title: CGP 47969A: a novel inhibitor of the synthesis of inflammatory cytokines.
abstract: CGP 47969A is a novel piperazine derivative that inhibits the synthesis of inflammatory cytokines, such as interleukin-1 alpha (IL-1), IL-1 beta and tumor necrosis factor alpha (TNF), in human monocytes stimulated with lipopolysaccharide (LPS), zymosan or IL-1 itself. IC50 values are in the range of 0.3-5 mumol/l. CGP 47969A does not inhibit total protein or RNA synthesis indicating selectivity for cytokine inhibition. CGP 47969A exerts its inhibitory effect at a post-transcriptional level, most probably by reducing translational efficiency of IL-beta mRNA, as steady-state levels of IL-1 beta mRNA are not inhibited while the primary translation product, the 31 kD IL-1 beta precursor molecule, is dose-dependently inhibited by CGP 47969A. The compound is devoid of cyclooxygenase and phospholipase A2 inhibitory activity but efficiently inhibits the generation of PGE2 and LTC4 in zymosan-stimulated mouse macrophages with an IC50 of 1.2 and 0.6 mumol/l, respectively. Antagonism of IL-1 and/or TNF is thought to have a beneficial effect on the course of inflammatory diseases. CGP 47969A may therefore represent a mechanistically new approach to the treatment of such diseases.
authors.affiliation: Research Laboratories, Ciba-Geigy Ltd., Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Rordorf-Adam
authors.forename: T
authors.initials: T
authors.lastname: Geiger
authors.forename: R
authors.initials: R
authors.lastname: Henn
authors.forename: J
authors.initials: J
authors.lastname: Arnold
authors.forename: R
authors.initials: R
authors.lastname: Solf
authors.forename: I
authors.initials: I
authors.lastname: Wiesenberg
authors.forename: P G
authors.initials: PG
authors.lastname: Ferrini
authors.forename: K
authors.initials: K
authors.lastname: Vosbeck
mesh_terms: D000818:Animals; D002417:Cattle; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010741:Phospholipases A / Q000187:drug effects; D054467:Phospholipases A2; D010879:Piperazines / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D012669:Seminal Vesicles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C092257:CGP 47969A; D016207:Cytokines; D010879:Piperazines; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2