DESIGN, SYNTHESIS, AND STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF NOVEL IPERIDYL)METHYL]-1H-2-METHYLIMIDAZO[4,5-C]PYRIDINE DERIVATIVES AS POTENT, ORALLY-ACTIVE PLATELET-ACTIVATING-FACTOR ANTAGONISTS

Replacement of the polar head of our previous series of yl-4-[(2-methy l-3-pyridyl)-cyanomethyl]piperazines with a 2-methylimidazo[4,5-c]pyri dine group has led to the identification of a new series of iperidyl)m ethyl]-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 teste d, diaryl- or alkylarylpropanoyl derivatives, their 3-hydroxy-substitu ted analogues, and urea, carbamate and amino acid derivatives. The opt imal compound 19 (UR-12670), bearing the 3,3-diphenylpropanoyl moiety, exhibited very high in vitro and in vivo potency (IC50 = 0.0076 mu M for the in vitro PAF-induced platelet aggregation assay, ID50 = 0.0086 mg/kg for the in vivo PAF-induced hypotension test in normotensive ra ts, and ID50 = 0.092 mg/kg po and 0.0008 mg/kg iv for the PAF-induced mortality test in mice). Compound 19 also showed long duration of acti vity. It gave 100% protection against PAF-induced mortality in mice 7 h after iv administration of a single dose of 1 mg/kg and also provide d 100% inhibition of PAF-induced aggregation in dog whole blood 6 h af ter iv administration of the same dose. The lead structure 19 has been selected for in-depth pharmacological evaluation.