SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF CYL-4-((2-METHYL-3-PYRIDYL)CYANOMETHYL)PIPERAZINES AS PAF ANTAGONISTS

A second generation of (cyanomethyl)piperazines, l-4-((2-methyl-3-pyri dyl)cyanomethyl)-piperazines, with increased oral activity was prepare d and evaluated in vitro in a PAF-induced platelet aggregation assay ( PAG) and in vivo in a PAF-induced hypotension test in normotensive rat s (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 ty pes 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 interest ing compounds, 26 (UR-12460, PAG IC50 = 0.040 muM, HYP, ID50 = 0.021 m g/kg iv, MOR, ID50 = 0.30 mg/kg po) and 58 (UR- 12519, PAG IC50 = 0.04 1 muM, HYP, ID50 = 0.015 mg/kg iv, MOR, ID50 = 0.044 mg/kg po), compar e favorably with WEB-2086. Compounds 26 and 58 were also tested in act ive anaphylactic shock (AAS) and endotoxin-induced mortality (EIM) tes ts. On the basis of these data, compounds 26 and 58 have been selected for further pharmacological development.