New polycyclic pyrimidine derivatives with antiplatelet in vitro activity: synthesis and pharmacological screening.
Bioorg Med Chem
; 9(3): 629-36, 2001 Mar.
Article
em En
| MEDLINE
| ID: mdl-11310597
ABSTRACT
The preparation and the pharmacological screening of novel anti-aggregatory/antiphlogistic polycyclic pyrimidine derivatives are described. The compounds were developed starting from bioactive 2-aminobenzopyranopyrimidine derivatives in order to assess the importance of the benzopyrano[4,3-d]pyrimidine structure and the role of an amino basic moiety in position 2. Antiplatelet activity was assessed in vitro against ADP and arachidonic acid-induced aggregation in guinea-pig plasma. Anti-inflammatory/analgesic/antipyretic activities were studied in rat paw oedema, mouse writhing test and E. coli-induced rat fever. Ulcerogenic and gastroprotective effects were also investigated in vivo on rat gastric mucosa. Among the tested compounds, the 5-substituted benzopyranopyrimidine derivatives 3d and 4d proved to be the most active antiplatelet agents as potent as acetylsalicylic acid against arachidonic acid-stimulated aggregation. Furthermore the 2-methylthio derivative 4d was endowed with greater efficacy against ADP aggregation suggesting that additional non-TXA2 dependent mechanisms are involved in its biological activity. Orally administered at 100 mg kg(-1) in rats this latter compound displayed antiphlogistic acitivity comparable to indomethacin (10 mg kg(-1)) coupled with an unusual gastroprotective effect on ethanol-induced ulcers. In conclusion, these findings indicate that the 5-pyrrolidino-2-methylthiobenzopyrano[4,3-d]pyrimidine 4d fulfils the chemical requirements to exhibit antiplatelet activity associated with gastroprotective effect.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Inibidores da Agregação Plaquetária
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Limite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2001
Tipo de documento:
Article
País de afiliação:
Itália