Suppression of immunoglobulin production by a novel dihydroorotate dehydrogenase inhibitor, S-2678.
We discovered a novel dihydroorotate dehydrogenase (DHO-DH) inhibitor, S-2678 ([2-fluoro-2',5'-dimethyl-4'-[6-(3-methyl-2-butenyloxy) pyridin-3-yl] biphenyl-4-yl]-(3-methyl-2-butenyl) amine). Its inhibitory activity against DHO-DH was more potent than that of A77 1726, an active metabolite of the anti-rheumatic drug leflunomide. S-2678 suppressed immunoglobulin production in mouse B cells and human peripheral blood mononuclear cells in vitro, with little or no inhibition of cell proliferation, probably through inhibition of class switch recombination in the immunoglobulin heavy chain loci in B cells. In vivo antibody production induced by systemic immunization with ovalbumin was dramatically suppressed by oral administration of S-2678, without any toxicological signs. However, S-2678 did not affect T-cell activation in vitro, and cytokine production induced by intravenous anti-CD3 antibody in mice. S-2678 did not affect host defense in a mouse model of Candida infection, whereas leflunomide severely impaired it. In conclusion, S-2678 selectively acts on B cells, resulting in antibody production, which suggests that it is useful for the treatment of humoral immunity-related diseases.
Discovery Research Laboratories, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
Masashi
M
Deguchi
Junji
J
Kishino
Maki
M
Hattori
Yoko
Y
Furue
Mina
M
Yamamoto
Izumi
I
Mochizuki
Motofumi
M
Iguchi
Yosuke
Y
Hirano
Kanji
K
Hojou
Morio
M
Nagira
Yoshinori
Y
Nishitani
Kenichi
K
Okazaki
Kiyoshi
K
Yasui
Akinori
A
Arimura
D000284:Administration, Oral; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003437:Crotonates; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006885:Hydroxybutyrates / Q000494:pharmacology; D007143:Immunoglobulin Heavy Chains / Q000187:drug effects / Q000378:metabolism; D007136:Immunoglobulins / Q000096:biosynthesis / Q000187:drug effects*; D007555:Isoxazoles / Q000009:adverse effects / Q000494:pharmacology; D000077339:Leflunomide; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009570:Nitriles; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology*; D014052:Toluidines
C538781:(2-fluoro-2',5'-dimethyl-4'-(6-(3-methyl-2-butenyloxy)pyridin-3-yl) biphenyl-4-yl)-(3-methyl-2-butenyl)amine; D000814:Aniline Compounds; D001713:Biphenyl Compounds; D003437:Crotonates; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D006885:Hydroxybutyrates; D007143:Immunoglobulin Heavy Chains; D007136:Immunoglobulins; D007555:Isoxazoles; D009570:Nitriles; D011725:Pyridines; D014052:Toluidines; C527525:teriflunomide; D044925:Oxidoreductases Acting on CH-CH Group Donors; D000077339:Leflunomide