INHIBITORY EFFECTS OF THE NEW ANTIPLATETLET AGENT KBT-3022 AND ITS METABOLITE ON RABBIT NEUTROPHIL FUNCTION IN-VITRO

The effects of the new anti-platelet agent KBT-3022, ethyl (4-methoxyp henyl)-thiazol-2-yl]pyrrol-1-ylacetate, and its metabolite desethyl KB T-3022 on rabbit neutrophil function were investigated in comparison w ith the effects of acetylsalicylic acid (ASA), ticlopidine hydrochlori de (TP), cilostazol (CIL) and indomethacin (IM). The adhesion and migr ation of neutrophils induced by formyl-methionyl-leucyl-phenylalanine (fMLP) were inhibited by all the compounds tested, their rank order of potency being KBT-3022 = desethyl KBT-3022 > TP = CIL = IM > ASA. KBT -3022, desethyl KBT-3022, CIL and IM all suppressed fMLP-induced incre ases in the intracellular free Ca2+ concentration ([Ca2+](i)) in neutr ophils, their potencies correlating with their inhibitory effects on f MLP-induced adhesion and migration. KBT-3022 (1 mu M), desethyl KBT-30 22 (1-10 mu M) and CIL (10 mu M) but not IM significantly inhibited bo th neutrophil migration and the increase in [Ca2+](i) induced by leuko triene B-4 (LTB(4)). KBT-3022 (1 mu M) and desethyl KBT-3022 (1 mu M) suppressed the increase in [Ca2+](i) induced by complement C5a. Althou gh KBT-3022 and desethyl KBT-3022 did not influence [H-3]LTB(4) and [I -125]C5a specific binding, [H-3]fMLP specific binding was inhibited by desethyl KBT-3022 (IC50: 1.9 mu M). Neutrophil adhesion and superoxid e anion production stimulated by phorbol 12-myristate 13-acetate were partially inhibited by KBT-3022 (1 mu M) and desethyl KBT-3022 (1-10 m u M). These results suggest that KBT-3022 and desethyl KBT-3022 have a wider spectrum of action and are more potent inhibitors of neutrophil activation than ASA, TP, CIL and IM.