Replacement of the polar head of our previous series of 1-acyl-4-[(2-methyl-3-pyridyl)-cyanomethyl]piperazines with a 2-methylimidazo[4,5-c]pyridine group has led to the identification of a new series of 1-[(1-acyl-4- piperidyl)methyl]-1H-2-methylimidazo[4,5-c]pyridine derivatives as potent, orally active platelet-activating factor (PAF) antagonists. On the basis of the general structure--activity relationship trends found for the acyl substituent in our earlier series, five groups of compounds were tested, diaryl- or alkylarylpropanoyl derivatives, their 3-hydroxy-substituted analogues, and urea, carbamate and amino acid derivatives. The optimal compound 19 UR-12670), bearing the 3,3-diphenylpropanoyl moiety, exhibited very high in vitro and in vivo potency IC50 = 0.0076 microM for the in vitro PAF-induced platelet aggregation assay, ID50 = 0.0086 mg/kg for the in vivo PAF-induced hypotension test in normotensive rats, and ID50 = 0.092 mg/kg po and 0.0008 mg/kg i.v. for the PAF-induced mortality test in mice). Compound 19 also showed long duration of activity. It gave 100% protection against PAF-induced mortality in mice 7 h after i.v. administration of a single dose of 1 mg/kg and also provided 100% inhibition of PAF-induced aggregation in dog whole blood 6 h after i.v. administration of the same dose. The lead structure 19 has been selected for in-depth pharmacological evaluation.