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Novel anti-inflammatories reducing MCP-1, p40 and CX3CR1 levels

[Category : - HEALTH- Organic Chemistry]
[Viewed 918 times]

The technology includes novel 1-benzyl-3-hydroxymethylindazole derivatives able to reduce levels of MCP-1, p40 and CX3CR1, resulting as promising agents for the treatment of many inflammatory pathologies.

Monocyte Chemotactic Protein-1 (MCP-1 or CCL2) is a well known chemokine able to stimulate specifically monocytes and macrophages migration. It is involved in several inflammatory processes and it is a new pharmacologically validated target in various inflammatory pathologies and other severe diseases including viral infections. The CX3CL1 chemokine and its receptor CX3CR1 represent key factors in regulating monocyte migration and adhesiveness, exerting a key role in the physiopathology of inflammatory diseases and constituting attractive targets for the treatment of inflammatory diseases.

The technology relates to four patent families disclosing novel 1-benzyl-3-hydroxymethylindazole derivatives designed starting from the chemical structure of bindarit, an inhibitor of MCP-1 and related family members. The new derivatives are indeed capable to reduce production and expression of MCP-1 and to reduce expression of CX3CR1 and p40 in the micromolar range while having no effect on IL8 production, and they are being developed as new agents for the treatment of inflammatory pathologies (such as rheumatoid arthritis and diabetic nephropathy) and other severe conditions including atopic dermatitis, atherosclerosis, complications following surgical interventions, cancer, and metabolic diseases (such as insulin resistance and obesity). Selected molecules show optimal physicochemical characteristics for oral administration and the parent compound bindarit has been safely used in interventional clinical studies in patients with Diabetic nephropathy. The asset also includes intermediate compounds and derivatives among which physiologically acceptable addition salts are included.

Selected novel bindarit derivatives are able to selectively reduce levels of MCP-1, thus exerting prominent anti-inflammatory effects while showing safer profile and improved tolerability over commonly used anti-inflammatory drugs.

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