title: Novel naphthalene derivatives as inhibitors of human immunoglobulin E antibody production.
abstract: A series of naphthalene derivatives with a variety of substituents at the 2-position was prepared in order to evaluate their suppressive effect on immunoglobulin E (IgE) antibody production by human peripheral blood mononuclear cells provoked with anti-CD40 antibody (alpha-CD40), interleukin-4 (IL-4), and interleukin-10 (IL-10). Compounds having a 1,4-phenylene spacer moiety tethered between the 2-naphthyl nucleus and anthranilic acid suppressed IgE antibody production in vitro in preference to that of IgG antibody without affecting cell viability. Deletion of the anthranilic acid moiety diminished the inhibitory activities. Changing the 2-naphthyl to a 1-naphthyl or phenyl nucleus led to no change in the potency, indicating that the aromatic group at this position is indispensable for the inhibitory activities. On the other hand, changing the 1,4-phenylene spacer to a 1,3-phenylene one resulted in reduced potency. Similarly, inhibitory activities were lost when the CO2H moiety at the 2-position was moved to the 3- or 4-position on the terminal benzene. These observations suggest that the conformation around the anthranilic acid moiety affects the inhibitory activities toward IgE biosynthesis. 2-(4-(2-Naphthyloxy)benzamido)benzoic acid (29) seemed to be a more potent inhibitor of IgE production than of IgG production. Insertion of a methylene between the inter-phenylene and the amide moiety resulted in 2-((4-(2-naphthyloxy)phenyl)acetamido)benzoic acid (31), which provided a stronger inhibition of both IgE and IgG production, although the selectivity toward IgE was lower than that of 29. Introduction of a benzyl group at the 6-position on the naphthalene ring considerably increased the inhibitory activity toward IgE production with an IC50 of 8.3 nM (36). The potency of 31 and 36 was retained when hydrocortisone or lipopolysaccharide was used instead of alpha-CD40 and IL-10 as costimulatory factors with IL-4, implying that these compounds may interfere with signal transduction between IL-4/IL-4 receptor cognition and genetic transcription that induce class-switching of immunoglobulin in B cells. These novel naphthalene derivatives are thus excellent candidates for further investigation with a view toward a therapeutic remedy against IgE-mediated allergic diseases.
authors.affiliation: Teijin Institute for Bio-Medical Research, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hasegawa
authors.forename: K
authors.initials: K
authors.lastname: Takenouchi
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Takeuchi
authors.forename: K
authors.initials: K
authors.lastname: Komoriya
authors.forename: Y
authors.initials: Y
authors.lastname: Uejima
authors.forename: T
authors.initials: T
authors.lastname: Kamimura
mesh_terms: D000917:Antibody Formation / Q000187:drug effects*; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D015847:Interleukin-4 / Q000494:pharmacology; D009281:Naphthalenes / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D007074:Immunoglobulin G; D009281:Naphthalenes; D015847:Interleukin-4; C031721:naphthalene; D007073:Immunoglobulin E