Synthesis and Biological Evaluation of New 1,2-Dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for Treatment of Autoimmune Disorders:  Structure−Activity Relationship

Abstract

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).

Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer

“…Doses of roquinimex that inhibit tumour growth in the mouse induce a proinflammatory reaction in the dog. Its main characteristics are fever, neutrophilia and an increase in acute-phase reactant levels (Jönsson et al, 2004). When the toxicity of tasquinimod was assessed in dogs, only occasional increases in acute-phase reactants and white blood cell counts were observed (unpublished observation), and hence inducing systemic inflammatory reactions seems to have less significance for tasquinimod.…”

Updates on the Treatment of Lupus Nephritis

“…61 This oral immunomodulator shows therapeutic benefits in various animal models of autoimmune disease, including SLE, and is currently being studied for treatment of lupus nephritis in humans. Although the exact mechanism of action of laquinimod is unknown, in animal models, the drug reduces leukocyte infiltration into target tissues (glomeruli in SLE and optic nerves in multiple sclerosis), downregulates MHC class II gene expression (and hence antigen presentation), and modulates cytokine balance.…”

Managed Approaches to Multiple Sclerosis in Special Populations

“…[21][22][23] Laquinimod, a pharmacologically and chemically distinct molecule, was selected based on structure/ function testing as well as efficacy and safety in experimental autoimmune encephalomyelitis (EAE) models. 24,25 Although the exact mechanism(s) of action of laquinimod is/are incompletely understood, this drug has been reported to (a) decrease secretion of proinflammatory cytokines and enhance secretion of antiinflammatory cytokines and (b) upregulate brainderived neurotrophic factor. 26,27 In addition, laquinimod was shown in an in vitro study to suppress genes associated with antigen presentation and inflammation in peripheral blood mononuclear cells from both healthy controls and patients with relapsing MS. 28 Laquinimod has been evaluated in 2 large, randomized phase 3 studies known as ALLEGRO (Assessment of oraL Laquinimod in prEventing proGRession Of MS; NCT00509145), which has a placebo control arm, and BRAVO (Benefit-Risk Assessment of Avonex and Laquinimod; NCT00605215), in which the active comparator is IFNβ-1a 30 mcg per week.…”