CGP 47969A - A NOVEL INHIBITOR OF THE SYNTHESIS OF INFLAMMATORY CYTOKINES

CGP 47969A is a novel piperazine derivative that inhibits the synthesi s of inflammatory cytokines, such as interleukin-1 alpha (IL-1), IL-1 beta and tumor necrosis factor alpha (TNF), in human monocytes stimula ted with lipopolysaccharide (LPS), zymosan or IL-1 itself. IC50 values are in the range of 0.3-5 mu mol/l. CGP 47969A does not inhibit total protein or RNA synthesis indicating selectivity for cytokine inhibiti on. CGP 47969A exerts its inhibitory effect at a post-transcriptional level, most probably by reducing translational efficiency of IL-beta m RNA, as steady-state levels of IL-1 beta mRNA are not inhibited while the primary translation product, the 31 kD IL-1 beta precursor molecul e, is dose-dependently inhibited by CGP 47969A. The compound is devoid of cyclooxygenase and phospholipase A(2) inhibitory activity but effi ciently inhibits the generation of PGE(2) and LTC(4) in zymosan-stimul ated mouse macrophages with an IC50 Of 1.2 and 0.6 mu mol/l, respectiv ely. Antagonism of IL-1 and/or TNF is thought to have a beneficial eff ect on the course of inflammatory diseases. CGP 47969A may therefore r epresent a mechanistically new approach to the treatment of such disea ses.