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Discovery of a Novel Enhydrazinone Ester (CEE‐1) That Inhibits the Degranulation of Both Mast Cells and Eosinophils

Allergen‐dependent activation of mast cells and eosinophils is a fundamental process in the pathophysiology of allergic diseases. We have previously reported that the novel enhydrazinone ester CEE‐1 (ethyl 4‐phenylhydrazinocyclohex‐3‐en‐2‐oxo‐6‐phenyl‐1‐oate) – possess potent anti‐inflammatory activity. We have now tested whether the compound also possess anti‐allergic effects using IgE‐dependent degranulation of rat mast cell line (RBL‐2H3) and the degranulation of isolated human blood eosinophils. RBL‐2H3 cells were passively sensitized with anti‐DNP IgE, pre‐treated with CEE‐1 for 10 min before being stimulated with the antigen, DNP‐BSA. Released β‐hexoseaminidase was determined as index of degranulation. Aliquots of purified human eosinophils, were similarly pre‐treated with CEE‐1 before stimulation with human C5a (30 nM) plus cytochalasin B (5 µg/ml) for 30 min. The amount of released granular eosinophil peroxidase (EPO) was determined by the O‐phenylenediamine method. Results showed that pre‐treatment of sensitized mast cells with CEE‐1 resulted in a strong concentration‐dependent inhibition of β‐hexoseaminidase release. The IC50 value was 4.5 µM, and at 30 μM inhibition was more than 80%. The compound also inhibited C5a‐stimulated EPO release from human eosinophils with even greater potency (IC50 = 0.1 μM). These results show that CEE‐1 possesses strong anti‐allergic properties exerted on both mast cells and eosinophils, and therefore has the potential to be a useful therapy for allergic diseases.