title: Phosphodiesterase type IV inhibition. Structure-activity relationships of 1,3-disubstituted pyrrolidines.
abstract: 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 enable structure-activity relationships to be assessed. Groups which render the pyrrolidine nitrogen of 2 nonbasic yielded potent PDE-IV inhibitors. Analogs of amides, carbamates, and ureas of 2 were synthesized to determine the effects that substitution on these functional groups had 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 selective for inhibiting PDE-IV versus representative PDEs from families I-III and V. Furthermore, these same three inhibitors demonstrated potent functional activity (IC50 < 1 microM) by inhibiting tumor necrosis factor-alpha (TNF-alpha) release from lipopolysaccharide (LPS)-activated purified human peripheral blood monocytes and mouse peritoneal macrophages. These compounds were also tested orally in LPS-injected mice and demonstrated dose-dependent inhibition of serum TNF-alpha levels.
authors.affiliation: Glaxo Research Institute, Research Triangle Park, North Carolina 27709, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Feldman
authors.forename: M F
authors.initials: MF
authors.lastname: Brackeen
authors.forename: D J
authors.initials: DJ
authors.lastname: Cowan
authors.forename: B E
authors.initials: BE
authors.lastname: Marron
authors.forename: F J
authors.initials: FJ
authors.lastname: Schoenen
authors.forename: J A
authors.initials: JA
authors.lastname: Stafford
authors.forename: E M
authors.initials: EM
authors.lastname: Suh
authors.forename: P L
authors.initials: PL
authors.lastname: Domanico
authors.forename: D
authors.initials: D
authors.lastname: Rose
authors.forename: M A
authors.initials: MA
authors.lastname: Leesnitzer
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D010726:Phosphodiesterase Inhibitors; D011759:Pyrrolidines; D014409:Tumor Necrosis Factor-alpha