INHIBITION OF HUMAN PLATELETS AND POLYMORPHONUCLEAR NEUTROPHILS BY THE POTENT AND METABOLICALLY STABLE PROSTAGLANDIN-D-2 ANALOG ZK-118.182

The actions of the novel metabolically stable and selective prostaglandin D-2 receptor agonist ZK 118.182 ((5Z,13E)(9R,11R,15S)-9-chloro-15-cyclohexyl-15-hydroxy-16,17,18,19,20-pentanor-3-oxa-5,13-prostadienoic acid) were studied in human platelets and polymorphonuclear neutrophils in vitro and compared to the naturally occuring agonist prostaglandin D-2. ZK 118.182 inhibited collagen and ADP induced platelet aggregation more potently than prostaglandin D-2 (IC50: 15 nM versus 60 nM) but was less effective than the stable prostacyclin mimetic iloprost (IC50: 3 nM). The same rank order of potencies was observed for the inhibition of collagen-induced platelet ATP secretion. A dose-dependent activation of adenylate cyclase could be demonstrated by ZK 118.182 which was comparable to that of prostaglandin D-2 with respect to the concentration needed for half maximal stimulation (ED(50)) maximal cAMP level achievable. ZK 118.182 also dose dependendly reduced the formyl-methionyl-leucyl-phenylalanine (FMLP) or platelet-activating factor (PAF) induced activation of polymorphonuclear neutrophils. Both, the oxygen burst resulting in the generation of superoxide anions and the degranulation of polymorphonuclear neutrophils accompanied by release of the lysosomal enzyme beta-glucuronidase, were significantly and dose dependently inhibited. ZK 118.182 was more potent than prostaglandin D-2 in inhibiting polymorphonuclear neutrophil activation in all tests performed. In summary, ZK 118.182 is a prostaglandin D-2 mimetic exerting potent inhibitory effects on human platelets and polymorphonuclear neutrophils.