platelet aggregation induced by collagen in human platelet-rich plasma (PRP) and to protect mice against experimental thrombosis. The results showed that the compounds were in vitro inhibitors of collagen-induced platelet aggregation. Most of them were also effective in reducing mortality in the mouse antithrombotic assay. 2-(1,1,3-Trioxo-2,3-dihydro-1,2-benzisothiazol-2-yl)ethyl 2,6-dimethyl-5-(ethoxycarbonyl)-4-methyl-1,4-dihydropyridinecarboxyla te (4A) is the most promising compound. This compound did not show any cardiovascular effects either in the anesthetized cat or in the anesthetized rat at iv doses up to 750 or 500 micrograms/kg, respectively. Likewise, antiplatelet and cardiovascular effects of compound 4A were simultaneously studied in anesthetized rats and compared with those of nitrendipine.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00118a004