149692-12-6Relevant academic research and scientific papers
Synthesis and Structure-Activity Relationships of 1-Acyl-4-(2-methyl-3-pyridyl)cyanomethyl)piperazines as PAF Antagonists
Carceller, Elena,Merlos, Manuel,Giral, Marta,Almansa, Carmen,Bartroli, Javier,et al.
, p. 2984 - 2997 (2007/10/02)
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 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 acylsubstituents 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 μM, HYP, ID50 = 0.021 mg/kg iv, MOR, ID50 = 0.30 mg/kg po) and 58 (UR-12519, PAG IC50 = 0.041 μM, HYP, ID50 = 0.015 mg/kg iv, 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.
