Azaprostanoic acid derivatives. Inhibitors of arachidonic acid induced platelet aggregation.
A series of 13-azaprostanoic acids (4a-h) and a 15-azaprostanoic acid (11a) have been prepared. Synthesis of the 15-aza derivative is based on a novel transformation of a ketone to an N-substituted ethylenamine using a formylmethylimino phosphate derivative. Several of the azaprostanoic acid derivatives were found to be potent inhibitors of platelet aggregation induced by arachidonic acid, whereas no effect was observed on ADP-induced primary aggregation, indicating blockade of the platelet arachidonic acid cascade. The compounds do not inhibit bovine cyclooxygenase activity and are postulated as acting beyond the synthesis of the prostaglandin endoperoxides. The inhibitory effect of the 13-aza series is highly sensitive to both stereochemistry and length of the amino side chain. Any deviation from the natural prostaglandin skeletal arrangement results in decreased biological activity.
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D002417:Cattle; D016861:Cyclooxygenase Inhibitors; D005227:Fatty Acids / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008722:Methods; D008968:Molecular Conformation; D010974:Platelet Aggregation / Q000187:drug effects*; D011466:Prostanoic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D012669:Seminal Vesicles / Q000201:enzymology; D013329:Structure-Activity Relationship
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D005227:Fatty Acids; D011466:Prostanoic Acids; D000244:Adenosine Diphosphate