roquinimex and laquinimod

Roquinimex-related 3-quinolinecarboxamide derivatives were prepared and evaluated for treatment of autoimmune disorders. The compounds were tested in mice for their inhibitory effects on disease development in the acute experimental autoimmune encephalomyelitis model and selected compounds in the beagle dog for induction of proinflammatory reaction. Structure-activity relationships are discussed. Compound 8c, laquinimod, showed improved potency and superior toxicological profile compared to the lead compound roquinimex (1b, Linomide) and was selected for clinical studies (currently in phase II).

Topics: Adjuvants, Immunologic; Animals; Autoimmune Diseases; Dogs; Encephalomyelitis, Autoimmune, Experimental; Female; Hydroxyquinolines; Mice; Mice, Inbred C57BL; Quinolones; Structure-Activity Relationship

A new orally active drug, laquinimod (ABR-215062), was shown to completely inhibit the development of murine acute experimental autoimmune encephalomyelitis (EAE). Furthermore, leukocyte infiltration into the central nervous system (CNS) was abolished in the laquinimod-treated animals. By direct comparison based on dose and total exposure, laquinimod was approximately 20 times more potent than the immunomodulator roquinimex. Laquinimod also had clear therapeutic effect when given after clinical onset in a chronic relapsing EAE model. It therefore represents a new orally active immunoregulatory drug without general immunosuppressive properties for the treatment of the autoimmune disease multiple sclerosis.

Topics: Adjuvants, Immunologic; Animals; Anti-Inflammatory Agents; B-Lymphocytes; Cells, Cultured; Central Nervous System; Chemotaxis, Leukocyte; Dexamethasone; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Female; Hydroxyquinolines; Immunosuppression Therapy; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Neuroimmunomodulation; Quinolones; T-Lymphocytes

The therapeutic effects of ABR-215062, which is a new immunoregulator derived from Linomide, have been evaluated in experimental autoimmune neuritis (EAN), a CD4(+) T cell-mediated animal model of Guillain-Barré syndrome in man. In previous studies, we reported that Linomide suppressed the clinical EAN and myelin antigen-reactive T and B cell responses. Here EAN induced in Lewis rats by inoculation with peripheral nerve myelin P0 protein peptide 180-199 and Freund's complete adjuvant was strongly suppressed by ABR-215062 administered daily subcutaneously from the day of inoculation. ABR-215062 dose-dependently reduced the incidence of EAN, ameliorated clinical signs and inhibited P0 peptide 180-199-specific T cell responses as well as also the decreased inflammation and demyelination in the peripheral nerves. The suppression of clinical EAN was associated with inhibition of the inflammatory cytokines IFN-gamma and TNF-alpha, as well as the enhancement of anti-inflammatory cytokine IL-4 in lymph node cells and periphery nerve tissues, respectively, in a dose-dependent manner. These effects indicate that ABR-215062 may mediate its effects by regulation of Th1/Th2 cytokine balance and suggest that ABR-215062 is potentially a new chemical entity for effective treatment of autoimmune diseases.

Topics: Adjuvants, Immunologic; Animals; Cell Movement; Dose-Response Relationship, Drug; Dose-Response Relationship, Immunologic; Hydroxyquinolines; Injections, Subcutaneous; Interferon-gamma; Male; Neuritis, Autoimmune, Experimental; Peripheral Nerves; Quinolones; Rats; Rats, Inbred Lew; Th1 Cells; Th2 Cells; Tumor Necrosis Factor-alpha