Abstract
The synthesis and the biological evaluation of new potent phosphodiesterase type 4 (PDE4) inhibitors are presented. This new series was elaborated by replacement of the metabolically resistant phenyl hexafluorocarbinol of L-791,943 ( 1) by a substituted aminopyridine residue. The structure–activity relationship of N-substitution on 3 led to the identification of (−)- 3n which exhibited a good PDE4 inhibitor activity (HWB-TNFα=0.12 μM) and an improved pharmacokinetic profile over L-791,943 (rat t 1/2=2 h). (−)- 3n was well tolerated in ferret with an emetic threshold of 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig (54%, 0.1 mg/kg, ip) as well as the ascaris-induced bronchoconstriction model in sheep (64%/97%, early/late, 0.5 mg/kg, iv).
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