title: New polycyclic pyrimidine derivatives with antiplatelet in vitro activity: synthesis and pharmacological screening.
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.
authors: Dipartimento di Scienze Farmaceutiche, Università degli Studi, Genova, Italy.
authors: O
authors: O
authors: Bruno
authors: S
authors: S
authors: Schenone
authors: A
authors: A
authors: Ranise
authors: F
authors: F
authors: Bondavalli
authors: E
authors: E
authors: Barocelli
authors: V
authors: V
authors: Ballabeni
authors: M
authors: M
authors: Chiavarini
authors: S
authors: S
authors: Bertoni
authors: M
authors: M
authors: Tognolini
authors: M
authors: M
authors: Impicciatore
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005753:Gastric Mucosa / Q000187:drug effects; D006168:Guinea Pigs; D020128:Inhibitory Concentration 50; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D000893:Anti-Inflammatory Agents; D010975:Platelet Aggregation Inhibitors; D011083:Polycyclic Compounds; D011743:Pyrimidines