Synthesis of acylguanidine analogues: inhibitors of ADP-induced platelet aggregation.
Routine screening of compounds for inhibition of ADP-induced platelet aggregation in vitro revealed that 1,1'-hexamethylenebis[3-cyclohexyl-3-[(cyclohexylimino) (4-morpholinyl) methyl]urea] (1) was active and represented the first example of a bis(acylguanidine) with possible antithrombotic activity. In order to develop a structure-activity relationship for this class of compounds, we synthesized a number of new bis(acylguanidines). These were tested in vitro, and several analogues were also active. Ex vivo testing revealed that compounds 22, 41, 58, and 70-73 were orally active in rats or guinea pigs.
Thomas
E W
EW
Upjohn Company, Kalamazoo, Michigan 49001.
Nishizawa
E E
EE
Zimmermann
D C
DC
Williams
D J
DJ
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D003959:Diamines / Q000138:chemical synthesis* / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D009025:Morpholines / Q000138:chemical synthesis* / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis*; D051381:Rats; D013329:Structure-Activity Relationship
D003959:Diamines; D006146:Guanidines; D009025:Morpholines; D010975:Platelet Aggregation Inhibitors; C058124:1,1'-hexamethylenebis(3-cyclohexyl-3-((cyclohexylimino)(4-morpholinyl)methyl)urea); D000244:Adenosine Diphosphate