Projets en développement

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Sciences de la vie

Thérapie topique pour le psoriasis léger à modéré

Psoriasis is a chronic, noncommunicable, painful, disfiguring, and disabling skin disease, globally affecting 125 million people. There is currently no cure for this disease, which can develop into chronic inflammatory arthritis (psoriatic arthritis), leading to an erosive, polyarticular disease with joint destruction and loss of functionality. Psoriasis is also associated with a high risk of cardiovascular disease, diabetes, and mental illnesses.

Various treatments, adapted to patients, can help to control the symptoms. Light to moderate psoriasis requires the use of topical treatments based on corticosteroid drugs and vitamin D analogs. When topical therapies become inefficient, UVB radiations are recommended, either as single therapy or in combination with other drugs. Ultimately, patients may be given a systemic treatment involving methotrexate, cyclosporine, and even "biologgics", compounds known to be toxic. Consequently, there is a real need for novel highly potent and less toxic antipsoriatic drugs that will improve the quality of life of patients.

To this end, the research groups of Profs René C-Gaudreault and Stéphane Gobeil are developing a new class of substituted phenyl urea derivatives that are more potent and less toxic than many therapeutic options for the topical treatment of psoriasis. These compounds, which can inhibit the production of pro-inflammatory cytokines (e.g. IL-1β, IL-6, TNFa) or chimiokines (e.g. IL-8), could be used either for local or systemic applications.

Références

  • C-Gaudreault R, S Gobeil, and J Rousseau. Novel urea compounds and bioisosteres thereof and their use as IL-6 expression inhibitors. Patent pending. Assignee: Université Laval

  • Borel M et al. (2007). N-(4-iodophenyl)-N'-(2-chloroethyl)urea as a microtubule disrupter: in vitro and in vivo profiling of antitumoral activity on CT-26 murine colon carcinoma cell line cultured an grafted to mice. Br J Cancer 96: 1684-1691.

  • Bouchon B et al. (2005). Alkylation of beta-tubulin on Glu 198 by a microtubule disrupter. Mol Pharmacol 68: 1415-1422.

  • C-Gaudreault R et al. (1988) 1-Aryl-3-(2-chloroethyl) ureas: synthesis and in vitro assay as potential anticancer agents. J Pharm Sci 77: 185-187.

  • Deschesnes RG et al. (2007). Microtubule-destabilizing agents induce focal adhesion structure disorganization and anoikis in cancer cells. J Pharmacol Exp Ther 320: 853-864.

  • Fortin JS et al. (2008). Selective alkylation of beta(II)-tubulin and thioredoxin-1 by structurally related subsets of aryl chloroethylureas leading to either anti-microtubules or redox modulating agents. Bioorg Med Chem 16: 7277-7290.

  • Fortin JS et al. (2008). Aromatic 2-chloroethyl urea derivatives and bioisosteres. Part 2: Cytocidal activity and effects on the nuclear translocation of thioredoxin-1, and the cell cycle progression. Bioorg Med Chem 16: 7477-7488.

  • Fortin JS et al. (2007). Alkylation potency and protein specificity of aromatic urea derivatives and bioisosteres as potential irreversible antagonists of the colchicine-binding site. Bioorg Med Chem 15: 4456-4469.

  • Fortin S et al. (2011). Characterization of the covalent binding of N-phenyl-N'-(2-chloroethyl)ureas to {beta}-tubulin: importance of Glu198 in microtubule stability. J Pharmacol Exp Ther 336: 460-467.

  • Fortin S et al. (2008). A comparative molecular field and comparative molecular similarity indices analyses (CoMFA and CoMSIA) of N-phenyl-N'-(2-chloroethyl)ureas targeting the colchicine binding site as anticancer agents. Bioorg Med Chem 16: 1914-1926.

  • Fortin S et al. (2009). Mechanism of action of N-phenyl-N'-(2-chloroethyl)ureas in the colchicine binding site at the interface between alpha- and beta-tubulin. Bioorg Med Chem 17: 3690-3697.

  • Mounetou E et al. (2010). N-4-iodophenyl-N'-2-chloroethylurea, a novel potential anticancer agent with colon-specific accumulation: radioiodination and comparative in vivo biodistribution profiles. Invest New Drugs 28: 124-131.

Gso 17 659

Opportunities

Substituted phenyl urea derivatives constitute a new class of promising compounds for the control of psoriasis (topical formulation) and potentially other inflammatory diseases such as arthritis, diabetes, intestinal inflammatory diseases, and cancer (systemic administration).

SOVAR and Université Laval seek a partner for co-development, licensing, or commercialization of this technology.

Available resources

The medicinal chemistry research group is determining the biopharmaceutical properties of a library of phenyl-3-(2-cycloalkyl) urea derivatives, to identify lead compounds to further develop.