PHOSPHODIESTERASE TYPE-IV INHIBITION - STRUCTURE-ACTIVITY-RELATIONSHIPS OF 1,3-DISUBSTITUTED PYRROLIDINES

The synthesis of 1,3-disubstituted pyrrolidines 2 and their activities as type IV phosphodiesterase (PDE) inhibitors are described. Various groups were appended to the nitrogen of the pyrrolidine nucleus to ena ble structure-activity relationships to be assessed. Groups which rend er the pyrrolidine nitrogen of 2 nonbasic yielded potent PDE-IV inhibi tors. Analogs of amides, carbamates, and ureas of 2 were synthesized t o determine the effects that substitution on these functional groups h ad on PDE-IV inhibitor potency. The structural requirements for PDE-IV inhibitor potency differed among the three classes. A representative amide, carbamate, and urea (2c,d,h) were shown to be >50-fold selectiv e for inhibiting PDE-IV versus representative PDEs from families I-III and V. Furthermore, these same three inhibitors demonstrated potent f unctional activity (IC50 < 1 mu M) by inhibiting tumor necrosis factor -alpha (TNF-alpha) release from lipopolysaccharide (LPS)-activated pur ified human peripheral blood monocytes and mouse peritoneal macrophage s. These compounds were also tested orally in LPS-injected mice and de monstrated dose-dependent inhibition of serum TNF-alpha levels.