title: Synthesis and structure-activity relationships of 1-acyl-4-((2-methyl-3-pyridyl)cyanomethyl)piperazines as PAF antagonists.
abstract: A second generation of (cyanomethyl)piperazines, 1-acyl-4-((2-methyl-3-pyridyl)cyanomethyl)-piperazines, with increased oral activity was prepared and evaluated in vitro in a PAF-induced platelet aggregation assay (PAG) and in vivo in a PAF-induced hypotension test in normotensive rats (HYP). Oral activity was ascertained through a PAF-induced mortality test in mice (MOR). Attachment of a methyl group at position 2 of our earlier pyridine derivatives resulted in an improvement of 1 order of magnitude or greater in the ID50 of the oral test. Three different types of acyl substituents of similar potency emerge from this work: N-(diphenylmethylamino)acetyl, 3-substituted 3-hydroxy-3-phenylpropionyl, and N-substituted 3-amino-3-phenylpropionyl groups. The most interesting compounds, 26 (UR-12460, PAG IC50 = 0.040 microM, HYP, ID50 = 0.021 mg/kg i.v., MOR, ID50 = 0.30 mg/kg po) and 58 (UR-12519, PAG IC50 = 0.041 microM, HYP, ID50 = 0.015 mg/kg i.v., MOR, ID50 = 0.044 mg/kg po), compare favorably with WEB-2086. Compounds 26 and 58 were also tested in active anaphylactic shock (AAS) and endotoxin-induced mortality (EIM) tests. On the basis of these data, compounds 26 and 58 have been selected for further pharmacological development.
authors.affiliation: Chemistry and Pharmacology Laboratories, J. Uriach & Cía, S.A., Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Carceller
authors.forename: M
authors.initials: M
authors.lastname: Merlos
authors.forename: M
authors.initials: M
authors.lastname: Giral
authors.forename: C
authors.initials: C
authors.lastname: Almansa
authors.forename: J
authors.initials: J
authors.lastname: Bartrolí
authors.forename: J
authors.initials: J
authors.lastname: García-Rafanell
authors.forename: J
authors.initials: J
authors.lastname: Forn
mesh_terms: D000707:Anaphylaxis / Q000188:drug therapy; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004731:Endotoxins / Q000633:toxicity; D004926:Escherichia coli; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D004731:Endotoxins; D010879:Piperazines; D010972:Platelet Activating Factor; D011725:Pyridines; C083600:1-(3-(N-(methoxycarbonyl)amino)-3-phenylpropanoyl)-4-((2-methyl-3-pyridyl)cyanomethyl)piperazine; C083601:2-(N-(diphenylmethyl)amino)propanoic acid-4-((2-methyl-3-pyridinyl)cyanomethyl)piperazine