PMID- 9046329
OWN - NLM
STAT- MEDLINE
DCOM- 19970326
LR  - 20121115
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 40
IP  - 4
DP  - 1997 Feb 14
TI  - Novel naphthalene derivatives as inhibitors of human immunoglobulin E antibody 
      production.
PG  - 395-407
AB  - 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.
FAU - Hasegawa, M
AU  - Hasegawa M
AD  - Teijin Institute for Bio-Medical Research, Tokyo, Japan.
FAU - Takenouchi, K
AU  - Takenouchi K
FAU - Takahashi, K
AU  - Takahashi K
FAU - Takeuchi, T
AU  - Takeuchi T
FAU - Komoriya, K
AU  - Komoriya K
FAU - Uejima, Y
AU  - Uejima Y
FAU - Kamimura, T
AU  - Kamimura T
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Immunoglobulin G)
RN  - 0 (Naphthalenes)
RN  - 207137-56-2 (Interleukin-4)
RN  - 2166IN72UN (naphthalene)
RN  - 37341-29-0 (Immunoglobulin E)
SB  - IM
MH  - Antibody Formation/*drug effects
MH  - Humans
MH  - Immunoglobulin E/*immunology
MH  - Immunoglobulin G/immunology
MH  - Interleukin-4/pharmacology
MH  - Naphthalenes/*chemistry
MH  - Structure-Activity Relationship
EDAT- 1997/02/14 00:00
MHDA- 1997/02/14 00:01
CRDT- 1997/02/14 00:00
PHST- 1997/02/14 00:00 [pubmed]
PHST- 1997/02/14 00:01 [medline]
PHST- 1997/02/14 00:00 [entrez]
AID - jm9605041 [pii]
AID - 10.1021/jm9605041 [doi]
PST - ppublish
SO  - J Med Chem. 1997 Feb 14;40(4):395-407. doi: 10.1021/jm9605041.