Structure-activity relationships within a series of 1,3,4-trisubstituted pyrrolidines, novel and selective inhibitors of cAMP-specific phosphodiesterase (PDE IV), are discussed.Phosphodiesterases comprise a family of enzymes whose role in mammalian ceils is to regulate the levels of the ubiquitous second messenger cyclic nucleotides, cAMP and cGMP, by their degradation to inactive 5'-monophoshate metabolites. 1 Within inflammatory ceils, such as monocytes and macrophages, the cAMPspecific phosphodiesterase type IV (PDE IV) has been shown to be the principal PDE isotype. 2 The observation that an elevation of cAMP in these proinflammatory cells can suppress their activation 3 has stimulated wide interest in developing therapeutic agents for chronic inflammatory diseases through selective inhibition of PDE IV. 4Rolipram [(R, S)-4-(3-cyclopentoxy-4-methoxyphenyl)-2-pyrrolidinone] (1) is a selective inhibitor of PDE IV 5 and has served as the starting point for a number of medicinal chemistry groups whose aim has been both to improve its potency against PDE IV and to moderate its dose-limiting side effects. A number of groups, including our own, have reported the synthesis of PDE IV inhibitors derived from rolipram, in which the modifications were made to the pyrrolidinone ring.6, 7 In particular, we have shown that selective PDE IV inhibition can be preserved by a simple modification to rolipram, namely transposing the rolipram lactam carbonyl to an exocyclic position, thereby generating a 1,3-substituted pyrrolidine as represented by the generic structure 2. 6e In this Letter we describe the synthesis and structure-activity relationships of a series of 1,3,4 substituted pyrrolidines, exemplified by the methyl ketone 3. Lacking any structural data on our enzyme target, we reasoned that the added substitution at C3 of the pyrrolidine ring in 3 and related compounds might provide us with a better understanding of the steric and electronic requirements necessary for PDE IV inhibition.