(Pyridylcyanomethyl)piperazines as orally active PAF antagonists.
A series of (pyridylcyanomethyl)piperazines was prepared and evaluated for PAF-antagonist activity. Compounds were tested in vitro in a PAF-induced platelet aggregation assay and in vivo in a PAF-induced hypotension test in normotensive rats. Oral activity was ascertained through a PAF-induced mortality test in mice. The main structure-activity trends of the series were established. Activity was mainly found in four skeletons: 1-acyl-4-(3-pyridylcyanomethyl)piperazine, 1-acyl-4-(4-pyridylcyanomethyl)piperazine, 1-acyl-4-(3-pyridylcyanomethyl)piperidine, and 1-acyl-4-cyano-4-(3-pyridylamino)piperidine. The acyl substituents, diphenylacetyl and 3,3-diphenylpropionyl, provided the most active compounds, and the introduction of an amine or hydroxy group in the 3,3-diphenylpropionyl substituent led to further improvement in oral activity. As a result, three of the most active compounds (100, 114, and 115) have been selected for further pharmacological development.
Carceller
E
E
Chemistry Laboratory, J. Uriach & Cía.S.A., Barcelona, Spain.
Almansa
C
C
Merlos
M
M
Giral
M
M
Bartrolí
J
J
García-Rafanell
J
J
Forn
J
J
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D010879:Piperazines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D010879:Piperazines; D010880:Piperidines; D010972:Platelet Activating Factor