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Abstract: It has been reported that chymase activity was increased in allergic conjunctivitis patients and this activity was correlated with the severity of the disease. However, the precise roles of chymase in allergic conjunctivitis are unclear, and whether chymase inhibitors are effective for allergic conjunctivitis has not been reported even in experimental animal models. In this study, the roles of chymase in the pathogenesis were evaluated using a selective chymase inhibitor, ONO-WH-236, in a guinea pig model of allergic conjunctivitis induced by cedar pollen. Sensitized guinea pigs were challenged by the pollen, followed by assessing redness and edema in the conjuntiva, and counting the frequency of eye scratching as an itch-associated response. Treatment with the ONO-WH-236 (40 and 80 mg/kg, p.o.) dose-dependently inhibited the induction of redness, edema and scratching behavior. An anti-histaminic drug, ketotifen (3 mg/kg, p.o.), also significantly inhibited conjunctivitis symptoms. Chymase activity was increased in ophthalmic lavage fluid immediately after the pollen challenge. The increase in chymase activity was inhibited by in vivo treatment with ONO-WH-236. Interestingly, increased histamine in the ophthalmic lavage fluid immediately after the challenge was also inhibited by the chymase inhibitor. Administration of human recombinant chymase by eye dropping (0.09 and 0.9 μg/eye) dose-dependently induced scratching behavior, which was inhibited by not only ONO-WH-236 but also ketotifen; however, chymase administration induced only weak redness in the conjunctiva, which was resistant to treatment with anti-histaminic drugs. In conclusion, it was suggested that chymase was released from mast cells after antigen challenge, followed by the induction of conjunctivitis symptoms through histamine release from mast cells. Thus, chymase could be a potential target for pharmacotherapy for allergic conjunctivitis. [Copyright &y& Elsevier]

2-(Acylamino)benzylphosphonic acid 6 derived from an artificial substrate of sphingomyelinase was found to show inhibitory activity of TNF-α production. Structural optimization was started with the chemical modification of 6. The discovery of another chemical leads 7, 8, 10 and 16 for the development of structurally new inhibitors of TNF-α production is reported. [Copyright &y& Elsevier]

Discovery of new chemical leads of inhibitors for TNF-α production starting from the chemical modification of 1 is reported. Further biological studies of 1 to disclose the site of its action strongly suggested that 1 inhibits LPS-induced TNF-α expression in the liver and spleen of mice. Structure–activity relationships (SARs) are also discussed and full details including the chemistry are reported. [Copyright &y& Elsevier]

Design and synthesis of metabolically stabilized inhibitors of TNF-α production, which could be new drug candidates, are reported. Conformational analysis of an active diastereoisomer was performed based on biological evaluations of the conformationally fixed indane derivatives 17 and 18. Structure–activity relationships (SARs) based on biological evaluations of the optically active derivatives are also discussed. Full details including chemistry are reported. [Copyright &y& Elsevier]