roquinimex and Nephritis

A series of linomide-related quinoline-3-carboxamides and their analogues was prepared and evaluated for antinephritic activities. The 6-MeS derivative 7a was highly effective in two nephritis models, namely chronic graft-versus-host disease and autoimmune MRL/l mice.

Topics: Amides; Animals; Antibodies, Antinuclear; Autoimmune Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Graft vs Host Disease; Mice; Mice, Inbred MRL lpr; Nephritis; Proteinuria; Quinolines; Structure-Activity Relationship

A series of quinoline-3-carbothioamides and their analogues was prepared via four synthetic routes and evaluated for their antinephritic and immunomodulating activities. The optimal compound 9g strongly inhibited the T-cell independent antibody production in mice immunized with TNP-LPS and was highly effective in two nephritis models, namely chronic graft-versus-host disease and autoimmune MRL/l mice.

Topics: Adjuvants, Immunologic; Administration, Oral; Animals; Antibody Formation; Autoimmune Diseases; Disease Models, Animal; Dogs; Graft vs Host Disease; Half-Life; Immunization; Mice; Nephritis; Proteinuria; Quinolines; Structure-Activity Relationship; Thioamides

Nitric oxide is involved as a messenger molecule in a large number of physiologic and pathologic responses. Local generation of high nitric oxide output through the expression of the calcium-independent, cytokine-inducible form of nitric oxide synthase (iNOS) can result in either protective or damaging effects. The development of drugs that specifically suppress iNOS expression or inhibit its activity may therefore provide an excellent therapeutic tool for treatment of a diverse set of dysfunctions, including asthma, inflammatory processes, and autoimmune disease. We show compelling evidence that linomide, an immunomodulator known to ameliorate autoimmune diseases, prevents accumulation in the macrophages of mRNA encoding iNOS in mice injected with LPS. This effect is partially mediated by the blocking of TNF-alpha and IL-beta production by activated macrophages. Here, we also present evidence that kidneys from MRL/Mp-lpr/lpr mice express high iNOS levels when the mice develop glomerulonephritis. The administration of linomide to MRL/Mp-lpr/lpr mice significantly decreases iNOS mRNA levels and prevents the development of glomerulonephritis, extending the half-life of mice of this strain. This linomide effect is compatible with its role in preventing the development of autoimmune disease and extends its possible use to other pathologic manifestations associated with iNOS expression, such as the systemic lupus erythematosus-associated glomerulonephritis present in MRL/Mp-lpr/lpr mice.

Topics: Adjuvants, Immunologic; Animals; Enzyme Induction; Hydroxyquinolines; Kidney; Lipopolysaccharides; Lupus Erythematosus, Systemic; Macrophage Activation; Mice; Mice, Inbred MRL lpr; Nephritis; Nitric Oxide Synthase; Shock, Septic