Inhibition of mast cell tryptase by APC 366



APC 366 [N-(1-hydroxy-2-naphthoyl)-L-arginyl-L-prolinamide], is a novel selective inhibitor of mast cell tryptase. It is a small molecule, first-generation peptidic inhibitor that has been shown efficacy in experimental models of allergic asthma, and it inhibits antigen- induced early asthmatic response (EAR), late asthmatic response (LAR), and bronchial hyperresponsiveness (BHR). APC 366 showed an inhibitory potential with a Ki value of 530 nM and an IC50 value of 1400 ± 240 nM after incubation with human tryptase about 4 h.

Biological Activity

In preclinical studies, APC 366 exhibits a certain inhibitory effectiveness in a sheep model of allergic asthma. Administered by inhalation, the compound blocked allergen-induced bronchoconstriction and reversed airway hyperresponsiveness to carbachol challenge. Research has shown that APC 366 attenuates the EAR, the LAR, BHR, and accompanying influx of inflammatory leukocytes on aerosol challenge with an antigenic extract. APC 366 inactivates tryptase in a time-dependent and irreversible manner involving slow isomerization of the hydroxynaphthyl group of APC 366 followed by nucleophilic attack of a tryptase amino acid side chain to result in the formation of a nonhydrolyzable covalent adduct between inhibitor and enzyme.


The mast cell is a major effector cell in acute allergic reactions. Histamine, heparin, proteases tryptase, chymase and carboxypeptidase are contained in the mast cell granules, and tryptase has been suggested as a good marker for mast cell degranulation. Tryptase has also been implicated in the pathogenesis of asthma, as elevated levels have been found in bronchoalveolar lavage (BAL) fluid from asthmatics. APC 366 has the potential role in the treatment of allergic diseases including asthma, allergic rhinitis, and allergic conjunctivitis, and human mast cell tryptase also has been proven that it can stimulate collagen synthesis in the human lung fibroblast cell line and can have both direct and indirect effects on connective tissue metabolism. Thus, as a tryptase inhibitors, APC 366 might be useful for treating fibrotic diseases such as idiopathic pulmonary fibrosis and scleroderma, in which mast cell involvement has been noted.


1. Krishna, M. T., Chauhan, A., Little, L., Sampson, K., Hawksworth, R., Mant, T., ... & Holgate, S. (2001). Inhibition of mast cell tryptase by inhaled APC 366 attenuates allergen-induced late-phase airway obstruction in asthma. Journal of Allergy and Clinical Immunology, 107(6), 1039-1045.

Sylvin, H., Dahlbäck, M., Van Der Ploeg, I., & Alving, K. (2002). The tryptase inhibitor APC‐366 reduces the acute airway response to allergen in pigs sensitized to Ascaris suum. Clinical & Experimental Allergy, 32(6), 967-971.

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